Clinical trial NCT04093362
Conditions: Advanced Cholangiocarcinoma FGFR2 Gene Rearrangements
Keywords: Futibatinib Advanced Cholangiocarcinoma FGFR2 Fusion Rearrangement TAS-120
Sponsor: Taiho Oncology, Inc.
Start date: 2021-01-06; Completion date: 2024-04-22
Enrollment: 10 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: 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. arm 2: 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.
Interventions: intervention 1: Futibatinib intervention 2: Cisplatin intervention 3: Gemcitabine
Intervention descriptions: intervention 1: Oral tablets intervention 2: IV infusion intervention 3: IV infusion

Protocol documents:
Prot_000.pdf: 
Official Title: Phase 3, Open-Label, Randomized Study of Futibatinib Versus Gemcitabine Cisplatin 
Chemotherapy as First-Line Treatment of Patients with Advance Cholangiocarcinoma Harboring 
FGFR2 Gene Rearrangements
NCT Number: NCT04093362   
Document Date: Protocol Amendment 1.0: 29 January 2020


TAS-120
Protocol TAS-120-301 Amendment 1
Confidential - Proprietary Information
1
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
Protocol Number: TAS-120-301
Original Protocol Issue Date: 13 September 2019
Amendment 1 Issue Date: 29 January 2020
IND Number: 121062
EudraCT Number: 2019-004630-42
Sponsors
Taiho Pharmaceutical Co., Ltd.
1-27 Kandanishiki-cho,
Chiyoda-ku, Tokyo, 101-8444, Japan
Taiho Oncology, Inc.
101 Carnegie Center, Suite 101
Princeton, NJ 08540, USA
This clinical study will be conducted in accordance with the International Council for Harmonisation 
of Technical Requirements for Pharmaceuticals for Human Use (ICH), Good Clinical Practice (GCP) 
guidelines and applicable regulatory requirements.
CONFIDENTIAL
The information contained in this document is the property of Taiho Pharmaceutical Co., Ltd. (TPC) 
and/or Taiho Oncology, Inc. (TOI). This document contains strictly confidential information and no part 
of this document may be published or disclosed without the prior written approval of TPC and/or TOI, 
except by request from competent authorities.


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SUMMARY OF PROTOCOL AMENDMENTS
The original protocol for Study TAS-120-301 was approved on 13 September 2019; this 
document is Amendment 1, issued 29 January 2020.  Apart from updates to the document date 
and headers, a total of 2 changes were made in this amendment:
1. An erroneous EudraCT number on the cover page was corrected; and
2. The requirement that phosphorus be assessed on Day 4 of Cycle 1 was removed from
Table 1 (Schedule of Events) and throughout the protocol (the schedule for all other
chemistry assessments remains the same as in the original version).
No other changes, including editorial changes, were made to the document.


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PROTOCOL SYNOPSIS
Name of Sponsor/Company:
Taiho Pharmaceutical Co., Ltd. and Taiho Oncology, 
Inc.
Name of Investigational Product:
Futibatinib (TAS-120)
Title of Study:
FOENIX-CCA3: 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
Phase of Development: 
Phase 3
Countries:
Global
Estimated Number of Sites:
175
Study Rationale:
Aberrations in fibroblast growth factor (FGF) or the FGF receptor (FGFR) are a reported genetic modification in 
cholangiocarcinoma (CCA); in particular, FGFR2 gene rearrangements, including gene fusions, have been 
identified as an early driver of oncogenic events in approximately 15% of CCA patients.  Futibatinib (TAS-120), 
an oral, highly selective, irreversible tyrosine kinase inhibitor (TKI) that inhibits both mutant and wild-type
FGFR1-4 isoforms, has shown promising antitumor activity in preclinical studies against a variety of tumor cell 
lines or tumor models harboring FGFR aberrations.  In an ongoing Phase 1/2 clinical study (Study TAS-
120-101), treatment with futibatinib resulted in further evidence of efficacy.
The Phase 3 study described in this protocol will evaluate the efficacy and safety of futibatinib against that of the 
current standard of care (gemcitabine-cisplatin chemotherapy) in the first-line treatment of patients with locally 
advanced, metastatic, or recurrent unresectable intrahepatic CCA (iCCA) harboring FGFR2 gene rearrangements.
Objectives and Endpoints:
The objectives of this study are to compare the following endpoints in patients with locally advanced, metastatic, 
or recurrent unresectable iCCA harboring FGFR2 gene rearrangements, who are treated with either futibatinib 
monotherapy or gemcitabine-cisplatin chemotherapy: 
Primary

Progression-free survival (PFS) by independent central review (ICR), based on Response Evaluation
Criteria in Solid Tumors, Version 1.1 (RECIST 1.1)
Secondary

Objective response rate (ORR)

Disease control rate (DCR)

Overall survival (OS)

PFS according to Investigator assessment of radiologic images

Safety and tolerability
Exploratory

PFS on next-line therapy (PFS2)

Duration of response (DOR)

Patient-reported outcomes (PRO)

To assess the population pharmacokinetics (Pop PK) of futibatinib and to explore the relationship
between PK and efficacy or toxicity.


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Name of Sponsor/Company:
Taiho Pharmaceutical Co., Ltd. and Taiho Oncology, 
Inc.
Name of Investigational Product:
Futibatinib (TAS-120)
Title of Study:
FOENIX-CCA3: 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
STUDY DESIGN AND POPULATION
Study Design: 
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:
o
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
o
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.
Randomization / Stratification Factors: 
Randomization will be stratified by the following factors:

Prior surgical excision of the primary tumor (yes vs. no); 

Geographic region (Asia vs. rest of the world); and

Locally advanced vs. metastatic disease.
Number of Patients: 
Approximately 216 patients with iCCA harboring centrally confirmed FGFR2 gene rearrangements will be 
randomized.
Inclusion/Exclusion Criteria:
Inclusion:
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. 


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Name of Sponsor/Company:
Taiho Pharmaceutical Co., Ltd. and Taiho Oncology, 
Inc.
Name of Investigational Product:
Futibatinib (TAS-120)
Title of Study:
FOENIX-CCA3: 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
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 
3 months after the last dose. 
Willing and able to comply with scheduled visits and study procedures.
Exclusion:
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.


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Name of Sponsor/Company:
Taiho Pharmaceutical Co., Ltd. and Taiho Oncology, 
Inc.
Name of Investigational Product:
Futibatinib (TAS-120)
Title of Study:
FOENIX-CCA3: 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

Patients with locoregional therapy, eg, 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 whose natural history or treatment has the 
potential to interfere with the safety or efficacy assessment of the investigational regimen in the opinion 
of the investigator.
Pregnant or breast-feeding female.
The patient is unable to take oral medication.
EVALUATION CRITERIA
Efficacy:
Measurements of disease will be performed throughout study treatment using RECIST guidelines (version 1.1, 
2009).  Radiographic tumor assessments (computed tomography [CT] or magnetic resonance imaging [MRI]) 
will be performed at baseline and at the end of every 2 cycles (±7 days) up to Cycle 4 (or as clinically indicated).  
Following Cycle 4, scans will be performed after every 3 cycles (± 7 days) or as clinically indicated, and at study 
completion.  Efficacy endpoints will be as follows:

PFS per central assessment (primary): defined as the time from date of randomization to the date of
documentation of disease progression by ICR, or date of death, whichever occurs first.

ORR (secondary): 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.

DCR (secondary): defined as the proportion of patients experiencing a best overall response of stable
disease (SD), PR, or CR (per RECIST 1.1), based on central assessment of radiologic images.

OS (secondary): measured from the date of randomization until the date of death due to any cause.

PFS per Investigator assessment (secondary): 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.

DOR (exploratory): defined as the time from the first documentation of response (per RECIST 1.1 and
based on central assessment of radiologic images) to the first documentation of objective tumor
progression or death due to any cause, whichever occurs first.

PFS2 (exploratory): defined as the time from randomization to subsequent disease progression per
Investigator assessment after initiation of next-line therapy or death from any cause (whichever occurs
first).


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Name of Sponsor/Company:
Taiho Pharmaceutical Co., Ltd. and Taiho Oncology, 
Inc.
Name of Investigational Product:
Futibatinib (TAS-120)
Title of Study:
FOENIX-CCA3: 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
Safety:
The assessment of safety will be based on the incidence of treatment-emergent (TE) adverse events (AEs), 
serious adverse events (SAEs), AEs leading to discontinuation, AEs leading to dose interruption, modification, 
and deaths. Additional safety assessments include clinical laboratory tests, vital signs, and 12-lead ECG.  
Grading of TEAEs will be performed using National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) (Version 5.0).
Patient-Reported Outcomes:
PRO will be assessed using:

The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire
(EORTC QLQ-C30) is an integrated system for assessing the health-related quality of life (QoL) of
cancer patients participating in international clinical trials.

The EORTC QLQ-BIL21 is a validated tool for the assessment of QoL in patients with CCA and cancer
of the gallbladder.
Pharmacokinetics:
Blood samples for Pop PK analysis will be obtained from all patients receiving futibatinib (including crossover 
patients) on Cycle 2, Day 1, pre-dose (from -30 min to just before dose) and at 1 hour and 3 hours (±30 min) 
post-dose.
Pharmacodynamics:
Blood samples will be collected for measurement of circulating tumor marker CA19-9 during screening and in 
conjunction with tumor assessments/scans throughout the study. In addition, circulating tumor DNA (ctDNA)
will be collected to assess FGF/FGFR aberrations at screening and at the end of therapy. For patients who cross-
over from the Control to the Experimental Arm, an additional ctDNA sample will be collected at the end of 
futibatinib therapy. Samples, or a subset of samples, will be used to assess comparability of FGFR test results to 
tumor tissue results and verify utility of ctDNA as an alternative to tumor biopsy as a matrix for the potential 
companion diagnostics.
STATISTICAL METHODS
Sample Size Determination:
Assuming median PFS of 6 months in the Control Arm and 10 months in the Experimental Arm, a total of 162 
PFS events will be needed to detect a hazard ratio of 0.60 with 90% power at a 2-sided alpha level of 0.05. 
Considering an enrollment rate of 4 patients per month in the first 10 months and 8 patients per month from 
Month 11 to Month 32, approximately 216 patients are planned to be randomized in 1:1 ratio to the Experimental 
Arm and Control Arm. It is estimated that 162 PFS events would occur approximately 40 months (32-month 
enrollment period and 8-month follow up period) after the first patient randomized. These calculations further 
assume a 10% loss to follow-up annually.


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Name of Sponsor/Company:
Taiho Pharmaceutical Co., Ltd. and Taiho Oncology, 
Inc.
Name of Investigational Product:
Futibatinib (TAS-120)
Title of Study:
FOENIX-CCA3: 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
Primary Statistical Analysis (Efficacy):
Comparison of PFS (per ICR) between arms will be performed when at least 162 PFS events have been observed. 
The comparison will test the null hypothesis:  
H0:  PFS in experimental arm = PFS in control arm,
against the alternative hypothesis: 
H1:  PFS in experimental arm ӆ PFS in control arm.
The difference in PFS will be compared by stratified log-rank test at 2-sided α=0.05. The tests will be by the 
stratification factors used in the randomization. The hazard ratio and the corresponding 95% confidence intervals 
(CIs) will be estimated using the Cox regression model stratified by the same stratification factors.  The median 
PFS, and the PFS rates at 6, 12 and 18 months, will be calculated using the Kaplan-Meier (KM) product-limit 
estimates for each treatment arm, and presented with 2-sided 95% CIs. The KM estimates of PFS will be plotted 
over time. The PFS censoring rules and definition of progression date will follow the Food and Drug 
Administration (FDA) “Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics (2007).”
Secondary Statistical Analyses (Efficacy):
The fixed sequence procedure will be used to control the overall type I error rate of analyses for the secondary 
endpoints at α = 0.05 (2-sided) after the superiority for primary efficacy endpoint, PFS, is declared. The order of 
testing for secondary endpoints will follow the order that they are presented below.
In the ordered sequence, each secondary endpoint will be tested at the 5% level until the first nonsignificant 
outcome occurs. If the first nonsignificant outcome occurs, then the results of the analysis of the subsequent 
endpoints will be presented for descriptive purposes only. 
1.
ORR
ORR will be calculated for each treatment arm with exact 95% CIs using the method of Clopper and Pearson. 
The analysis of ORR for comparison between treatment arms will be performed using the Cochran-Mantel-
Haenszel (CMH) test stratified by the stratification factors used in the randomization. 
2.
DCR
DCR will be calculated for each treatment arm with exact 95% CIs using the method of Clopper and Pearson. 
The analysis of DCR for comparison between treatment arms will be performed using the CMH test stratified by 
the stratification factors used in the randomization. 
3.
OS
OS will be evaluated using KM estimates and the comparison in OS between the two arms will use a stratified 
log-rank test with the randomization stratification factors. The corresponding estimate of the hazard ratio (HR)
calculated from Cox proportional hazard model with treatment group as a factor and stratified by the 
randomization stratification factors will be presented with a 2-sided 95% CI. 
No multiplicity adjustments will be used for other secondary efficacy endpoints.


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Name of Sponsor/Company:
Taiho Pharmaceutical Co., Ltd. and Taiho Oncology, 
Inc.
Name of Investigational Product:
Futibatinib (TAS-120)
Title of Study:
FOENIX-CCA3: 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
Safety Analyses:
The safety analysis will be performed in all treated patients. Descriptive statistics of safety will be presented 
using NCI-CTCAE v. 5.0 by treatment arm. AEs, drug-related AEs, SAEs, and drug-related SAEs will be 
tabulated using worst grade per NCI-CTCAE v. 5.0 criteria, by system organ class and preferred term. On-study 
lab parameters including hematology, chemistry, liver function, and renal function will be summarized using 
worst grade per NCI CTCAE v. 5.0 criteria.
PRO Analyses:
A separate pre-specified PRO analysis following FDA and EMEA PRO Guidelines will be performed and 
detailed in a separate Statistical Analysis Plan (SAP) and PRO report. Scoring of PRO instruments and derivation 
of utility for health economic analysis will also be described in a separate analysis document.
Interim Analyses:
No interim analysis of efficacy is planned. Interim analyses for safety monitoring will occur when approximately 
25%, 50%, and 75% of the planned total number of patients have been treated. A Data Monitoring Committee 
(DMC) will meet to assess the cumulative safety data and recommend study continuation, discontinuation, or 
study modification. A description of the roles and responsibilities of the DMC and details of the review processes 
are provided in a separate DMC charter.


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Table 1:
Schedule of Events
Evaluations on Day 1 (D1) of a cycle should be performed within 24 hours prior to dosing, unless otherwise noted.  Procedures 
already performed during the screening period within 72 hours prior to dosing do not need to be repeated on Cycle 1, Day 1 (C1D1). 
The End of Treatment (EOT) visit must be performed 0-7 days after the decision is made to discontinue study treatment (for patients 
who discontinue at a planned study visit, that visit may be considered the EOT visit if all assessments required at EOT are performed).
Please note: assessments for patients who enter the study extension phase following study completion (see protocol Section 
Section 3.4) are detailed in Table 1A.
Screening 
(days prior to 
randomization)
Randomization
Treatment Period (1 cycle = 21 days)
Safety 
Follow-up
Survival Follow-up 
Period
Notes
Cycle 1
Cycles 
≥2
End of Tx
(+0-7 days)
30 (±3) days After 
Last Dose
The first dose of study therapy should 
be administered within 72 hours after 
randomization.  Notes that refer to 
timing with respect to dosing refer 
only to on-treatment assessments; 
post-discontinuation assessments may 
be performed at any time.
28 days
14 days
Day
Day
1 
8
(±3d)
15
(±3d)
1 (±3d)
Written informed consent 
(pre-screening ICF)
See notes
To be obtained prior to any pre-
screening evaluations.
Assessment of FGFR2 gene 
rearrangement status 
(Pre-Screening)
See notes
Testing by designated central 
laboratory at any time prior to signing 
of main ICF.
Written informed consent 
(main ICF)
X
May be obtained at any time after 
confirmation of FGFR2 gene 
rearrangement status and prior to 
randomization.
Demographics/medical history
X
Pre-existing signs and 
symptoms
X
X
Physical examination
X
X
X
X
X
Within 24 hours prior to dosing on D1 
of each treatment cycle.
Vital signs
X
X
X
X
X
Heart rate, blood pressure, body 
temperature, and respiration rate.
Height and weight
X
X
X
X
X
Height at screening only.


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Screening 
(days prior to 
randomization)
Randomization
Treatment Period (1 cycle = 21 days)
Safety 
Follow-up
Survival Follow-up 
Period
Notes
Cycle 1
Cycles 
≥2
End of Tx
(+0-7 days)
30 (±3) days After 
Last Dose
The first dose of study therapy should 
be administered within 72 hours after 
randomization.  Notes that refer to 
timing with respect to dosing refer 
only to on-treatment assessments; 
post-discontinuation assessments may 
be performed at any time.
28 days
14 days
Day
Day
1 
8
(±3d)
15
(±3d)
1 (±3d)
Ophthalmological examination
X
(X)
X
X
At screening and 4-6 weeks after first 
dose; additional on-study evaluation 
as needed due to local requirements, 
physician judgment, and/or symptoms 
or signs of mineral deposits.
ECOG performance status
X
X
X
X
X
Within 24 hours prior to dosing on D1 
of each cycle.
12-Lead electrocardiogram 
X
X
X
X
X
ECG on C2D1 performed prior to 
collection of PK samples for that day.
Hematology and coagulation
X
X
X
X
X
X
X
Within 24 hours prior to treatment on 
D1 of each cycle, prior to treatment 
on C1D8 and C1D15, and as 
clinically indicated.
Chemistry (serum or plasma)
X
X
X
X
X
X
X
Within 24 hours prior to treatment on 
D1 of each cycle, prior to treatment 
on C1D8 and C1D15, and as 
clinically indicated.  
Pregnancy test
See notes.
X
X
X
X
Serum pregnancy test required for 
WOCBP at screening (within 7 days 
prior to randomization) and end of 
treatment; serum or urine pregnancy 
test required at all other timepoints.
Blood PK sampling (required 
for patients receiving 
futibatinib only)
X
Blood samples (1 mL) collected 
C2D1 pre-dose (from -30 min to just 
before dose) and at 1h and 3h (±30 
min) post-dose.  
ctDNA blood samples
X
X
Minimum of 20 mL whole blood at 
screening and EOT.  Patients who 
cross-over from the Control to the 
Experimental arm should provide an 
additional sample at the EOT for 
futibatinib.


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Screening 
(days prior to 
randomization)
Randomization
Treatment Period (1 cycle = 21 days)
Safety 
Follow-up
Survival Follow-up 
Period
Notes
Cycle 1
Cycles 
≥2
End of Tx
(+0-7 days)
30 (±3) days After 
Last Dose
The first dose of study therapy should 
be administered within 72 hours after 
randomization.  Notes that refer to 
timing with respect to dosing refer 
only to on-treatment assessments; 
post-discontinuation assessments may 
be performed at any time.
28 days
14 days
Day
Day
1 
8
(±3d)
15
(±3d)
1 (±3d)
Blood for CA19-9
X
X
X
Samples collected at the same time as 
samples for clinical laboratory 
assessments at the end of every 2 
cycles up to C4, and every 3 cycles 
thereafter (or as clinically indicated). 
Prior & concomitant 
medications, AE assessments
X
X
X
Collect from the time main informed 
consent is signed through 30 days 
after administration of the last dose of 
study therapy or until the start of new 
anticancer therapy, whichever is 
earlier.  AEs directly associated with a 
pre-screening procedure should be 
reported as described in the study 
protocol.
PRO (EORTC QLQ-BIL21, 
EORTC QLQ-C30)
X
X
X
Evaluated at screening and as close as 
possible to the tumor assessment 
schedule: at the end of every 2 cycles 
(± 7 days) through Cycle 4 and every 
3 cycles (±7 days) thereafter until 
disease progression or initiation of 
new anticancer therapy (whichever is 
first).
Baseline tumor assessments / 
scans
X
Baseline tumor assessments/scans 
must be obtained within 28 days prior 
to randomization.


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Screening 
(days prior to 
randomization)
Randomization
Treatment Period (1 cycle = 21 days)
Safety 
Follow-up
Survival Follow-up 
Period
Notes
Cycle 1
Cycles 
≥2
End of Tx
(+0-7 days)
30 (±3) days After 
Last Dose
The first dose of study therapy should 
be administered within 72 hours after 
randomization.  Notes that refer to 
timing with respect to dosing refer 
only to on-treatment assessments; 
post-discontinuation assessments may 
be performed at any time.
28 days
14 days
Day
Day
1 
8
(±3d)
15
(±3d)
1 (±3d)
Tumor assessments / scans
X
X
(X)
Tumor assessments/scans at the end 
of every 2 cycles (± 7 days) up to 
Cycle 4. Thereafter, tumor 
assessments may be performed every 
3 cycles (± 7 days), or as clinically 
indicated, until radiologic PD or 
initiation of new anticancer therapy 
(whichever occurs first). 
At EOT, tumor assessment must be 
performed if the prior scan was 
performed ≥9 weeks prior to 
discontinuation of treatment if the 
patient discontinued for reasons other 
than radiologic disease progression. 
After EOT, patients who discontinued 
for reasons other than radiologic 
disease progression should continue to 
receive tumor assessments every 3 
cycles (± 7 days), or as clinically 
indicated, until radiologic disease 
progression or initiation of new 
anticancer therapy (whichever occurs 
first).


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Screening 
(days prior to 
randomization)
Randomization
Treatment Period (1 cycle = 21 days)
Safety 
Follow-up
Survival Follow-up 
Period
Notes
Cycle 1
Cycles 
≥2
End of Tx
(+0-7 days)
30 (±3) days After 
Last Dose
The first dose of study therapy should 
be administered within 72 hours after 
randomization.  Notes that refer to 
timing with respect to dosing refer 
only to on-treatment assessments; 
post-discontinuation assessments may 
be performed at any time.
28 days
14 days
Day
Day
1 
8
(±3d)
15
(±3d)
1 (±3d)
Survival status
X
After discontinuation of treatment, 
survival follow-up should occur every 
3 months (±2 weeks) for up to 18 
months after the randomization of the 
last patient.
Administer futibatinib
X
Continuous dosing (patients 
randomized to or crossing over to 
futibatinib only)
Administer gemcitabine / 
cisplatin
X
X
X
On Days 1 and 8 of each Cycle, up to 
a maximum of 8 cycles (patients 
randomized to gemcitabine / cisplatin 
only).


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Table 1A:
Schedule of Events – Study Extension Phase
Treatment Period (1 cycle = 21 days)
Safety 
Follow-up
Notes
Daily
At Least
Every 3 Cycles 
30 (±3) Days After last Dose 
Physical examination
X
X
Within 24 hours prior to dosing on D1 of each 
treatment cycle.
Vital signs
X
X
Heart rate, blood pressure, body temperature, 
and respiration rate.
Weight
X
X
Ophthalmological examination
(X)
X
As needed due to local requirements, physician 
judgment, and/or symptoms or signs of mineral 
deposits.
ECOG performance status
X
X
Within 24 hours prior to dosing on D1 of each 
cycle.
12-Lead electrocardiogram 
X
X
Hematology and coagulation
X
X
Within 24 hours prior to treatment on D1 of 
each cycle and as clinically indicated.
Chemistry (serum or plasma)
X
X
Within 24 hours prior to treatment on D1 of 
each cycle 
Pregnancy test
X
X
Serum or urine pregnancy test required at all 
timepoints.
Prior & concomitant 
medications, AE assessments
X
X
Collect from the time main informed consent is 
signed through 30 days after administration of 
the last dose of study therapy or until the start 
of new anticancer therapy, whichever is earlier.  
Tumor assessments / scans
X
Tumor assessments may be performed as 
necessary to determine continued benefit from 
treatment, every 3 cycles (± 7 days), or as 
clinically indicated, until radiologic PD or 
initiation of new anticancer therapy (whichever 
occurs first). 
Administer futibatinib
X
Continuous dosing


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TABLE OF CONTENTS
SUMMARY OF PROTOCOL AMENDMENTS ...........................................................................2
PROTOCOL SYNOPSIS ................................................................................................................3
TABLE OF CONTENTS...............................................................................................................16
LIST OF TABLES.........................................................................................................................21
LIST OF FIGURES .......................................................................................................................21
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................................................22
1.
INTRODUCTION......................................................................................................24
1.1.
Disease Background ...................................................................................................24
1.2.
Futibatinib (TAS-120) ................................................................................................24
1.2.1.
Background and Nonclinical Overview......................................................................24
1.2.2.
Clinical Overview.......................................................................................................25
1.3.
Summary of Study Rationale......................................................................................26
2.
OBJECTIVES AND ENDPOINTS............................................................................27
3.
INVESTIGATIONAL PLAN.....................................................................................28
3.1.
Overview of Study Design..........................................................................................28
3.2.
Scientific Rationale for Study Design ........................................................................29
3.3.
Study Period................................................................................................................29
3.3.1.
Study Periods and Visits for Each Patient ..................................................................29
3.3.1.1.
Pre-Screening..............................................................................................................29
3.3.1.2.
Screening Period.........................................................................................................29
3.3.1.3.
Patient Enrollment ......................................................................................................29
3.3.1.4.
Treatment Period and End of Treatment Visit............................................................29
3.3.1.5.
Safety Follow-Up Period and 30-Day Safety Follow-Up Visit..................................30
3.3.1.6.
Post-Discontinuation Considerations..........................................................................30
3.4.
Study Completion and Study Extension.....................................................................31
3.5.
Randomization and Blinding......................................................................................31
3.5.1.
Randomization............................................................................................................31
3.5.2.
Blinding ......................................................................................................................32
3.6.
Independent Data Monitoring Committee..................................................................32
4.
SELECTION AND WITHDRAWAL OF PATIENTS..............................................33
4.1.
Inclusion Criteria ........................................................................................................33


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4.2.
Exclusion Criteria.......................................................................................................34
4.3.
Entry Criteria for Crossover .......................................................................................35
4.4.
Screen Failure .............................................................................................................36
4.5.
Discontinuation of Treatment.....................................................................................36
4.6.
Withdrawal from the Study ........................................................................................37
5.
STUDY TREATMENT..............................................................................................38
5.1.
Study Drug Administration.........................................................................................38
5.1.1.
Futibatinib...................................................................................................................38
5.1.2.
Gemcitabine / Cisplatin ..............................................................................................38
5.1.3.
Treatment Duration.....................................................................................................38
5.2.
Dose and Schedule Modifications ..............................................................................39
5.2.1.
Dose and Schedule Modifications for Futibatinib......................................................39
5.2.1.1.
General Considerations...............................................................................................39
5.2.1.2.
Futibatinib Dose Modifications for Nonhematologic Toxicities................................39
5.2.1.3.
Futibatinib Dose Modifications for Hematologic Toxicities......................................42
5.2.2.
Dose and Schedule Modifications for Gemcitabine and Cisplatin.............................42
5.2.2.1.
General Considerations...............................................................................................42
5.2.2.2.
Gemcitabine and Cisplatin Dose Modifications for Non-Hematologic 
Toxicities ....................................................................................................................42
5.2.2.3.
Gemcitabine and Cisplatin Dose Modifications for Hematologic Toxicities.............44
5.3.
Treatment Compliance................................................................................................44
5.4.
Concomitant Medications and Therapies ...................................................................44
5.4.1.
Prohibited Medications and Therapies .......................................................................45
5.4.2.
Drug Interactions ........................................................................................................45
5.5.
Effective Contraception During Study .......................................................................45
5.6.
Study Drug Materials and Management.....................................................................46
5.6.1.
Description of Study Drug..........................................................................................46
5.6.2.
Packaging and Labeling..............................................................................................47
5.6.3.
Accountability.............................................................................................................47
6.
STUDY ASSESSMENTS ..........................................................................................48
6.1.
Study Assessments and Procedures............................................................................48
6.1.1.
Determination of FGFR2 Gene Rearrangement Status (Pre-Screening)....................48
6.1.2.
General Assessments ..................................................................................................48


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6.1.3.
Efficacy Assessments .................................................................................................49
6.1.4.
Ophthalmological Examination..................................................................................49
6.1.5.
Laboratory Assessments .............................................................................................50
6.1.6.
Safety Evaluations ......................................................................................................50
6.1.7.
Pharmacokinetic and Pharmacodynamic Evaluations................................................50
6.1.8.
Crossover Evaluations ................................................................................................50
7.
PHARMACOKINETICS ...........................................................................................52
8.
EFFICACY EVALUATIONS....................................................................................53
8.1.
Efficacy Criteria..........................................................................................................53
8.1.1.
Method of Imaging .....................................................................................................53
8.1.2.
Tumor Definitions ......................................................................................................53
8.2.
Efficacy Endpoints......................................................................................................55
8.2.1.
Response Criteria........................................................................................................55
8.2.1.1.
Target and Non-Target Response Assessments..........................................................55
8.2.1.2.
Objective Response Assessment.................................................................................57
9.
SAFETY EVALUATIONS........................................................................................58
9.1.
Adverse Events ...........................................................................................................58
9.1.1.
Definitions of Adverse Events....................................................................................58
9.1.2.
Reporting of Adverse Events......................................................................................58
9.1.2.1.
Terms of Reported Adverse Events............................................................................58
9.1.2.2.
Severity of Adverse Events ........................................................................................59
9.1.2.3.
Causal Relationship with Study Drug.........................................................................59
9.1.2.4.
Outcome of Adverse Events.......................................................................................59
9.1.2.5.
Follow-up of Adverse Events .....................................................................................59
9.2.
Laboratory Assessments .............................................................................................60
9.2.1.
Reporting and Evaluation of Laboratory Test Results ...............................................60
9.2.2.
Repeat Testing ............................................................................................................60
9.3.
Serious Adverse Events..............................................................................................60
9.3.1.
Definitions of Serious Adverse Events.......................................................................60
9.3.2.
Reporting of Serious Adverse Events (within 24 hours)............................................61
9.3.3.
Reporting of Deaths (within 24 hours).......................................................................61
9.4.
Other Safety Information............................................................................................62
9.4.1.
Pregnancy ...................................................................................................................62


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9.4.2.
Overdose.....................................................................................................................62
9.4.3.
Medication Errors .......................................................................................................62
10.
ANALYSES OF BIOMARKERS..............................................................................64
10.1.1.
Objectives and Background........................................................................................64
10.1.2.
Assessment of FGF/FGFR Aberrations in Blood ......................................................64
10.1.3.
Measurement of Tumor Marker CA19-9....................................................................64
10.1.4.
Tumor Samples...........................................................................................................64
11.
STATISTICS ..............................................................................................................65
11.1.
Estimation of Sample Size..........................................................................................65
11.2.
Planned Interim Analysis............................................................................................65
11.3.
Analysis Populations ..................................................................................................65
11.4.
Criteria for Handling of Patient Data..........................................................................66
11.5.
Statistical Analyses.....................................................................................................66
11.5.1.
Demographic and Baseline Characteristics ................................................................66
11.5.2.
Efficacy Analyses .......................................................................................................66
11.5.2.1.
Primary Efficacy Analysis..........................................................................................67
11.5.2.2.
Secondary Efficacy Analyses .....................................................................................67
11.5.2.3.
Exploratory Efficacy Analyses...................................................................................68
11.5.3.
Safety Analyses ..........................................................................................................68
11.5.4.
Pharmacodynamic/Biomarker Analysis .....................................................................68
11.5.5.
Pharmacokinetic Analysis ..........................................................................................68
11.5.6.
PRO Analyses.............................................................................................................68
12.
ADMINISTRATIVE CONSIDERATIONS ..............................................................69
12.1.
Protocol Compliance ..................................................................................................69
12.2.
Protocol Deviations ....................................................................................................69
12.3.
Protocol Amendments ................................................................................................69
12.4.
Study Termination ......................................................................................................69
12.5.
Case Report Forms .....................................................................................................69
12.6.
Access to Source Data/Documents.............................................................................70
12.6.1.
Source Data/Documents .............................................................................................70
12.6.2.
Access to Source Data ................................................................................................70
12.7.
Data Handling.............................................................................................................70
12.8.
Responsibilities of Recordkeeping .............................................................................70


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12.8.1.
Investigator and Study Site.........................................................................................70
12.8.2.
Sponsor .......................................................................................................................71
12.9.
Monitoring..................................................................................................................71
12.10.
Financial Disclosure ...................................................................................................71
12.11.
Compensation for Health Injury.................................................................................71
12.12.
Study Administrative Structure ..................................................................................71
13.
QUALITY CONTROL AND QUALITY ASSURANCE .........................................72
13.1.
Quality Control ...........................................................................................................72
13.2.
Quality Assurance.......................................................................................................72
14.
ETHICS ......................................................................................................................73
14.1.
Ethical Conduct of the Study......................................................................................73
14.2.
Written Informed Consent..........................................................................................73
14.3.
Institutional Review Board/Independent Ethics Committee ......................................73
15.
PUBLICATION POLICY ..........................................................................................74
15.1.
Publication Policy.......................................................................................................74
15.2.
Secondary Use of Data ...............................................................................................74
16.
REFERENCES ...........................................................................................................75
APPENDIX A.
ECOG PERFORMANCE STATUS..................................................................76
APPENDIX B.
DIETARY GUIDELINES FOR TREATMENT OF 
HYPERPHOSPHATEMIA ........................................................................................77
APPENDIX C.
CLASSIFICATION OF SUBSTRATES, INHIBITORS, AND 
INDUCERS OF CYP ENZYMES AND TRANSPORTERS ....................................78
APPENDIX D.
SUPPLEMENTAL REQUIREMENTS FOR JAPAN......................................81


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LIST OF TABLES
Table 1:
Schedule of Events .....................................................................................................10
Table 2:
Objectives and Endpoints ...........................................................................................27
Table 3:
Futibatinib Dosing Modification for Related Nonhematologic Toxicities.................40
Table 4:
Recommendations for Hyperphosphatemia Management..........................................41
Table 5:
Futibatinib Dose Interruption and Modification Criteria for Related 
Hematologic Toxicities...............................................................................................42
Table 6:
Cisplatin Dose Modification Guidelines for Renal Toxicity......................................43
Table 7:
Gemcitabine-Cisplatin Dose Modification Guidelines for Non-Hematologic 
Toxicity.......................................................................................................................43
Table 8:
Gemcitabine-Cisplatin Dose Modification Guidelines for Hematologic 
Toxicity.......................................................................................................................44
Table 9:
Futibatinib Product Description and Packaging Information.....................................46
Table 10:
Pharmacokinetic Blood Sample Collection................................................................52
Table 11:
Efficacy Endpoints......................................................................................................55
Table 12:
Target and Non-target Lesions ...................................................................................56
Table 13:
Time Point Response for Patients with Target (±Non-target) Disease.......................57
Table 14:
Time Point Response for Patients with Only Non-target Disease..............................57
Table 15:
Analysis Populations ..................................................................................................65
Table 16:
Efficacy Endpoint Definitions....................................................................................66
LIST OF FIGURES
Figure 1:
Study Schema .............................................................................................................28


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
BCRP
breast cancer resistance protein
CCA
cholangiocarcinoma
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
CR
complete response
CT
computed tomography
ctDNA
circulating tumor DNA
CYP
Cytochrome P450
DCR
disease control rate
DMC
Data Monitoring Committee
DOR
duration of response
eCCA
extrahepatic cholangiocarcinoma
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EOT
end of treatment
FDA
Food and Drug Administration
FGF
fibroblast growth factor
FGFR
fibroblast growth factor receptor
GCP
Good Clinical Practice
I.V.
intravenous
iCCA
intrahepatic cholangiocarcinoma
ICF
informed consent form
ICH
International Conference on Harmonisation
ICR
independent central review
IEC
independent ethics committee
IRB
institutional review board
IXRS
Interactive Voice/Web Response System
KM
Kaplan-Meier
MRI
magnetic resonance imaging
NCI-CTCAE
National Cancer Institute – Common Terminology Criteria for Adverse Events
ORR 
objective response rate
OS
overall survival


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PD
progressive disease
PFS
progression-free survival
PFS2
PFS on next-line therapy
P-gp
P-glycoprotein
PI
prescribing information
PK
pharmacokinetic(s)
Pop PK
population pharmacokinetics
PR 
partial response
PRO
patient-reported outcomes
PS
performance status
QD
daily
QTcF
Fridericia's corrected QT interval
RECIST 1.1
Response Evaluation Criteria in Solid Tumors, Version 1.1 
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
stable disease
SOP
standard operating procedure
TEAE
treatment-emergent adverse event
TID
three times per day
ULN
upper limit of normal
WBC
white blood cell
WOCBP
woman/women of child-bearing potential


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1.
INTRODUCTION
1.1.
Disease Background
Cholangiocarcinoma (CCA), a bile duct cancer, is a rare tumor that arises from the malignant 
transformation of epithelial cells of the bile ducts.  It is typically classified as either intrahepatic 
(iCCA) or extrahepatic (eCCA).  Intrahepatic cholangiocarcinoma develops in the smaller bile 
ducts inside the liver and is the least common form of the disease (approximately 10%), whereas 
eCCA includes cancers in the peri-hilar (also known as Klatskin tumour) and distal bile duct area 
and is most common (approximately 90%) (Khan et al. 2002).
For disease that is localized at diagnosis, surgical resection offers the only chance of cure in 
patients with CCA.  Unfortunately, symptoms are not usually apparent until CCA is at an 
advanced stage; thus, most patients (>65%) have disease which is unresectable at diagnosis.  
The prognosis of patients with Stage III or IV CCA is extremely poor, with 5-year survival rates 
of 10% and 0%, respectively (Lamarca et al. 2014), and a median overall survival (OS) of 8 to 
12 months (Goral 2017).  Since the majority of patients are diagnosed after the opportunity for 
surgical resection has passed, this translates to very high mortality among affected patients.  The 
life-threatening nature of the malignancy is compounded by a gradually rising incidence 
(Goral 2017) and mortality (Khan et al. 2008), especially among patients with iCCA.
Although there are no approved treatments in this setting, gemcitabine/cisplatin is the current 
standard first-line chemotherapy regimen for patients with advanced, metastatic, unresectable 
CCA. This was based on a randomized study comparing cisplatin plus gemcitabine with 
gemcitabine alone in randomized 410 patients with biliary tract cancer where median 
progression-free survival (mPFS) was 8.0 months in the cisplatin–gemcitabine group and 5.0 
months in the gemcitabine-only group (Valle et al. 2010).  In other prospective studies published 
between 2004 and 2013 in patients with advanced biliary tract cancers, treatment with 
gemcitabine/cisplatin resulted in mPFS ranging from 4.0 to 8.0 months and median OS ranging 
from 4.6 to 11.7 months (Park et al. 2015).
1.2.
Futibatinib (TAS-120)
1.2.1.
Background and Nonclinical Overview
The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling axis has 
been well characterized for its role in proliferation, differentiation, migration, and survival of 
cells, and it is fundamental to embryonic development, regulation of angiogenesis, and wound 
healing in adults.  Accordingly, dysregulation of this signaling pathway has been associated with 
many developmental disorders and cancer.
Futibatinib is a novel and selective small molecule FGFR inhibitor, which is the first irreversible, 
covalent inhibitor of FGFR1–4 being tested in humans.  Futibatinib selectively and irreversibly 
binds to FGFR to exert an inhibitory effect on the FGF/FGFR pathway. Preclinical studies have 
shown that futibatinib selectively inhibits the cell growth of human cancer cell lines bearing 
FGFR gene abnormalities; strong antitumor efficacy has been observed with futibatinib in nude 
mouse or nude rat xenograft models bearing tumors with FGFR gene abnormalities.


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Of note, aberrations in FGF or the FGFR are a reported genetic modification in CCA 
(Ang 2015).  In iCCA, FGFR2 gene rearrangements (including gene fusions) have been 
identified as an early driver of oncogenic events; these gene rearrangements are present in an 
estimated 10% to 20% of patients (Ang 2015; Arai et al. 2014; Borad et al. 2015; Goyal et al. 
2017).  Therefore, inhibiting the FGFR pathway in patients with CCA is a plausible therapeutic 
strategy for appropriately selected patients with this disease.  
1.2.2.
Clinical Overview
On the basis of encouraging in vitro and in vivo data, briefly excerpted above and outlined in full 
in the Investigator’s Brochure, a clinical development program was initiated for futibatinib. To 
date, 2 clinical studies in healthy volunteers have been completed: 1 bioequivalence study 
assessing 2 dosage forms, and 1 food effect study.  Two studies assessing the safety, efficacy, 
and pharmacokinetics (PK) of futibatinib in advanced cancers are currently ongoing: 
Study 10059010, a Phase 1 trial in Japanese patients with advanced solid tumors, and 
Study TAS-120-101, a Phase 1/2 trial in three parts:

A Phase 1 Dose Escalation portion (completed with a total of 86 patients receiving either 
daily or 3-times-per-week dosing);

A Phase 1 Dose Expansion portion, which includes additional cohorts in CCA, gliomas, 
urothelial carcinoma, and basket cohorts with FGF/FGFR aberrations; and

A Phase 2 study initiated in April 2018, evaluating futibatinib at a daily (QD) dose of 
20 mg, in patients with iCCA harboring FGFR2 gene rearrangements.
The Phase 2 portion of this study was initiated based on strong evidence of antitumor activity in 
CCA in the Phase 1 part of the study.  As of 01 January 2019, 54 patients with iCCA harboring 
FGFR2 rearrangements were treated at 16 mg and 20 mg QD and followed for at least 6 months.  
The objective response rate (ORR) assessed by independent central review (ICR) was 25.9%, 
and the overall disease control rate (DCR) was 74.1% (95% confidence interval [CI]: 60.4, 85.0). 
Median duration of treatment was 6.1 months.  Nine of the 54 patients were ongoing as of data 
cut-off.
Collectively, safety data from clinical trials suggest that futibatinib is tolerable in patients with 
advanced cancers.  The most frequently reported treatment-related adverse event (AE) overall 
has been hyperphosphatemia (approximately 87%), mostly of Grades 1-2 (approximately 15% 
were Grade 3) and without clinical complications.  Other frequently reported treatment-related 
AEs included the gastrointestinal system disorders of diarrhea, dry mouth, nausea, and stomatitis. 
Dry skin and increased liver enzymes were also reported, most of which were mild to moderate 
in severity.
Safety concerns that have been identified from preclinical studies of futibatinib include an 
increase of inorganic phosphorus in plasma, ectopic mineralization in various organs and tissues, 
lesions in bone/cartilage, and corneal lesions.  An embryo-fetal developmental toxicity study 
conducted in rats showed that futibatinib inhibited normal development of the rat embryo-fetus 
and resulted in embryo-fetal lethality.  Effective contraception is mandated for any patients 
receiving futibatinib who are of child-bearing potential and their partners.


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1.3.
Summary of Study Rationale
Aberrations in FGF or the FGFR are a reported genetic modification in CCA.  In iCCA, FGFR2
gene rearrangements, including gene fusions, have been identified as an early driver of 
oncogenic events.  Futibatinib, a selective small molecule FGFR inhibitor, has shown promising 
antitumor activity in preclinical studies and ongoing clinical studies against a variety of tumor 
types harboring FGFR aberrations.  
The Phase 3 study described in this protocol will evaluate the safety and efficacy of futibatinib 
against that of the current standard of care (gemcitabine-cisplatin chemotherapy) in the first-line 
treatment of patients with advanced CCA harboring FGFR2 gene rearrangements (including 
gene fusions).
The maximum tolerated dose of futibatinib is 20 mg QD (continuous daily dosing), based on the 
results of the Phase 1 dose escalation portion of Study TAS-120-101.  Accordingly, the starting 
dose of futibatinib in this Phase 3 study is 20 mg QD.


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2.
OBJECTIVES AND ENDPOINTS
The objective of this study is to compare the following endpoints (Table 2) in patients with 
advanced iCCA harboring FGFR2 gene rearrangements, who are treated with either futibatinib 
monotherapy or gemcitabine-cisplatin chemotherapy.
Table 2:
Objectives and Endpoints
Primary

PFS by ICR, based on Response 
Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST 1.1)
PFS per central assessment, defined as the time from date of 
randomization to the date of documentation of disease 
progression by ICR, or date of death, whichever occurs first.
Secondary

ORR
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.

DCR
DCR, defined as the proportion of patients experiencing a best 
overall response of stable disease (SD), PR, or CR (per 
RECIST 1.1), based on central assessment of radiologic images.

OS
OS, measured from the date of randomization until the date of 
death due to any cause.

PFS according to Investigator
assessment of radiologic images based 
on RECIST 1.1
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.

Safety and tolerability
Treatment-emergent adverse events (TEAEs), including serious 
adverse events (SAEs), clinical laboratory tests, vital signs,
ophthalmological exams, and 12-lead electrocardiogram (ECG).
Exploratory

Duration of response (DOR).
DOR, defined as the time from the first documentation of 
response (per RECIST 1.1 and based on ICR) to the first 
documentation of objective tumor progression or death due to 
any cause, whichever occurs first.

Patient-reported outcomes (PRO)
PRO measured by the European Organization for Research and 
Treatment of Cancer (EORTC) QLQ-BIL21 and QLQ-C30.

PFS on next-line therapy (PFS2)
PFS2, defined as the time from randomization to subsequent 
disease progression per ICR after initiation of next-line therapy 
or death from any cause (whichever occurs first).  

Population pharmacokinetics (Pop PK) 
of futibatinib.
Blood samples for Pop PK analysis will be obtained from all 
patients receiving futibatinib on Cycle 2, Day 1, pre-dose and at 
1 hour and 3 hours (±30 min) post-dose.


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3.
INVESTIGATIONAL PLAN
3.1.
Overview of Study Design
Study TAS-120-301 (Figure 1) 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 QD on every day of a 21-day cycle.

Control Arm: On Days 1 and 8 of a 21-day cycle, patients will receive:
o
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
o
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.  Patients who discontinue gemcitabine-cisplatin for 
other reasons (eg, safety, withdrawal of consent, Investigator decision) are eligible for crossover 
following subsequent ICR-confirmed PD.
Abbreviations: EOT=end of treatment; FGFR2=fibroblast growth factor receptor 2; iCCA=intrahepatic 
cholangiocarcinoma; ICR=independent central review; PD=progressive disease.
Figure 1:
Study Schema


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3.2.
Scientific Rationale for Study Design
Please see Section 1.3.
3.3.
Study Period
3.3.1.
Study Periods and Visits for Each Patient
The study periods / visits described in this section are defined for all patients; please see Table 1
(Schedule of Events) for an outline of all assessments to be performed during each study period / 
visit.  Please note:

For all patients, the Safety Assessment Period begins at the time the informed consent 
form (ICF) is signed for the study (that is, the beginning of the Screening Period) and 
continues until at least 30 days after the last day of study therapy (that is, the end of the 
Safety Follow-up Period).  After the 30-day Safety Follow-Up Visit (see below), patients 
will be assessed for drug-related SAEs only.

For each patient, the Study Duration is defined as the time from day of ICF signature to 
the last day of Disease Assessment Follow-up / Survival Follow-up (see below).
3.3.1.1.
Pre-Screening
Determination of FGFR2 gene rearrangement status per the methods described in Section 6.1 of 
this protocol is required in order to assess eligibility for this study.  This determination is 
considered a pre-screening assessment, and should be performed prior to all other screening / 
baseline evaluations.  A pre-screening ICF, separate and distinct from the main study ICF, must 
be signed before any pre-screening evaluations may be performed.
3.3.1.2.
Screening Period
The Screening Period is defined as the time from the time the patient completes the main study 
ICF until the date and time of first dose of study therapy.  Determination of eligibility is based on 
the entry criteria enumerated in Section 4.1 and Section 4.2.   No protocol-specific procedures or 
assessments may be performed prior to completion of the ICF, except for pre-screening (see 
above) or procedures that represent standard-of-care.
3.3.1.3.
Patient Enrollment
Once the ICF is signed, the patient will be assigned a unique patient identification number.  Once 
study eligibility is confirmed, the patient will be randomized into the appropriate treatment 
cohort (see Section 3.5).  The patient should receive the first dose of study therapy within 3 days 
following randomization.  
3.3.1.4.
Treatment Period and End of Treatment Visit
Treatment discontinuation may occur for any of the reasons listed in Section 4.5.  The treatment 
period is the time from the date of first dose of study therapy (Day 1) to the date of last dose of 
study therapy.  An end-of-treatment (EOT) visit must be performed within 7 days after the 
decision is made to discontinue study treatment; at this visit, every effort should be made to 
perform the assessments outlined in Table 1. For patients who discontinue at a planned study 


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visit, that visit may be considered the EOT visit if all assessments required at EOT are 
performed.
3.3.1.5.
Safety Follow-Up Period and 30-Day Safety Follow-Up Visit
The safety follow-up period is the time from the date of last dose of study therapy through the 
30-day safety follow-up visit, which must be performed 30 days (±3 days) following the last 
dose of study therapy.  If the patient starts new anticancer therapy within 30 days of the last dose 
of study therapy, the 30-day safety follow-up visit should be performed before the start of new 
anticancer therapy.  Every effort should be made to perform the assessments outlined in Table 1.  
If the patient is unable to return to the study site, a follow-up phone call can be made by the 
study site to collect any new safety information that occurred during the Safety Follow-up 
Period.
After the 30-day Safety Visit, only AEs that are serious and drug-related will be assessed.
3.3.1.6.
Post-Discontinuation Considerations
3.3.1.6.1. Crossover
Patients randomized to the Control Arm who experience documented PD per RECIST 1.1 (by 
ICR) are eligible to crossover to receive futibatinib 20 mg QD. Patients who discontinue 
gemcitabine-cisplatin for other reasons are not eligible to crossover until there is documentation 
of ICR-confirmed radiographic disease progression. Crossover is optional and is at the discretion 
of the Investigator.  Patients who crossover should receive their first dose of futibatinib in the 
crossover period within 30 days after documentation of PD by ICR or within 30 days after 
completion of the 30-day safety follow-up period, whichever is later.
Please note that for patients who crossover, the 30-day safety follow-up period must be 
completed prior to the first dose of futibatinib in the crossover period.  A new tumor scan must 
be performed as a new baseline if the most recent scan was performed >6 weeks prior to the first 
dose of futibatinib in the crossover period.
In addition to the above considerations, patients must meet all of the criteria in Section 4.3 in 
order to be eligible for crossover.
3.3.1.6.2. Discontinuations for Reasons Other than Disease Progression
Patients who discontinue without documented disease progression per RECIST 1.1 should 
continue to undergo tumor assessments/scans according to the Schedule of Events (that is, every 
6 weeks or 9 weeks ±7 days until PD is documented, new anticancer therapy is initiated, the 
study is terminated, or the patient dies, withdraws consent, or is lost to follow-up).
3.3.1.6.3. Survival Follow-Up
Once disease progression per RECIST 1.1 is confirmed or the first subsequent new anticancer 
therapy is initiated, whichever occurs first, the survival follow-up period begins.  During this 
period, the patient or family should be contacted for survival follow-up every 12 weeks 
(±2 weeks) until withdrawal of consent, death, or loss to follow up, until study completion as 
defined in Section 3.4.  In addition, all subsequent anticancer treatments will be recorded.


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3.4.
Study Completion and Study Extension
The study will be considered complete:

12 months after the last event has been observed for the primary analysis of efficacy (that 
is, 12 months after 162 PFS events are reported); or

The trial is halted early for any reason.
Following Study Completion, patients still receiving and deriving benefit from study therapy in 
the opinion of the Investigator following discussion with the Sponsor will be permitted to 
continue treatment in a Study Extension phase. During the Study Extension, patients may receive 
treatment until withdrawal criteria are met.  
During this period, all safety assessments are to continue according to the schedule in Table 1A.
However, electronic data collection will be reduced.  Specifically, study extension data 
collection is to include, at a minimum:

Study drug administration;

Study drug accountability;

Serious adverse events;

Non-serious adverse events that are related to study treatment or result in treatment 
discontinuation; and

Any cases of pregnancy, overdose, or medication error.
3.5.
Randomization and Blinding
3.5.1.
Randomization
This is a randomized study.  The eligibility of all patients must be verified prior to enrollment. 
Study sites will enter patient demographic and baseline data into the electronic data capture 
(EDC) system in order to obtain a subject number.
Once patient confirmation of eligibility and the criteria for randomization have been met, 
Investigators will enroll patients. Patients will be centrally randomized in a 1:1 ratio to 
futibatinib or gemcitabine-cisplatin via an Interactive Voice/Web Response System (IXRS).
Patients will be stratified by the following balancing factors:

Prior surgical excision of the primary tumor (yes vs. no); 

Geographic region (Asia vs. rest of the world); and

Locally advanced vs. metastatic disease.
The IXRS will assign kit numbers corresponding to the patient’s administration assignment, 
inform the study site user of the kit number that has been assigned to the patient, and provide 
instructions for the dispensing of the study drug. 
No patients will be replaced at any time during this study.


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3.5.2.
Blinding
Futibatinib is administered orally, while the comparator treatment (gemcitabine-cisplatin) is 
administered by I.V. infusion.  Accordingly, this is an open-label (non-blinded) study.
3.6.
Independent Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) will be established to monitor data on an 
ongoing basis to ensure the continuing safety of the patients enrolled in this study. The 
committee will meet to review interim data. After the review, the DMC will make 
recommendations regarding the continuation of the study. The details will be provided in a 
separate DMC charter.


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4.
SELECTION AND WITHDRAWAL OF PATIENTS
Determination of FGFR2 gene rearrangement status should be completed before the patient 
undergoes any protocol-specific procedures. Waivers will not be granted for any of the eligibility 
criteria.
4.1.
Inclusion Criteria
A patient must meet all of the following inclusion criteria to be eligible for 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:

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤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 cell (WBC) count ≥ 2000/mm3 (≥ 2.0 × 109/L)

Absolute neutrophil count (ANC) ≥ 1000/mm3 (ie, ≥ 1.0 × 109/L) 

Platelet count ≥ 100,000/mm3 (≥ 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 3 months after the last dose. 
Willing and able to comply with scheduled visits and study procedures.


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4.2.
Exclusion Criteria
A patient must not meet any of the following exclusion criteria to be eligible for participation in 
this study:
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 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, selective 
internal radiotherapy, 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.


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
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 whose natural history or treatment 
has the potential to interfere with the safety or efficacy assessment of the investigational 
regimen in the opinion of the Investigator.
Pregnant or breast-feeding female
The patient is unable to take oral medication.
4.3.
Entry Criteria for Crossover
In addition to the considerations outlined in Section 3.3.1.6.1, patients must meet all of the 
following criteria to be eligible for crossover:

Any gemcitabine-cisplatin-induced toxicity has resolved to National Cancer Institute –
Common Terminology Criteria for Adverse Events (NCI-CTCAE) Grade ≤1;

ECOG PS 0-1

Adequate organ function as defined by:
o
AST and ALT ≤3 × the ULN; if liver function abnormalities are due to 
underlying liver metastasis, AST and ALT ≤ 5 × ULN;
o
Total bilirubin ≤ 1.5 × ULN, or ≤ 3 × ULN for patients with Gilbert’s syndrome.  
o
ANC ≥ 1000/mm3 (≥ 1.0 × 109/L)
o
Platelet count ≥ 75,000/mm3 (≥ 75 × 109/L by IU)
o
Hemoglobin ≥9.0 g/dL
o
Phosphorus ≤ 1.5 × ULN
o
Creatinine clearance: ≥ 40 mL/min.

Does not meet any of the following exclusion criteria:
o
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.
o
Current evidence of uncontrolled ventricular arrhythmias 
o
QTcF > 470 ms on ECG.  
o
A serious illness or medical condition(s) including, but not limited to, the 
following:


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
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.
o
Pregnant or breast-feeding female.
4.4.
Screen Failure
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently randomly assigned to the study intervention or entered in the study. A minimal set 
of screen failure information is required to ensure transparent reporting of screen failure patients
to respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAE occurring after completion of the ICF.
Patients who do not meet the criteria for participation in this study (screen failure) may be 
rescreened a maximum of 3 times. Rescreened patients should be assigned the same subject 
identification code as for the initial screening.
4.5.
Discontinuation of Treatment
If a patient meets any of the following conditions during the clinical study period, study
treatment may be discontinued.

Radiographic PD based on RECIST 1.1 as determined by ICR;

Clinical or radiographic PD per Investigator assessment;

Unacceptable AEs, or change in underlying condition such that the patient can no longer 
tolerate therapy, as evidenced by a dose delay > 21 days from the scheduled start date of 
the next cycle or need for more than the allowable number of dose reductions outlined in 
this protocol;

Physician’s decision, including need for other anticancer therapy not specified in the 
protocol, or surgery or radiotherapy to the only site(s) of disease being followed in the 
study;

Pregnancy;

A significant protocol deviation which, in the opinion of the Investigator and/or Sponsor, 
renders the patient unsuitable for further study treatment;

Loss to follow-up;


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
Death;

Termination of the study by the Sponsor; or

At the patient’s request at any time irrespective of the reason. 
Please note: patients who discontinue treatment for any reason other than radiographic PD per
ICR (including clinical PD or radiographic PD per Investigator) should continue to undergo
tumor assessments according to the schedule outlined in Table 1 until ICR-determined disease
progression (unless the patient withdraws consent for these assessments or continued
assessments are medically unfeasible in the opinion of the Investigator).
Patients who withdraw consent for further treatment may choose to remain on study (tumor
assessments, survival follow-up, etc); in such a case, all study evaluations should continue as
outlined in this protocol.  If the patient withdraws consent to all follow-up assessments, the
patient should be considered to have discontinued the study as described in Section 4.6.
4.6.
Withdrawal from the Study
A patient may be discontinued from all study interventions and assessments (that is, discontinued 
from the study without follow-up) for any of the following reasons: 
1. Death;
2. Loss to follow-up / contact despite best effort of investigative site personnel (that is, after 
at least 2 documented attempts to contact the patient and/or family); or
3. Patient withdrawal of consent to further follow-up assessments, irrespective of the 
reason.


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5.
STUDY TREATMENT
5.1.
Study Drug Administration
A treatment cycle is defined as 21 days for both arms.  However, patients in the Experimental 
Arm (or patients in the Control Arm who crossover to futibatinib treatment following PD per 
RECIST 1.1) receive continuous QD futibatinib with no planned interruption between cycles.
5.1.1.
Futibatinib
Futibatinib is supplied as 4-mg tablets and will be taken orally (PO) at a dose of 20 mg QD.  
Futibatinib should be administered under fasting conditions.  It should be taken with a glass of 
water, on an empty stomach, every 24 hours in the morning or evening at the same time each 
day, if possible. No food should be consumed for 2 hours prior and 1 hour after the dose of 
futibatinib, but patients will be permitted to drink water during this period.
When a PK sample is collected on Cycle 2, Day 1 futibatinib should be administered on site after
collection of the first PK sample.
In the event of a dosing delay up to 12 hours after the scheduled dosing time, the patient should 
still take that day’s dose.  If the dosing delay continues for >12 hours after the scheduled dosing 
time, or if the patient vomits after a dose, the patient should skip dosing for that day and not 
make up for it the following day.
5.1.2.
Gemcitabine / Cisplatin 
Gemcitabine and cisplatin will be administered to patients in the Control Arm on Days 1 and 8 of 
each 21-day cycle for up to 8 cycles.  
The hydration and electrolyte regimen (KCl +/- MgSO4) for cisplatin administration will be 
determined by locally agreed pharmacy procedures and guidelines.  Anti-emetic premedication 
according to local guidelines is permitted.
Cisplatin will be administered at a dose of 25 mg/m2 (in 1000 mL 0.9% saline) by I.V. infusion 
over 1 hour, followed by infusion of 500 mL 0.9% saline over approximately 30 minutes.  After 
completion of the cisplatin and saline infusions, gemcitabine will be administered at a dose of 
1000 mg/m2 (in 250-500 mL 0.9% saline) by I.V. infusion over approximately 30 minutes.
5.1.3.
Treatment Duration
Patients in the Control Arm may receive gemcitabine-cisplatin chemotherapy for up to 8 cycles 
or until PD or other withdrawal criteria are met (see Section 4.5), whichever comes first.
Patients in the Experimental Arm (or patients in the Control Arm who crossover to futibatinib 
treatment following PD per RECIST 1.1) may continue to receive futibatinib until PD or other 
withdrawal criteria are met (see Section 4.5), whichever comes first.


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5.2.
Dose and Schedule Modifications
5.2.1.
Dose and Schedule Modifications for Futibatinib
5.2.1.1.
General Considerations
This section defines general dose modification guidelines for patients receiving futibatinib in the 
Experimental Arm (or patients in the Control Arm who crossover to futibatinib treatment 
following PD).
The starting dose of futibatinib is 20 mg QD for all patients.  A maximum of 2 dose reductions 
are permitted, to reduced doses of 16 mg QD (first reduction) and 12 mg QD (second reduction). 
If dose reduction fails to result in achieving minimal criteria to resume treatment, or if toxicities 
occur which would necessitate reduction of the dose of futibatinib below 12 mg QD, the patient 
should be discontinued from futibatinib. 
Following a dose reduction, if a benefit/risk assessment favors an increase of futibatinib dose up 
to the initial starting dose (20 mg QD), an agreement with the Sponsor’s Medical Monitor is 
required prior to the dose increase. 
If toxicities requiring dose reduction(s) do not recover based on the criteria defined in Table 3
through Table 5 within 21 days after the last dose of futibatinib, the patient will be discontinued 
permanently from treatment (Section 4.5). If resumption criteria are met within 21 days of the 
last dose of futibatinib, the patient may resume futibatinib treatment at the appropriate dose level.
5.2.1.2.
Futibatinib Dose Modifications for Nonhematologic Toxicities
Dosing modification guidelines for nonhematologic toxicities are provided in Table 3. Dose 
modification guidelines for hyperphosphatemia is provided in Table 4.
If there is any uncertainty about continuing therapy or resuming therapy in a patient with 
nonhematologic AEs, the case must be discussed with the Sponsor’s Medical Monitor prior to 
continuing futibatinib.


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Table 3:
Futibatinib Dosing Modification for Related Nonhematologic Toxicities
Grade
Dose Interruption/Resumption
Dose Adjustment
Grade 1 or 2
Maintain treatment at the same dose 
level
None
Grade 3
Withhold treatment until return to 
baseline or Grade ≤1
Reduce by 1 dose level from the previous level, 
except for Grade 3 nausea and/or vomiting 
controlled by aggressive antiemetic therapy or 
Grade 3 diarrhea responsive to antidiarrheal 
medication which does not require a dose hold or 
reduction.
Grade 4 
Discontinue treatment 
Permanent discontinuation of futibatinib.
Grade 4 (lab 
abnormality 
AE)
Withhold treatment
Futibatinib will be permanently discontinued if 
assessed by the Investigator as life threatening.  
If it is in the best interest of the patient to continue 
treatment in the opinion of the Investigator and 
after discussion with the Sponsor, the patient can
resume treatment at a reduced dose level once 
toxicity returns to baseline or Grade ≤1.
Abbreviations: AE=adverse event.
Recommendations for hyperphosphatemia management are provided in Table 4. These are 
suggested guidelines based on emerging data from studies evaluating FGFR inhibitors, and from 
the experience of Investigators participating in ongoing studies of futibatinib. 


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Table 4:
Recommendations for Hyperphosphatemia Management
Serum Phosphorus Result 
(mg/dL and mmol/L)a
Gradeb
Futibatinib Dose Interruption and Modification
Recommended Phosphate Binder for Management of 
Hyperphosphatemiac
ULN < P <5.5 (mg/dL) 
ULN < P <1.78 (mmol/L)
Grade 1

No interruption, consider phosphate binder once serum 
phosphorus level is > ULN. 

Should serum phosphorus level rapidly increase within 
1 week, consider early phosphate-lowering therapy, eg, 
Sevelamer tablets 800 mg three times per day [TID]. 
5.5 ≤ P ≤7.0 (mg/dL) 
1.78 ≤ P ≤2.26 (mmol/L) 
Grade 2 

No interruption, implement phosphate binder 
(monotherapy or in combination), 

Start with Sevelamer monotherapy (range from 800 mg 
TID to 2400 mg TID). 

Re-assess serum phosphate within 7 days, and plan to 
escalate Sevelamer or add treatment with acetazolamide 
250 mg QD or TID and/or lanthanum carbonate 
(Fosrenol®)  1.0 g QD or TID, and further titrationd, if 
phosphate level continues to increase. 
7.0 < P ≤10.0 (mg/dL) 
2.26< P ≤3.23 (mmol/L) 
Grade 3 

Dose reduce futibatinib to the next lower dose level and 
intensify phosphate lowering therapy

If the serum phosphorus level has resolved to ≤ Grade 2 
within 14 days after dose reduction, continue futibatinib at 
the reduced dose level. 

Re-assess serum phosphate within 7 days and at least once 
a week. If the serum phosphorus level has not resolved to 
≤Grade 2 after 14 days, further reduce futibatinib from the 
last reduced dose level (or no lower than 12 mg QD).

If the serum phosphorus level has not resolved to ≤ Grade 
2 after 14 days of the second dose reduction of futibatinib 
(or no lower than 12 mg QD), interrupt dosing with 
futibatinib until it is resolved to ≤ Grade 2 before resuming 
futibatinib at the reduced dose prior to dose interruption.
P >10.0 (mg/dL) 
P >3.23 (mmol/L) 
Grade 4 

Interrupt futibatinib until it’s resolved to ≤ Grade 2, then 
resume futibatinib at the next lower dose level and 
intensify phosphate lowering therapy.

Re-assess serum phosphate within 7 days and at least once 
a week. If after 2 dose interruptions and 2 dose reductions 
the serum phosphorus level has not resolved to ≤ Grade 2 
after 14 days, permanently discontinue futibatinib.
Abbreviations: P=phosphorus; QD=once a day; TID=three times a day; ULN=upper limit of normal 
a.
mmol/L = mg/dL × 0.3229 (conversion factor).
b.
This grading for the range of serum phosphorus levels will be used for the protocol.
c.
Phosphate binders can be used as monotherapy or in combination. Please consult the drug package insert. Sevelamer 
should be preferably taken in the middle of meals, both tablets and powder, in order to improve gastrointestinal 
tolerance and compliance. If Sevelamer cannot be used, other phosphate binders or hyperphosphatemia treatment drugs 
can be used. Lanthanum carbonate should be taken instead just after meals – tablets of Fosrenol® are large, but may be 
cut if required. No dose adjustments are needed in patients with renal or hepatic impairment.
d.
Titrate the dose every 2-3 weeks until an acceptable serum phosphate level is reached.


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5.2.1.3.
Futibatinib Dose Modifications for Hematologic Toxicities
Criteria for dose interruption and resumption for hematologic toxicities are presented in Table 5.
Table 5:
Futibatinib Dose Interruption and Modification Criteria for Related 
Hematologic Toxicities
Worst toxicity 
CTCAE Grade (value) 
Recommended dose modification any time during a cycle 
of futibatinib
Anemia (Hgb)
Grade 1 (Hgb < LLN - 10.0 g/dL) 
Maintain dose level 
Grade 2 (Hgb < 10 – 8.0 g/dL) 
Maintain dose level 
Grade 3 (Hgb < 8.0 - 6.5 g/dL) 
Withhold dose until resolved to ≤ Grade 1 or baseline, 
• If resolved ≤7 days, then maintain dose level 
• If resolved >7 days, then reduce 1 dose level 
Grade 4 (life threatening consequences; urgent intervention 
indicated) 
Withhold dose until resolved to ≤ Grade 1 or baseline, then 
reduce 1 dose level 
Neutropenia (ANC)
Grade 1 (ANC < LLN - 1500/mm3) 
Maintain dose level 
Grade 2 (ANC < 1500 - 1000/mm3) 
Maintain dose level 
Grade 3 (ANC < 1000 - 500/mm3) 
Maintain dose level 
Grade 4 (ANC < 500/mm3) 
Withhold dose until resolved to ≤ Grade 2 or baseline, 
• If resolved ≤7 days, then maintain dose level 
• If resolved >7 days, then reduce 1 dose level 
Febrile neutropenia (ANC < 1000/mm3, with single 
temperature ≥ 38.3°C or sustained [>1 hour] temperature 
of ≥ 38.0°C) 
Withhold dose until resolved, then reduce 1 dose level 
Thrombocytopenia
Grade 1 (PLT < LLN - 75,000/mm3) 
Maintain dose level 
Grade 2 (PLT < 75,000 - 50,000/mm3) 
Maintain dose level 
Grade 3 (PLT < 50,000 - 25,000/mm3) 
Withhold dose until resolved to ≤ Grade 1 or baseline, 
• If resolved ≤7 days, then maintain dose level 
• If resolved >7 days, then reduce 1 dose level 
Grade 4 (PLT < 25,000/mm3) 
Withhold dose until resolved to ≤ Grade 1 or baseline, then 
reduce 1 dose level 
Abbreviations: ANC=absolute neutrophil count; CTCAE=Common Terminology Criteria for Adverse Events; 
Hgb=hemoglobin; LLN=lower limit of normal; PLT=platelets.
5.2.2.
Dose and Schedule Modifications for Gemcitabine and Cisplatin
5.2.2.1.
General Considerations
This section defines general dose modification guidelines for patients receiving gemcitabine and 
cisplatin in the Control Arm.  
5.2.2.2.
Gemcitabine and Cisplatin Dose Modifications for Non-Hematologic Toxicities
Renal Toxicity
Eligible patients must have baseline creatinine clearance ≥60 mL/min (measured within 72 hours 
prior to dosing on C1D1; please see Table 1).  At all administration timepoints, the dose of 
cisplatin is dependent upon renal function (that is, creatinine clearance); please see Table 6 for 
specific guidelines.
If a sudden increase in creatinine occurs, haemolytic uraemic syndrome should be ruled out.


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Table 6:
Cisplatin Dose Modification Guidelines for Renal Toxicity
CrCl (mL/min)
Cisplatin Dose
>60 mL/min
100% of planned dose
51 – 60 mL/min
75% of planned dose
40 – 50 mL/min
50% of planned dose
<40 mL/min
Repeat CrCl assessment, insuring adequate hydration

If repeat assessment shows CrCl ≥40 mL/min, proceed with 
cisplatin administration according to the guidelines in this table.

If repeat assessment shows CrCl <40 mL/min, cisplatin must be 
omitted until recovery of renal function
Abbreviations: CrCl=creatinine clearance.
If the cisplatin dose is reduced or omitted at any timepopint due to reduced renal function, 
gemcitabine may be administered without modification as long as CrCl remains ≥30 mL/min.  
Reduction to the dose of gemcitabine may be warranted in cases where CrCl is <30 mL/min.
Other Non-Hematologic Toxicity
Dose modification guidelines for other non-hematologic toxicities are summarized in Table 7.
Table 7:
Gemcitabine-Cisplatin Dose Modification Guidelines for Non-Hematologic 
Toxicity
Description of Toxicity
Recommended dose modification
No dose reduction / modification required
Alopecia (any grade)
Maintain dose level 
Fatigue / Asthenia (Grade ≤ 2)
Maintain dose level 
Nausea / Vomiting (Grade ≤ 2)
Maintain dose level; note that this includes patients with reductions from 
Grade 3-4 following appropriate use of anti-emetics.
Edema (Grade ≤ 2)
Maintain dose level; give postural advice and consider administration of 
appropriate diuretics.
Consider dose modification
Fatigue / Asthenia (Grade ≥ 3)
Reduce gemcitabine dose by 25%; if toxicity does not respond to dose 
reduction, discontinue both gemcitabine-cisplatin
Nausea / Vomiting (Grade ≥ 3)
Ensure optimal use of antiemetics (according to local policy) Delay until 
recovery to baseline, then: Omit cisplatin first. If no improvement reduce 
gemcitabine by 25%; if toxicity does not respond to anti-emetic treatment or 
dose reduction of both gemcitabine-cisplatin, discontinue both gemcitabine-
cisplatin
Peripheral neuropathy (Grade 2)
Delay cisplatin until recovery to baseline, then continue at full dose. If no 
recovery, treat as for Grade ≥3. Continue with gemcitabine (full dose).
Peripheral neuropathy (Grade ≥ 3)
Omit cisplatin from further treatment.  Continue with gemcitabine (full
dose).  
Edema (Grade ≥ 3)
Dipstick urine test for protein followed by full 24-hour urinary protein 
estimation if result ≥+ 
Delay until recovery to baseline (with use of appropriate diuretics). Then 
reduce gemcitabine by 25%; if toxicity does not respond to diuretic 
treatment or dose reduction,  discontinue both gemcitabine-cisplatin.
Tinnitus (any grade)
No dose modification required if full recovery between cycles. Omit 
cisplatin if no recovery between cycles.  Continue gemcitabine (full dose).
Pulmonary toxicity (Grade ≥ 2)
Discontinue gemcitabine-cisplatin treatment and initiate supportive therapy 
(high dose steroids) immediately.


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5.2.2.3.
Gemcitabine and Cisplatin Dose Modifications for Hematologic Toxicities
Gemcitabine should be dose-reduced if haematological toxicity occurs, according to Investigator
judgement and based on the guidelines outlined in Table 8.
Table 8:
Gemcitabine-Cisplatin Dose Modification Guidelines for Hematologic 
Toxicity
WBC
(x109/L)
ANC
(x109/L)
Platelets
(x1000/mm3)
Gemcitabine 
Dose
Cisplatin 
Dose
≥2
and
≥1
and
≥100
Full
Full
1 – 1.9
and/or
0.5 – 0.9
and/or
50 – 99
75% dose
Full
<1
and/or
<0.5
and/or
<50
Delaya
Delaya
Abbreviations: ANC=absolute neutrophil count; WBC=white blood cell(s).
a.
If the delay lasts >3 weeks, the patient should be discontinued from treatment.
5.3.
Treatment Compliance
Each patient will be instructed to comply with the dosage and dosing regimen of futibatinib.  
Gemcitabine and cisplatin will be administered to patients in the Control Arm only in the clinic 
under the supervision of clinic staff; all details of administration will be recorded in the 
electronic case report form (eCRF).
Compliance with all study medication administration should be documented in the patient’s 
source documents.
5.4.
Concomitant Medications and Therapies
The following therapies are permitted:

Bisphosphonates;

Denosumab; and/or

Steroids for patients with brain metastases.
Local or regional palliative cryotherapy or radiation, such as for bone pain or palliative surgery 
(non-anti-neoplastic intent), are permitted (provided the target lesion is not a site of measurable 
disease and is not indicative of disease progression). Study therapy should be ceased a minimum 
of 2 days prior to administration of palliative treatment, and may be resumed 7 days after the 
procedure or when the patient has recovered from the side effects of the procedure.
The following medications/therapies may be given concomitantly under the following 
guidelines: 
Hematologic Support: may be administered as medically indicated (that is, blood transfusions, 
granulocyte colony-stimulating factor, erythropoietin stimulating agents) according to the 
institutional site standards or American Society of Clinical Oncology (ASCO) guidelines 
(Smith et al. 2015). 


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Management of Diarrhea: Prophylactic treatment for diarrhea is permitted during the study if 
clinically indicated according to the institutional or published guidelines (Benson et al. 2004). 
Management of Nausea/Vomiting: Antiemetics may be administered as clinically indicated 
according to institutional standards or ASCO guidelines (Hesketh et al. 2017).
5.4.1.
Prohibited Medications and Therapies
Patients are not permitted to receive any other investigational or any other anticancer therapy, 
including chemotherapy, immunotherapy, biological response modifiers, or antineoplastic 
endocrine therapy during the study treatment period.  If extended field radiation therapy or 
palliative radiation to a focal site of measurable disease are deemed in the best interest of the 
patient following discussion between the Investigator and the Sponsor, the patient will be 
censored for the primary analysis of efficacy.
5.4.2.
Drug Interactions
Drug interaction studies with futibatinib have not been conducted in humans. The following 
information is based on results from in vitro studies. Caution is advised if these drugs are given 
concomitantly (see Appendix C).
Cytochrome P450 (CYP) 3A inhibitors and inducers: CYP3A is involved in the metabolism 
of futibatinib. CYP3A inhibitors and inducers may alter the concentration and activity of 
futibatinib.
CYP3A substrates: Futibatinib is a potential time-dependent inhibitor of CYP3A. Futibatinib
may increase the concentration and activity of CYP3A substrates.
P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitors: Futibatinib is a 
potential inhibitor of P-gp and BCRP. Futibatinib may alter the PK and activity of P-gp and 
BCRP substrates. 
P-gp and BCRP substrates: Futibatinib is a substrate of P-gp and BCRP. P-gp and BCRP 
inhibitors may alter the concentration and activity of futibatinib.
No specific drug interaction studies have been conducted for gemcitabine (gemcitabine 
prescribing information [PI]).  For cisplatin, plasma levels of anticonvulsant agents may become 
subtherapeutic during cisplatin therapy (cisplatin PI).  Please see the respective labels for 
gemcitabine and cisplatin for additional discussion of potential drug interactions with these 
agents.
5.5.
Effective Contraception During Study
Female patients considered not to be of child-bearing potential must have a history of being 
postmenopausal (no menses for 12 months without an alternative medical cause), or 
hysterectomy that is clearly documented in the patient’s source documents. 
For WOCBP, including female study participants and partners of male participants, effective 
contraception is required during the study and for 3 months after the last dose of study 
medication. Effective contraception is defined as follows:


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
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation:
o
oral
o
intravaginal
o
transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulation:
o
oral
o
injectable
o
implantable

Intrauterine device

Intrauterine hormone-releasing system

Bilateral tubal occlusion 

Vasectomized partner with documentation of the success of the vasectomy 

Complete abstinence from heterosexual intercourse (periodic abstinence is not a safe 
method) 
Male patients with partners who are WOCBP should use a combination of male condom with 
cap, diaphragm, or sponge with spermicide during the study and for 3 months after the last dose 
of study medication. Donation of sperm or ova is not allowed during the study and for 3 months
following the last dose of study drug.
5.6.
Study Drug Materials and Management
Futibatinib will be supplied by the Sponsor; gemcitabine and cisplatin will be supplied by the 
Sponsor or procured by investigative sites, depending on local operational and regulatory 
requirements. Detailed information, including requirements for accountability, and disposal of 
study drug will be provided in a separate Pharmacy Manual.
5.6.1.
Description of Study Drug
A description of the futibatinib study drug and packaging information are provided in Table 9.  
Please refer to the respective product labels for descriptions of gemcitabine and cisplatin.
Table 9:
Futibatinib Product Description and Packaging Information
Product Description and 
Dosage Form
Potency/
Strength
Appearance
Primary Packaging
Futibatinib Tablet
4 mg
Round, white, film-coated tablet
Aluminum/Aclar blister


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5.6.2.
Packaging and Labeling
Futibatinib tablets will be packaged and labeled according to local regulations. Additional 
clinical labeling will be added as necessary.
Gemcitabine and cisplatin will follow the packaging and labeling specified on the respective 
labels, and will receive additional clinical labeling as required by local regulations.
5.6.3.
Accountability
The Investigator is responsible for ensuring that all futibatinib received at the site is inventoried 
and accounted for throughout the study. Futibatinib will be stored and disposed of according to 
the Sponsor's instructions. The dispensing of futibatinib to the patient and the return of 
futibatinib from the patient must be documented in the patient’s source documents/the drug 
accountability form. Patients must be instructed to return all original containers, whether empty 
or containing study drug.  
Gemcitabine and cisplatin will be stored according to the product label and disposed of 
according to the Sponsor's instructions.  
At the conclusion of the study, all study drugs supplied by the Sponsor must be destroyed or 
returned to the designated depot, per the instructions provided in the Pharmacy Manual. 


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6.
STUDY ASSESSMENTS
6.1.
Study Assessments and Procedures
The Schedule of Events (Table 1) summarizes the frequency and timing of all applicable study 
assessments, including allowable windows for study visits and assessments / procedures. Written 
informed consent must be provided before any study-related procedures are performed.
The study schedule must be followed; however, in unavoidable circumstances (e.g., holidays, 
weekends, etc.) a window of ± 3 days is allowable for study procedures as long as the proper 
order of procedures and assessments is maintained. The ± 3-day window does not apply to 
assessments on Day 1 of Cycle 1.
6.1.1.
Determination of FGFR2 Gene Rearrangement Status (Pre-Screening)
Determination of eligibility is based in part on the determination of FGFR2 gene rearrangement 
status based on testing by the designated central laboratory, 
Determination of FGFR2 gene rearrangement status should be performed prior to any other 
screening / baseline assessments.  Any AEs directly associated with a pre-screening procedure 
should be reported as described in Section 9.1.2. There is no need to record AEs and SAEs that 
occur between signing the pre-screening ICF and main study ICF if the events are unrelated to 
the pre-screening procedures, unless reporting is mandatory by local regulations.
6.1.2.
General Assessments
The following general assessments are performed as indicated in the Schedule of Events.

Demographics / medical history: Includes sex, age, clinical diagnosis, date and method 
of diagnosis, prior cancer therapy, and relevant medical history (past and concurrent).

Review eligibility criteria: Eligibility is assessed during the screening period and should 
be confirmed on Day 1 of Cycle 1, prior to first dose of study therapy.

Physical examination

Vital signs: Pulse rate, systolic and diastolic blood pressure, body temperature, and 
respiration rate. Any abnormal reading should be repeatedly immediately.

Height and body weight: Height is collected for the purpose of body mass index 
calculations at baseline only.

ECOG performance status: See Appendix A.

Pregnancy test: Serum β-human chorionic gonadotrophin (human chorionic stimulating
hormone) test required for WOCBP at screening and end of treatment; serum or urine test 
required at all other timepoints listed in the Schedule of Events.

Concomitant medication: Including all medications / therapies administered from the
time ICF is signed through 30 days after administration of the last dose of study therapy
or until the start of new anticancer therapy.


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
12-Lead ECG: Single, resting, semirecumbent 12-lead ECG will be performed locally.  
Data collection includes RR interval (heart rate), QT interval, QTcF interval and
abnormal findings; the Investigator is responsible for interpreting and measuring ECG 
data.
6.1.3.
Efficacy Assessments
On-site tumor assessments (including computed tomography [CT]/magnetic resonance imaging 
[MRI]) will be performed by the Investigator/local radiologist according to RECIST 1.1 
guidelines (Eisenhauer et al. 2009). Results of these assessments, including response for target 
and non-target lesions and appearance of new lesions, will be the basis for the continuation or 
discontinuation of study therapy. Response definitions are provided in Section 8.1 . 
If the Investigator determines that a patient has developed clinical disease progression 
manifested by symptomatic deterioration but not supported by radiologic evidence of 
progression, the patient may stop treatment. Symptoms of clinical disease progression must be 
documented in the patient’s source documents and must be reported as AEs. Every effort should 
be made to document objective disease progression per RECIST 1.1 even after discontinuation of 
treatment. 
The same method of assessment and the same technique must be used to characterize each 
identified and reported lesion at screening, throughout the study, and during the follow-up 
period.  Please see Section 8 for more detailed discussion of efficacy evaluations.
Note that patients who discontinue without documented disease progression per RECIST 1.1 
should continue to undergo tumor assessments/scans according to the Schedule of Events until 
PD per RECIST 1.1 is documented, new anticancer therapy is initiated, the study is terminated, 
or consent is withdrawn.
Once disease progression per RECIST 1.1 is confirmed or the first subsequent new anticancer 
therapy is initiated, whichever occurs first, the survival follow-up period begins.  During this 
period, the patient or family should be contacted for survival follow-up every 12 weeks 
(±2 weeks) until withdrawal of consent, death, or loss to follow up, until study completion.
6.1.4.
Ophthalmological Examination
The cornea and conjunctiva are readily visible tissues, and therefore, abnormalities of the cornea 
and conjunctiva can usually be recognized via external ocular examination and routine slit lamp 
biomicroscopy. The retina is visible through fundoscopy after dilation of the pupil. 
Ophthalmologic examination will be performed at screening and 4-6 weeks after first dose; 
additional on-study evaluation as needed due to local requirements, physician judgment, and/or 
symptoms or signs of mineral deposits.  


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Each evaluation will encompass: 
1. External ocular examination
2. Routine slit lamp biomicroscopy of anterior ocular structures, including the anterior and 
posterior chambers (Fluorescein or rose Bengal or other dyes used to evaluate the ocular 
surface can be used according to institutional guidelines and local clinical practice)
3. Dilation of the pupil with direct/indirect fundoscopy per institutional guidelines and local 
clinical practice
6.1.5.
Laboratory Assessments
All laboratory assessments will be performed locally.  The laboratory must provide normal 
reference ranges for hematology, chemistry and coagulation tests. Laboratory results for 
hematology, chemistry, and coagulation assessments must be reviewed for clinically significant 
events. Any clinically significant events must be followed and reported as required by the
protocol (please see Section 9.1.2).

Hematology assessments include: Red blood cell count, hemoglobin, hematocrit, 
platelets, WBC count with differential (ANC, lymphocytes, monocytes, eosinophils, 
basophils)

Coagulation assessments include: Prothrombin time-international normalized ratio, 
activated partial thromboplastin time, fibrinogen

Chemistry (serum or plasma) assessments include: AST, ALT, alkaline phosphatase, 
total bilirubin, direct bilirubin, albumin, lactate dehydrogenase, inorganic phosphorus, 
triglyceride, total cholesterol, creatinine, urea or blood urea nitrogen, sodium, potassium, 
chloride, calcium (corrected value), magnesium, blood glucose, creatinine clearance 
For a calculated creatinine clearance (Ccr) value, use the Cockcroft-Gault formula:
Male Ccr (mL/min) = Body wt (kg)×(140-age)[72×serum creatinine (mg/dL)]
Female Ccr (mL/min) = male Ccr×0.85
6.1.6.
Safety Evaluations
For a detailed description of safety data collection, please refer to Section 9.
6.1.7.
Pharmacokinetic and Pharmacodynamic Evaluations
For detailed discussion of PK and pharmacodynamic evaluations planned in this study, please 
refer to Section 7.
6.1.8.
Crossover Evaluations
Patients who crossover should undergo all assessments in Table 1 for patients receiving 
futibatinib, including efficacy, safety, and PK assessments.  Frequency of assessments should 
follow the schedule in Table 1 as if the patient were newly enrolled.  In particular:


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
Radiographic assessments of disease should be performed  2 cycles (± 7 days) up to 
Cycle 4 of the crossover period and every 3 cycles (± 7 days) thereafter.

Hematology, coagulation, and serum chemistry assessments should be performed within 
24 hours prior to treatment on D1 of each cycle of the crossover period, and prior to 
treatment on D8 and D15 of the first crossover cycle.


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7.
PHARMACOKINETICS
The PK population will consist of all patients who received futibatinib and have evaluable blood 
samples for analyses. The blood samples will be used to determine plasma futibatinib 
concentrations. PK data analysis is described in Section 11.5.5.
Blood samples for Pop PK analysis will be obtained from all patients receiving futibatinib on 
Cycle 2, Day 1 (± 3 days), pre-dose (from -30 min to just before dose) and at 1 hour and 3 hours 
(±30 min) post-dose. A minimum of 1 mL of whole blood will be collected for PK analysis at
each timepoint. Thus, the total blood volume collected for the PK samples will be approximately 
3 mL per patient (Table 10). All 3 samples should be collected on the same day. 
In case that the patient interrupts medication after the pre-dose sample is collected and restarts 
the treatment on C2D1 at a later date, a pre-dose sample should be collected again. The second 
pre-dose sample will be recorded as the pre-dose sample for C2D1. The 3 samples will be 
collected on C2D1 of crossover treatment from patients who receive treatment with futibatinib. 
Dates and times of each sample collection must be recorded. Methods of sample collection and 
preparation will be described in a separate Laboratory Manual. 
Table 10:
Pharmacokinetic Blood Sample Collection
Day of Study
(Time Window)
Collection Time Point (hours) in 
Relation to Futibatinib 
Administration (Time Window)
Blood Volume
Day 1 of Cycle 2 ± 3 days
pre-dose (From -30 min to just before 
dose)
1 mL
1 h ± 30 min post-dose
1 mL
3 h ± 30 min post-dose
1 mL
Total volume per patient
Approximately 3 mL


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8.
EFFICACY EVALUATIONS
8.1.
Efficacy Criteria
The determination of antitumor efficacy will be based on the results of objective tumor 
assessments/scans interpreted by the ICR (primary analysis) and Investigator, according to 
RECIST 1.1.
8.1.1.
Method of Imaging
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at each assessment timepoint. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
antitumor effect of treatment. All measurements should be recorded in metric notation using a 
ruler or calipers.
Contrast-enhanced CT scans or MRIs are the preferred methods for tumor assessments. If a 
contrast agent is contraindicated in a patient, obtain a non-contrast chest CT and enhanced MRI 
of the abdomen (and pelvis if clinically indicated). A spiral CT should be performed using a 
≤5 mm contiguous reconstruction algorithm. Images must be acquired of the chest and abdomen 
(and pelvis if clinically indicated or obtained at Baseline) at each time point. Only CT scans and 
MRI may be used for tumor measurement. 
Clinical lesions will only be considered measurable when they are superficial (eg, skin nodules, 
palpable lymph nodes). In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended. 
Ultrasound should not be used to measure tumor lesions that are clinically not easily accessible 
for overall response evaluation (eg, visceral lesions). Ultrasound is a possible alternative to 
clinical measurements of superficial palpable nodes, subcutaneous lesions, and thyroid nodules. 
Ultrasound might also be useful to confirm the complete disappearance of superficial lesions 
usually assessed by clinical examination.
For additional guidance, refer to RECIST 1.1 specifications for standard anatomical radiological 
imaging.
8.1.2.
Tumor Definitions
Measurable Lesions: Only measurable lesions can be selected as target lesions.

Measurable visceral lesions: Lesions that can be accurately measured in at least 
1 dimension with the longest diameter (to be recorded) ≥10 mm by CT scan if using slice 
thickness of ≤5 mm, or at least double the slice thickness of the CT or MRI scan if the 
slice thickness is >5 mm. 

Measurable pathological lymph nodes: A malignant lymph node must be considered 
pathologically enlarged with high suspicion of metastasis and measure ≥15 mm in the 
short axis when assessed by CT scan. The short axis is defined as the longest linear 
dimension perpendicular to the node’s longest diameter as assessed within the same plane 
that the scan was acquired.


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Non-measurable Lesions: All non-measurable lesions can only be selected as non-target lesions.

Small visceral metastatic lesions that have a longest dimension <10 mm, or if slice 
thickness is >5 mm, less than twice the slice thickness 

Abnormal and suspected metastatic lymph nodes that are ≥10 mm to <15 mm in the short 
axis

Truly non-measurable lesions (eg, ascites and peritoneal carcinomatosis)
Target Lesions: 

All measurable lesions up to a maximum of 2 lesions/organ and 5 lesions in total, 
representative of all involved organs/tissues should be identified as target lesions

Target lesions should be selected on the basis of their size (visceral lesion with the 
longest diameter and lymph node with the measurement of short axis), be representative 
of all involved organs/tissues, but in addition should be those that lend themselves to 
reproducible repeated measurements

When recording tumor measurements, the longest diameter will be measured for each 
non-nodal target lesion. For measurable pathological lymph nodes that may be identified 
as target lesions, the short axis measurement will be combined with the measurements of 
non-nodal (ie, visceral lesion) target lesions. Therefore, in cases of CR when abnormal 
nodes have been used as target lesions, the sum of diameters will not reduce to a null 
value. 

Target lesions will be followed up and measured at each subsequent timepoint. If a target 
lesion disappears, the tumor measurement will be captured as zero.

The sum of the diameters for all target lesions will be calculated and recorded. The 
baseline sum will be used as a reference to further characterize any objective tumor 
assessment in the measurable dimension of the disease. 

Assign a measurement to all target lesions regardless of size. An option of “too small to 
measure” will be provided if a measurement cannot be assigned. A value of zero should 
only be assigned in the case of a CR. 

An option of “not assessable” for a lesion will only apply to lesions that cannot be read 
due to technical reasons including:

CT artifact

Patient positioning where the lesions are obstructed or cannot be seen

Lesions that may not be seen in their entirety due to CT slice thickness

In cases where a lesion divides into 2 lesions, the longest diameters of the fragmented 
portions should be added together to calculate the target lesion sum. 

In cases where 2 lesions coalesce, a plane between them may be maintained that would 
aid in obtaining maximal diameter measurements of each individual lesion. If the lesions 
have truly coalesced such that they are no longer separable, the vector of the longest 
diameter in this instance should be the maximal longest diameter for the “coalesced 
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Non-target Lesions:

Non-target lesions include all non-measurable lesions and measurable lesions that have 
not been selected as target lesions. 

The primary lesion should always be classified as a non-target lesion irrespective of its 
size and whether or not it can be accurately measured. 

Lymph nodes that have a short axis <1 mm are considered non-pathological and should 
not be recorded. 

Any equivocal lesion without clear diagnosis (eg, uncharacteristic solitary lung nodule 
without biopsy, uncharacteristic thyroid mass lesion without fine needle aspiration) may 
be considered a non-target lesion if it cannot be differentiated from a benign lesion. 

All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at Baseline. Measurements 
are not required, but their presence, absence, or unequivocal progression should be 
followed throughout the study. 

It is possible to record multiple non-target lesions involving the same organ as a single
item on the eCRF (eg, multiple enlarged pelvic lymph nodes or multiple liver 
metastases).
8.2.
Efficacy Endpoints
The efficacy evaluation criteria described above will be used to derive the following primary and 
secondary efficacy endpoints (Table 11).  Definitions of each endpoint are provided in 
Section 11.5.2.
Table 11:
Efficacy Endpoints
Primary
Secondary
PFS by ICR
ORR and DCR (by ICR)
OS
PFS by Investigator assessment
Abbreviations: DCR=disease control rate; ICR=independent central review; ORR=objective response rate; 
OS=overall survival; PFS=progression-free survival.
8.2.1.
Response Criteria
Efficacy evaluation will include the assessment of target and non-target tumor responses as well 
as objective responses. Responses will be assessed as defined in the Statistical Analysis Plan 
(SAP).
8.2.1.1.
Target and Non-Target Response Assessments
Assessments will be based on the definitions for target and non-target lesions described in 
Table 12.


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Table 12:
Target and Non-target Lesions
TARGET LESIONS
Lesions Response:
Definition:
Complete Response (CR)
Disappearance of all target lesions. Any pathological lymph node must 
have reduction in short axis to <10 mm
Partial Response (PR)
At least a 30% decrease in the sum of diameters of the target lesions, 
taking as a reference the baseline sum diameters
Progressive Disease (PD)
At least a 20% increase in the sum of diameters of the target lesions, taking 
as a reference the smallest sum on study, including the baseline sum. In 
addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. Definitive new lesion presence also 
indicates progression. 
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, referencing the smallest sum diameters while on study. 
NON-TARGET LESIONS
Lesions Response:
Definition:
Complete Response (CR)
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)
Partial Response (PR)
Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits
Progressive Disease (PD)
Unequivocal progression of existing non-target lesions (see following 
definition).
Abbreviations: CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease
Progression in Non-target Disease: There must be an overall level of substantial worsening in 
non-target disease such that, even in the presence of SD or PR in target disease, the overall tumor 
burden has increased sufficiently to merit discontinuation of therapy.
8.2.1.1.1. Additional Criteria to Consider When Making Tumor Response Assessments 
Because worsening in non-target disease cannot be easily quantified, a useful test that can be 
applied when assessing patients for unequivocal progression is to consider if the increase in 
overall disease burden based on the change in non-measurable disease is comparable in 
magnitude to the increase that would be required to declare PD for measurable disease (ie, an 
increase in tumor burden representing an additional 73% increase in “volume” [which is 
equivalent to a 20% increase in the diameter of a measurable lesion]). 
When effusions are known to be a potential adverse effect of treatment, cytological confirmation 
of the neoplastic origin of any effusion that appears or worsens during treatment when the 
measurable tumor has met criteria for response or SD is not mandatory, but might be performed 
to differentiate between response (or SD) and PD when substantial change of effusion and or 
ascites is noted. 
If a patient is discontinued from the study before PD occurs and receives local or regional 
palliative radiotherapy during the follow-up period, the irradiation site must be omitted from the 
response assessment of the patient; however, if the site is observed to demonstrate disease 
progression, this case should be judged as PD. 


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For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at 
the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected.
8.2.1.2.
Objective Response Assessment
Assessments will be based on the definitions provided in Table 13 and Table 14.
Table 13:
Time Point Response for Patients with Target (±Non-target) Disease
Target
Lesions
Non-Target 
Lesions
New 
Lesions
Objective 
Response
CR
CR
No
CR
CR
Non-CR/Non-PD or Not all evaluated
No
PR
PR
Non-PD or Not all evaluated
No
PR
SD
Non-PD or Not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any 
Yes or No 
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Abbreviations: CR=complete response; NE=not evaluable; PD=progressive disease; PR=partial response; 
SD=stable disease
Table 14:
Time Point Response for Patients with Only Non-target Disease
Non-Target Lesions
New Lesions
Objective Response
CR 
No 
CR 
Non-CR/Non-PD 
No 
SD 
Not all evaluated 
No 
NE
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Abbreviations: CR=complete response; NE=not evaluable; PD=progressive disease; PR=partial response; 
SD=stable disease


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9.
SAFETY EVALUATIONS
9.1.
Adverse Events
9.1.1.
Definitions of Adverse Events
An AE is any untoward medical occurrence in a clinical study patient and does not necessarily 
have a causal relationship with the study drug. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a study drug, whether or not related to the study drug. This includes any 
occurrence that is new in onset or aggravated in severity or frequency from the baseline 
condition, or abnormal results of diagnostic procedures, including laboratory test abnormalities.
All AEs will be collected from the time the main ICF is signed through 30 days after the last 
dose of any study therapy (safety follow-up) or until the start of new antitumor therapy, 
whichever is earlier.  For all AEs that occur between signing the pre-screening consent and main 
study ICF, there is no need to record those that are unrelated unless it is mandatory by local 
regulations. All AEs will be documented in the eCRF.  Any untoward medical event that occurs 
after the safety follow-up is not considered an AE, unless the Investigator considers that the AE 
is related to the study drug. Serious AEs related to study therapy will be collected through the 
survival follow-up.
All AEs will be documented in the eCRF. Documentation should include onset and 
resolution/stabilization dates, severity/grade, relationship to study drug, and outcome of the 
event.
Signs and symptoms of a pre-existing disease should not be considered an AE, but should rather 
be considered baseline signs and symptoms. Clinically significant worsening of pre-existing 
signs and symptoms is considered an AE.
For definitions and reporting of pregnancies, overdoses, and medication errors, refer to 
Section 9.4.1, Section 9.4.2, and Section 9.4.3, respectively.
9.1.2.
Reporting of Adverse Events
9.1.2.1.
Terms of Reported Adverse Events
All AEs will be documented in the eCRF according to the eCRF Completion Guidelines. 
Documentation should include onset and resolution/stabilization dates, severity/grade, 
relationship to study drug, and outcome of the event. However, all SAEs must be reported on an
SAE form as per the SAE form completion guidelines, as well as in the eCRF.
When a diagnosis for the reported signs or symptoms is known, the Investigator should report the 
diagnosis, not the symptoms or signs, as the AE(s).
AEs can be spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a patient. In order to prevent reporting bias, patients should not be questioned 
regarding the specific occurrence of one or more AEs.


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9.1.2.2.
Severity of Adverse Events
The NCI-CTCAE Version 5.0 will be used to grade the severity of AEs.
9.1.2.3.
Causal Relationship with Study Drug
The causal relationship between an AE and the study drug will be assessed using the following 
2-point scale, taking into account the patient’s condition, medical history, concomitant 
medications, and the temporal relationship between study drug administration and onset of the 
AE.
An AE is considered to be “Related” if the event follows a reasonable temporal sequence 
from administration of study drug and there is a reasonable possibility that at least one 
of the following conditions is true:

A positive dechallenge: This means that the event improves or resolves after the drug 
is stopped (temporarily or permanently).

A positive rechallenge: This means that the event reappears after the drug is restarted.

The event cannot be reasonably explained by the patient’s clinical state and/or other 
therapies administered.

A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure (eg, angioedema, Stevens-Johnson syndrome).
An AE is considered to be “Not related” if there is no reasonable possibility that:

The event occurred prior to study drug administration.

There is no reasonable possibility that the study drug caused the event. 

The event does not follow a reasonable temporal sequence from administration of 
study drug and could have been produced by a documented pre-existing condition, 
concomitant medication or patient’s clinical state. 
For the purposes of safety reporting, “no reasonable possibility” means there is no evidence to 
suggest a causal relationship between the study drug and the AE.
9.1.2.4.
Outcome of Adverse Events
Record the outcome of AEs as follows:
Resolved
Not resolved
Fatal
9.1.2.5.
Follow-up of Adverse Events
Any ongoing AEs should be followed until the earliest occurrence of one of the following:

The AE has resolved or stabilized

Completion of Safety Follow-up visit


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
Start of new antitumor therapy

Withdrawal of consent

Death

Other (eg, transfer to another hospital)
9.2.
Laboratory Assessments
9.2.1.
Reporting and Evaluation of Laboratory Test Results
All laboratory results must be reviewed by the Investigator. A new laboratory or instrumental 
abnormality that has a clinical impact on a patient (including eg, resulting in study drug dose 
reduction, treatment delay, treatment discontinuation or requirement of intervention) is 
considered an AE, unless it is considered part of clinical manifestations to a clinical diagnosis 
that is already reported as an AE.
All laboratory values that are out of the normal range are to be evaluated for their clinical impact
before exposing the patient to the next dose of futibatinib.
The NCI-CTCAE Version 5.0 will be used to grade the severity of laboratory data.
9.2.2.
Repeat Testing
Evaluation of any clinically significant laboratory test will be repeated, as clinically indicated, 
until the value returns to the baseline level or clinically stabilizes, or until another treatment is 
given.
9.3.
Serious Adverse Events
9.3.1.
Definitions of Serious Adverse Events
A SAE is any untoward medical occurrence that at any dose:

Results in death;

Is life-threatening;
The term "life-threatening" in the definition of "serious" refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event 
which hypothetically might have caused death if it were more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization to treat 
the AE. 
The following are not considered hospitalizations for the purposes of assessing 
seriousness:

Emergency room visits < 24 hours;

Hospitalizations for preplanned procedures;

Hospitalization for study-related treatment and procedures.


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
Results in persistent or significant disability/incapacity, where disability is defined as 
a substantial disruption of a person’s ability to conduct normal life functions, either 
reported or defined as per clinical judgment.

Is a congenital anomaly/birth defect (if exposure to product just before conception or 
during pregnancy resulted in an adverse outcome in the child).

Is any other important medical event that based upon appropriate medical judgement 
may jeopardize the patient or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the definitions above (eg, may not result in death, 
be life-threatening, or require hospitalization). Examples of such events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, and blood dyscrasias, or convulsions that do not result in inpatient 
hospitalization, or development of drug dependency or drug abuse.
9.3.2.
Reporting of Serious Adverse Events (within 24 hours)
All SAEs occurring from the time the ICF is signed through the Safety Follow-up Period 
(30 days after the last dose of study drug or discontinuation of the Safety Follow-up Period, 
whichever is earlier) must be reported to Sponsor’s Pharmacovigilance group or its designee 
within 24 hours from the time the Investigator first becomes aware of the SAE. 
Comprehensive information available at the time of initial reporting (including narrative 
description, medical history, and concomitant medications) needs to be provided with careful 
consideration regarding causality and serious criterion. The SAE reporting process and contact 
information are provided in supplement guidelines.
After the initial SAE notification to the Sponsor’s Pharmacovigilance group or its designee, all 
follow-up SAE information will be submitted each time they become available (for example, 
clinical diagnosis, outcome, causality assessment, results of specific investigations) on a follow 
up SAE form.
The investigator also must submit further information if it is required by the Sponsor or the 
director of the study site or an institutional review board (IRB)/independent ethics committee 
(IEC). Every SAE should be followed until it has resolved, stabilized, or returned to baseline.
9.3.3.
Reporting of Deaths (within 24 hours)
All deaths occurring from the time the ICF is signed through the Safety Follow-up Period (30 
days after the last dose of study drug or discontinuation, whichever is earlier) must be reported 
within 24 hours from the time the Investigator first becomes aware of the death. The primary 
cause of the death should be reported as the SAE term, if available.
When reporting a death, site personnel will be required to identify which of the following best 
describes the category for cause of death:

Toxicity caused by study drug

Radiographic disease progression

Clinical disease progression

Other causes


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9.4.
Other Safety Information
9.4.1.
Pregnancy
If a patient becomes pregnant while on study treatment or within 30 days following the last dose 
of study therapy, the study treatment must be immediately discontinued if ongoing. Pregnancy 
information in a female patient (or for the female partner of a male patient) should be reported as 
soon as possible from the time the Investigator first becomes aware of a pregnancy or its 
outcome. This should be performed by completing a paper Pregnancy Form and faxing or 
e-mailing it to Sponsor’s Pharmacovigilance group or its designee.
New and/or corrected information regarding the pregnancy obtained after submitting the 
Pregnancy Form must be submitted on an updated Pregnancy Form to the Sponsor’s
Pharmacovigilance group or its designee. Pregnancies must be followed to outcome by the 
Investigator, even after study completion.
If the outcome of the pregnancy is a stillbirth, congenital anomaly/birth defect, or a serious event 
in the mother, it should be reported as a SAE to the Sponsor’s Pharmacovigilance group or its 
designee. Live births will be followed up by the Investigator. Any information that may be 
associated with the study drug should be reported even after study completion.
9.4.2.
Overdose
An overdose for this clinical study is defined as taking or receiving an intentional or 
unintentional dose of futibatinib, gemcitabine, or cisplatin beyond the recommended dose for 
1 day or beyond the recommended total dose in each cycle.
An overdose of study therapy should be reported to the Sponsor’s Pharmacovigilance group or
its designee within 24 hours from the time the Investigator first becomes aware of the overdose, 
whether or not it was accidental or intentional, and whether or not the patient developed an AE 
(even if not fulfilling a seriousness criterion). 
There is no known antidote available in case of futibatinib overdose. Overdose should be 
managed with close monitoring and administration of prophylactic and symptomatic therapies to 
prevent or correct potential side effects.
9.4.3.
Medication Errors
A medication error is defined as any unintentional error in prescribing, dispensing, or 
administering the study drug while the study drug is in the control of the healthcare professional 
or patient.
The following types of medication errors, regardless of whether it is associated with an AE or 
SAE, should be reported to the Sponsor’s Pharmacovigilance or designee within 24 hours from 
the time the Investigator first becomes aware of its occurrence:

Medication errors with study medication or concomitant medication resulting in an AE

Medication errors with study medication resulting in an overdose

Incorrect route of study medication administration

Administration of the incorrect study medication


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Note: Medication errors with the study medication that result in the omission of an 
administration, an incorrect dose, or the administration of more than the prescribed dose (but 
does not meet the overdose criteria), will not be reported as a SAE, but will be identified through 
the recording of study drug accountability data in the eCRFs.


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10.
ANALYSES OF BIOMARKERS
10.1.1.
Objectives and Background
All biomarker assessments described in this section will be performed at the timepoints shown in 
the Schedule of Events (Table 1); methods of sample collection and preparation will be described 
in a separate Laboratory Manual.
The pharmacodynamic biomarker population will consist of all patients who received futibatinib 
or gemcitabine-cisplatin and have evaluable pharmacodynamic biomarker data. Detailed 
analytical procedures will be described in the SAP.
10.1.2.
Assessment of FGF/FGFR Aberrations in Blood
A blood sample will be collected to assess FGF/FGFR aberrations in circulating tumor DNA 
(ctDNA) prior to the first futibatinib administration on Day 1 of Cycle 1, and at the EOT visit or 
time of progression. In addition to assessing ctDNA as a pharmacodynamic biomarker, samples, 
or a set of samples, will be used to verify its utility as an alternative to tumor tissues for the 
potential companion diagnostic. Samples will be collected and stored, as per the Laboratory 
Manual, and analyzed in batches.
10.1.3.
Measurement of Tumor Marker CA19-9
Blood samples will be collected for measurement of circulating tumor marker CA19-9 during 
screening and in conjunction with tumor assessments/scans throughout the study.
10.1.4.
Tumor Samples
Archival or fresh tumor biopsy samples will be collected to confirm FGFR gene status at the 
Sponsor’s designated central laboratories. The remaining samples may be stored at the Sponsor’s 
designated central laboratories for up to 10 years after study completion for future testing.


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11.
STATISTICS
The statistical analysis methods will be documented in detail in the SAP.
11.1.
Estimation of Sample Size
Assuming median PFS of 10 months in the Experimental Arm and 6 months in the Control Arm, 
a total of 162 PFS events will be needed to detect a hazard ratio of 0.60 with 90% power at a 2-
sided alpha level of 0.05. 
Considering an enrollment rate of 4 patients per month in the first 10 months and 8 patients per 
month from Month 11 to Month 32, approximately 216 patients with iCCA harboring centrally 
confirmed FGFR2 gene rearrangements are planned to be randomized in 1:1 ratio to the 
Experimental Arm and Control Arm. It is estimated that 162 PFS events would occur 
approximately 40 months (32-month enrollment period and 8-month follow up period) after the 
start of randomization. These calculations further assume a 10% loss to follow-up annually.
11.2.
Planned Interim Analysis
No interim analysis of efficacy is planned. Interim analyses for safety monitoring will occur 
when approximately 25%, 50%, and 75% of the planned total number of patients have been 
treated. A DMC will meet to assess the cumulative safety data and recommend study 
continuation, discontinuation, or study modification. A description of the roles and 
responsibilities of the DMC and details of the review processes are provided in a separate DMC 
charter.
11.3.
Analysis Populations
The analysis study populations in this study are defined in Table 15.
Table 15:
Analysis Populations
Analysis Population
Definition
All Enrolled Population
All patients who sign a main study ICF (including screen failures).
All Randomized Patients / Full 
Analysis Dataset
All patients randomized to any treatment group in the study. This is the 
primary population for analyses of demography, protocol deviations, 
baseline characteristics and efficacy.
All Treated Population / Safety 
Analysis Dataset
All patients who received at least one dose of study drug. This is the 
primary population for dosing and safety analyses.
Per-Protocol Patients / Per-
Protocol Analysis Dataset
All randomized patients who have no relevant protocol deviations. For 
patients who have a relevant deviation during the study, data collected 
before the point of deviation will be included in the analysis preformed for 
this population. This is the population for efficacy sensitivity analysis.
Pharmacodynamic / Biomarker 
Evaluable Set
All patients in the All Treated Population who have evaluable 
pharmacodynamic/biomarker data for analyses.
Pharmacokinetic Evaluable Set
All patients who received futibatinib and have evaluable plasma data for 
analysis.
Abbreviations: ICF=informed consent form


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The treatment group As Randomized will be retrieved from the IXRS system. The treatment 
group As Treated will be the same as the arm randomized by IXRS. However, if a patient 
received the incorrect drug for the entire period of treatment, the patient’s treatment group will 
be defined as the incorrect drug the subject actually received.
11.4.
Criteria for Handling of Patient Data
The criteria for handling of patient data are provided in the Statistical Analysis Plan (SAP).
11.5.
Statistical Analyses
11.5.1.
Demographic and Baseline Characteristics
The number of patients in each study population and the reasons for exclusion will be 
summarized. In each analysis population, the distribution of main patient background, disease 
characteristics, and baseline laboratory values and clinical findings will be summarized. These 
patient attributes will be summarized using frequency distribution or descriptive statistics as 
appropriate.
11.5.2.
Efficacy Analyses
A description of each efficacy endpoint is provided in Table 16. Response assessments will be 
made based on RECIST 1.1; the primary evaluation of endpoints will be based on ICR except as 
otherwise noted.  Efficacy analyses will be performed in all randomized population by As 
Randomized treatment group unless otherwise specified. See the SAP for more detailed 
information on the efficacy analyses.
Table 16:
Efficacy Endpoint Definitions
Endpoint
Definition
PFS
Time from date of randomization to the date of documentation of disease 
progression, or date of death, whichever occurs first
ORR
Proportion of patients experiencing a best overall response of PR or CR 
(per RECIST 1.1).
DCR
Proportion of patients experiencing a best overall response of SD, PR, or 
CR (per RECIST 1.1).
OS
Measured from the date of randomization until the date of death due to 
any cause.
DOR
Time from the first documentation of response to the first documentation 
of objective tumor progression or death due to any cause, whichever 
occurs first
PFS2
Time from randomization to subsequent disease progression per ICR 
after initiation of next-line therapy or death from any cause (whichever 
occurs first).  
Abbreviations: CR=complete response; DCR=disease control rate; DOR=duration of response; 
ICR=independent central review; ORR=objective response rate; OS=overall survival; 
PFS=progression-free survival; PFS2=progression-free survival on next-line therapy; PR=partial 
response; RECIST=Response Evaluation Criteria in Solid Tumors; SD=stable disease.


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11.5.2.1.
Primary Efficacy Analysis
Comparison of PFS (per ICR) between arms will be performed when at least 162 PFS events 
have been observed. The comparison will test the null hypothesis:  
H0:  PFS in experimental arm = PFS in control arm,
against the alternative hypothesis: 
H1:  PFS in experimental arm ӆ PFS in control arm.
The difference in PFS will be compared by stratified log-rank test at 2-sided α=0.05. The tests 
will be by the stratification factors used in the randomization. The hazard ratio and the 
corresponding 95% CIs will be estimated using the Cox regression model stratified by the same 
stratification factors.  The median PFS, and the PFS rates at 6, 12 and 18 months, will be 
calculated using the Kaplan-Meier (KM) product-limit estimates for each treatment arm, and 
presented with 2-sided 95% CIs. The KM estimates of PFS will be plotted over time. The PFS 
censoring rules and definition of progression date will follow the Food and Drug Administration 
(FDA) “Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics (2007).”
11.5.2.2.
Secondary Efficacy Analyses
The fixed sequence procedure will be used to control the overall type I error rate of analyses for 
the secondary endpoints at α = 0.05 (2-sided) after the superiority for primary efficacy endpoint, 
PFS, is declared. The order of testing for secondary endpoints will follow the order that they are 
presented below.
In the ordered sequence, each secondary endpoint will be tested at the 5% level until the first 
nonsignificant outcome occurs. If the first nonsignificant outcome occurs, then the results of the 
analysis of the subsequent endpoints will be presented for descriptive purposes only. 
1. ORR
ORR will be calculated for each treatment arm with exact 95% CIs using the method of Clopper 
and Pearson. The analysis of ORR for comparison between treatment arms will be performed 
using the Cochran-Mantel-Haenszel (CMH) test stratified by the stratification factors used in the 
randomization. 
2. DCR
DCR will be calculated for each treatment arm with exact 95% CIs using the method of Clopper 
and Pearson. The analysis of DCR for comparison between treatment arms will be performed 
using the CMH test stratified by the stratification factors used in the randomization. 
3. OS
OS will be evaluated using KM estimates and the comparison in OS between the two arms will 
use a stratified log-rank test with the randomization stratification factors. The corresponding 
estimate of the hazard ratio calculated from Cox proportional hazard model with treatment group 
as a factor and stratified by the randomization stratification factors, will be presented with a 
2-sided 95% CI. 
No multiplicity adjustments will be used for other secondary efficacy endpoints.


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11.5.2.3.
Exploratory Efficacy Analyses
Analysis of exploratory endpoints will be discussed in a separate SAP.
11.5.3.
Safety Analyses
The safety analysis will be performed using the All-Treated Population, by As-Treated group.
AEs will be coded according to the Medical Dictionary for Regulatory Activities terminology 
and the severity of the toxicities will be graded according to the NCI-CTCAE (Version 5.0), 
where applicable.
Concomitant medications will be coded according to the World Health Organization Drug 
Dictionary for Concomitant Medication.
All AEs reported from the date of first dose of study therapy through 30 days after the last dose 
of study therapy will be summarized by System Organ Class, Preferred Term, toxicity/severity 
grade, and causal relationship to futibatinib. In addition, separate summaries of SAEs, deaths, 
and Grade 3 or 4 AEs will be presented.
By-patient listings of preferred AE terms, grade, onset date, action, outcome of AE, and causality 
will be provided. Hematological and chemistry laboratory parameters will be graded according 
to the NCI-CTCAE (Version 5.0) where applicable. The worst severity grade, time to maximum 
Grade 3 or 4 value, and time to resolution (return to baseline grade or below) will be 
summarized. Safety data (AEs and clinical laboratory results) will be summarized descriptively. 
A list of 12-lead ECG findings will be presented by patient.
11.5.4.
Pharmacodynamic/Biomarker Analysis
The exploratory pharmacodynamic/biomarker endpoints are described in Section 10. Analyses 
will be performed using all patients in the All Treated set who have evaluable data for 
pharmacodynamic/biomarker analyses. Pharmacodynamic and biomarker data will be 
summarized descriptively, and the exploratory analyses of the relationship between biomarker
and PK, efficacy or toxicity will be performed.
11.5.5.
Pharmacokinetic Analysis
The concentration vs. time data obtained in this study will be combined with data from other 
studies in the clinical development program to develop a Pop PK model. This model will be used 
to evaluate the effects of intrinsic and extrinsic covariates on the PK of futibatinib and to 
estimate measures of individual exposure (such as steady-state peak, trough and area under the 
plasma drug concentration-time curve). Model estimated exposures will be used for exposure-
response analyses of selected efficacy and safety endpoints. The results of Pop PK and exposure 
response analyses will be reported separately.
11.5.6.
PRO Analyses
A separate pre-specified PRO analysis following FDA and European Medicines Agency PRO 
Guidelines will be performed and detailed in a separate SAP and PRO report. Scoring of PRO 
instruments and derivation of utility for health economic analysis will also be described in a 
separate analysis document.


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12.
ADMINISTRATIVE CONSIDERATIONS
12.1.
Protocol Compliance
The Investigator will agree to comply with the protocol by signing the Declaration of 
Investigator . In the event that the Investigator is unable to continue the study and another 
suitable person is designated as the Investigator, the Sponsor must be notified in advance 
(30 days prior notice is requested). The new Investigator must accept the responsibility in writing 
and be approved by the Sponsor and the IRB/IEC.
12.2.
Protocol Deviations
The Investigator may implement a deviation from, or a change in, the protocol to eliminate an 
immediate hazard(s) to study patients without prior IRB/IEC approval/favorable opinion. As 
soon as possible, the implemented deviation or change and the reasons for it should be 
documented and submitted to the IRB/IEC and Sponsor.
The Investigator is to record any deviation from the protocol in the source documents, describing 
this departure and the circumstances under which it was required.
12.3.
Protocol Amendments
All protocol amendments must be issued by the Sponsor, and signed and dated by the 
Investigator. Documentation of amendment approval by the Investigator and IRB/IEC must be 
provided to the Sponsor.
If the changes involve only logistic or administrative aspects of the study, these changes will be 
notified in writing by the Sponsor.
12.4.
Study Termination
If the Sponsor and/or the Investigator should discover conditions arising during the study that 
indicate it should be terminated, an appropriate schedule for termination will be instituted. The 
Sponsor also reserves the right to discontinue this study for administrative or discretionary
reasons at any time.
12.5.
Case Report Forms
The Investigator should complete all eCRFs in accordance with the eCRF Completion 
Guidelines. Data in the eCRFs shall be consistent with source documents.
In this study, the Investigator and assigned personnel will be given access to the EDC system; 
passwords should not be shared. Data managers and Monitors will have the right to access the 
EDC system for performing source data verification. Data managers will have the right to access 
the EDC system as appropriate for their roles. Other relevant personnel may receive access to 
view EDC data.
An eCRF should be completed for each screened and enrolled patient (patients who are pre-
screened only do not require an eCRF).


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After verification of the eCRFs, the Sponsor or designee may query discrepancies or request 
additional information. The Investigator, or assigned personnel, should verify the data and 
correct as necessary prior to approval of the eCRFs.
12.6.
Access to Source Data/Documents
The Investigator or designated study personnel must make all study-related records available for 
study-related monitoring, audit, IRB/IEC review, and regulatory inspection.
12.6.1.
Source Data/Documents
Source documents are original documents, data, and records such as hospital records, clinical and 
office charts, laboratory notes, memoranda, patient’s evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, microfilm or magnetic media, X-ray, patient 
files, and records kept at the pharmacy, laboratories, and medical-technical departments involved 
in the study.
Specific details regarding source documents and source data to be recorded directly on the 
eCRFs for the study should be identified with the Investigator prior to and during the study.
12.6.2.
Access to Source Data
The Sponsor’s study monitor, or other representatives, should verify the entries in the eCRF and 
source documents to confirm the completeness and accuracy of the data. If there are any 
discrepancies between the entries in eCRFs and source documents, the monitor will query the 
site.
12.7.
Data Handling
All study information is confidential. The patient’s and Investigator’s personal data which may 
be included in the Sponsor’s database shall be treated in compliance with all applicable laws and 
regulations.
When processing and archiving personal data pertaining to the Investigator and to the patients, 
the Sponsor or its representatives shall take all appropriate measures to safeguard and prevent 
access to this data by any unauthorized third party.
12.8.
Responsibilities of Recordkeeping
12.8.1.
Investigator and Study Site
The Investigator and the study site are responsible for the retention of all study documents 
according to institutional policies, local laws, and International Conference on Harmonisation
(ICH) E6 Guideline.
The Investigator and the study site agree to inform the Sponsor in writing of the intention to 
remove or destroy any study-related records. Prior to contacting the Sponsor, the Investigator
and study site must ensure that the applicable regulatory requirements have been satisfied. The 
Sponsor will evaluate the requests from the Investigator and the study site and will provide 
authorization for destruction of such records in writing.


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In the event that all retention of records requirements have been fulfilled, but the Sponsor
requests that the Investigator and study site maintain the records for a longer period of time, 
additional arrangements will be made.
12.8.2.
Sponsor
The Sponsor must retain all Sponsor-specific essential documents in conformance with the 
applicable regulatory requirements of the countries where the product is approved, and where the 
Sponsor intends to apply for approvals.
If the Sponsor discontinues the clinical development of the study drug, the Sponsor must 
maintain all Sponsor-specific essential documents in conformance with the applicable regulatory 
requirements.
12.9.
Monitoring
The Sponsor and designee will be allowed to conduct site visits to the investigation facilities for 
the purpose of monitoring any aspect of the study. The Investigator agrees to allow the monitor 
to inspect the drug storage area, study drug stocks, drug accountability records, patient charts and 
study source documents, and other records relative to study conduct.
12.10.
Financial Disclosure
Financial disclosure for Investigators will be obtained and record keeping of financial records
will be in accordance with local regulatory requirements. Investigators will provide the Sponsor
with sufficient, accurate financial information upon the Sponsor’s request.
12.11.
Compensation for Health Injury
The clinical study is insured according to applicable regulatory requirements. A copy of the 
Compensation Policy Document will be provided to the study site by the Sponsor. In the case of 
a compensation claim, excluding claims that have arisen due to medical malpractice or 
negligence, the legally responsible person is clearly identified. Sponsor should address the 
policies and payment procedures of compensation for the event of study-related injuries as the 
Compensation Policy Document. When patients receive compensation, the policies and payment 
procedure of compensation should comply with the Compensation Policy Document.
12.12.
Study Administrative Structure
The study organization details will be maintained in a supplement.


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13.
QUALITY CONTROL AND QUALITY ASSURANCE
The Sponsor will perform quality control and quality assurance procedures in accordance with 
the Sponsor's standard operating procedures (SOPs) to ensure the quality of the clinical study.
13.1.
Quality Control
The Sponsor is responsible for controlling the quality of the clinical study according to the SOPs 
regarding, for example, study operation, monitoring, data collection and management, statistical
analysis, and handling of safety information to verify that the study-related activities have been 
fulfilled.
13.2.
Quality Assurance
To ensure compliance with Good Clinical Practice (GCP) and all applicable regulatory 
requirements, the Sponsor may conduct a quality assurance audit. Authorized representatives of 
the Sponsor, a regulatory authority, or an IRB/IEC may visit the site to perform audits or 
inspections, including source data verification. The Investigator will make every effort to help 
with the performance of the audits and inspections, giving access to all necessary facilities, data 
and documents pertaining to the clinical study.
The purpose of an audit or inspection is to systematically and independently examine all study-
related activities and documents to ensure that these activities were conducted, and data were 
recorded, analyzed, and accurately reported according to the protocol, ICH GCP E6 guidelines, 
and any applicable local regulatory requirements. The Investigator should contact the Sponsor
immediately if contacted by a regulatory agency regarding an inspection.
Any results arising from such inspections will be immediately communicated by the Investigator
to the Sponsor. The Investigator and the Sponsor will take corrective actions for all findings and 
observations found during audits and/or inspections. The auditors and inspectors will not 
disclose private information unless required by law.


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14.
ETHICS
14.1.
Ethical Conduct of the Study
It is mandatory that all considerations regarding the protection of patients be carried out in 
accordance with the latest versions of the protocol, ICH GCP Guidelines, the ethical principles 
that have their origin in the Declaration of Helsinki, and all applicable regulatory requirements.
14.2.
Written Informed Consent
The ICF(s) must be approved by the IRB/IEC before a patient signs consent for any study-related 
activity. It must be in a language that the patient can read and understand. The ICF process 
should be in accordance with principles that originated in the Declaration of Helsinki, current 
ICH and GCP guidelines, and applicable regulatory requirements. Each patient (or a legally 
acceptable representative) must give written consent according to local requirements. 
The Investigator(s) must maintain the original, signed ICF. A copy of the signed ICF must be 
given to the patient.
There must be documentation in each patient’s case history/medical record that informed consent 
was obtained prior to any study procedure being performed. Patients must be re-consented to the 
most current version of the ICF(s) during their participation in the study.
14.3.
Institutional Review Board/Independent Ethics Committee
The study must be approved by an appropriately constituted IRB/IEC, as required in the 
applicable local regulation such as ICH E6 Guidelines (Part 3), Code of Federal Regulations
Title 21, part 56, and Ordinance of the Ministry of Health and Welfare No. 28, Chapter IV, 
Section 1 before the study is initiated. At the end of the study, the Investigator will notify the 
IRB/IEC of the conclusion of the study and its outcome.


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15.
PUBLICATION POLICY
15.1.
Publication Policy
The Sponsor maintains the right to use the results of this study in their original form and/or in a 
global report for submission to governmental and regulatory authorities of any country or region.
The results of the study may be presented during scientific symposia and/or published in a 
scientific journal only after review by the Sponsor in accordance with the guidelines set forth in 
the applicable publication or financial agreement.
The Investigators and the Sponsor will discuss and determine the presenter(s) or author(s) and 
timing of any presentation or publication related to this study and/or its results. Authorship will 
be determined by mutual agreement and in line with International Committee of Medical Journal 
Editors authorship requirements.
15.2.
Secondary Use of Data
The Sponsor maintains the right to secondary use of data in this study.
Secondary use of data describes the use of data from this study for other study/studies for 
purposes including, but not limited to, drug development and/or academic research. Secondary 
use of data also includes external offerings of study data to domestic and/or foreign 
organization(s) and researcher(s), on a case by case basis.


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16.
REFERENCES
Ang C.  Role of the fibroblast growth factor receptor axis in cholangiocarcinoma.  J Gastroenterol 
Hepatol.  2015;30(7):1116-1122.
Arai Y, Totoki Y, Hosoda F, Shirota T, Hama N, Nakamura H, et al.  Fibroblast growth factor receptor 2 
tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma.  Hepatology. 
2014;59(4):1427-1434.
Benson AB, Ajani JA, Catalano RB, Engelking C, Kornblau SM, Martenson JA, et al.  Recommended 
guidelines for the treatment of cancer treatment-induced diarrhea.  J Clin Oncol. 2004;22:2918-2926.
Borad MJ, Gores GJ, Roberts LR. Fibroblast growth factor receptor 2 fusions as a target for treating 
cholangiocarcinoma. Curr Opin Gastroenterol. 2015;31(3), 264–268.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al.  New response evaluation 
criteria in solid tumours: revised RECIST guideline (version 1.1).  Eur J Cancer. 2009;45:228-247.
Goral V. Cholangiocarcinoma: new insights.  Asian Pac J Cancer Prev.  2017;18(6):1469-1473.
Goyal L, Saha SK, Liu LY, Siravegna G, Leshchiner I, Ahronian LG, et al.  Polyclonal Secondary 
FGFR2 Mutations Drive Acquired Resistance to FGFR Inhibition in Patients with FGFR2 Fusion-
Positive Cholangiocarcinoma.  Cancer Discov. 2017;7(3):252-263.
Hesketh PJ, Kris MG, Basch E, Bohlke K, Barbour SY, Clark-Snow RA, et al.  Antiemetics: American 
Society of Clinical Oncology Clinical Practice Guideline update.  J Clin Oncol.  2017;35:3240-3261.
Khan SA, Davidson BR, Goldin R, Pereira SP, Rosenberg WMC, Taylor-Robinson SD, et al.  Guidelines 
for the diagnosis and treatment of cholangiocarcinoma: consensus document.  Gut.  2002;51(Suppl 
VI):vi1-vi9.
Khan SA, Toledano MB, Taylor-Robinson SD.  Epidemiology, risk factors, and pathogenesis of 
cholangiocarcinoma.  HPB.  2008;10(2):77-82.
Lamarca A, Hubner RA, Ryder WD, Valle JW.  Second-line chemotherapy in advanced biliary cancer:  a 
systematic review. Ann Oncol.  2014;25:2328-2338.  
Oken MM, Creech, RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655.
Park JO, Oh D-Y, Hsu C, Chen J-S, Chen L-T, Orlando M, et al.  Gemcitabine plus cisplatin for advanced 
biliary tract cancer: a systematic review.  Cancer Res Treat.  2015;47(3):343-361.
Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, et al.  Recommendations for the use 
of WBC growth factors: American Society of Clinical Oncology Clinical Practice Guideline Update.  
J Clin Oncol. 2015;33:3199-3212.
Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, et al; ABC-02 Trial 
Investigators.  Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer.  N Engl J Med.  
2010;362(14):1273-1281.


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APPENDIX A. ECOG PERFORMANCE STATUS
GRADE 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, eg, light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead
From: Oken et al. 1982


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APPENDIX B. DIETARY GUIDELINES FOR TREATMENT OF 
HYPERPHOSPHATEMIA
The best way to limit phosphorus in the diet is to limit foods highest in phosphorus, including: 

Fast food, convenience foods, and processed foods, which may be full of phosphorus 
additives 

Beverages that contain phosphorus (look for the letters "phos" in the ingredient list) 
Also, look for any ingredient that contains "phos" in the term such as: 

Calcium phosphate 

Disodium phosphate 

Phosphoric acid 

Monopotassium phosphate 

Sodium acid pyrophosphate 

Sodium tripolyphosphate 
Listing of Some Lower and Higher Phosphorus Foods 
Higher Phosphorus Foods 
Lower Phosphorus Foods 
Milk, pudding, yogurt, soy milk, nondairy creamers 
and enriched rice milk 
Unenriched rice milk 
Processed cheeses and cheese spreads 
A small amount of Brie or Swiss cheese 
Hard cheeses, ricotta or cottage cheese, fat-free cream 
cheese 
Regular or low-fat cream cheese 
Ice cream or frozen yogurt 
Sherbet, sorbet or frozen fruit pops 
Soups made with higher phosphorus ingredients (milk, 
dried peas, beans, lentils) 
Soups made with lower phosphorus ingredients (broth-
or water-based with other lower phosphorus ingredients) 
Whole grains, including whole-grain breads, crackers, 
cereal, rice and pasta 
White bread, crackers, cereals, rice and pasta 
Quick breads, biscuits, cornbread, muffins, pancakes or 
waffles 
White dinner rolls, bread, bagels or English muffins 
Dried peas (split, black-eyed), beans (black, garbanzo, 
lima, kidney, navy, pinto) or lentils 
Green peas, green beans or wax beans 
Processed meats (ie, bologna, ham and hot dogs), and 
meat, poultry or seafood with "phos" in the ingredients 
All-natural lean beef, pork, lamb, poultry, seafood or 
other fish without "phos" in the ingredients 
Organ meats, walleye, pollock or sardines 
All-natural lean beef, pork, lamb, poultry, seafood or 
other fish without "phos" in the ingredients 
Nuts and seeds 
Popcorn or pretzels 
Peanut butter and other nut butters 
Jam, jelly or honey 
Chocolate, including chocolate drinks 
Jelly beans, hard candy, fruit snacks or gumdrops 
Colas and pepper-type sodas, some flavored waters, 
bottled teas, some drink mixes (any with "phos" in the 
ingredients) 
Lemon-lime soda, ginger ale, root beer, plain water or 
some drink mixes (any without "phos" in the 
ingredients) 
Although a food or drink may be low in phosphorus, limitation of portion size and the number of servings you eat 
or drink each day may still be recommended. 
From: Rachael Majorowicz, R.D.N., L.D. (Feb, 2016). Why is a low-phosphorus diet useful in managing kidney disease? What 
foods contain phosphorus? https://www.mayoclinic.org/food-and-nutrition/expert-answers/faq-20058408.


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APPENDIX C. CLASSIFICATION OF SUBSTRATES, INHIBITORS, AND 
INDUCERS OF CYP ENZYMES AND TRANSPORTERS
The classification below is based on the FDA Draft Guidance for Industry, Clinical Drug 
Interaction Studies —Study Design, Data Analysis, and Clinical Implications, October 2017. 
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
UCM292362.pdf)
CYP3A inhibitors and inducers: CYP3A is involved in the metabolism of futibatinib. CYP3A 
inhibitors and inducers may alter the concentration and activity of futibatinib.
CYP3A substrates: Futibatinib is a potential time-dependent inhibitor of CYP3A. Futibatinib 
may increase the concentration and activity of CYP3A substrates.
P-gp substrates and BCRP substrates: Futibatinib is a potential inhibitor of P-gp and BCRP. 
Futibatinib may alter the concentration and activity of P-gp and BCRP substrates.
P-gp inhibitors and BCRP inhibitors: Futibatinib is a substrate of P-gp and BCRP. P-gp and 
BCRP inhibitors may alter the concentration and activity of futibatinib.
Examples of CYP3A Inhibitors
CYP Enzyme
Strong Inhibitors:1 ≥ 5-fold 
increase in AUC or ≥ 80% 
decrease in CL
Moderate Inhibitors:2 ≥ 2 but < 
5fold increase in AUC or 50 –
80% decrease in CL
CYP3A
Boceprevir, clarithromycin, 
cobicistat, conivaptan, danoprevir 
and ritonavir, diltiazem, elvitegravir 
and ritonavir, grapefruit juice3, 
indinavir and ritonavir, idelalisib, 
itraconazole, ketoconazole, 
lopinavir and ritonavir, nefazodone, 
nelfinavir, paritaprevir and ritonavir 
and (ombitasvir and/or dasabuvir), 
posaconazole, ritonavir, saquinavir 
and ritonavir, telaprevir, tipranavir 
and ritonavir, troleandomycin, 
voriconazole
Aprepitant, cimetidine, 
ciprofloxacin, clotrimazole, 
crizotinib, cyclosporine, 
dronedarone, erythromycin, 
fluconazole, fluvoxamine, imatinib, 
tofisopam, verapamil
1 A strong inhibitor for a specific CYP is defined as an inhibitor that increases the area under 
concentration-time curve (AUC) of a sensitive index substrate for that CYP by equal to or more 
than 5-fold.
2 A moderate inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a 
sensitive index substrate for that CYP by less than 5-fold but equal to or more than 2-fold.
3 The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and 
preparationdependent. Studies have shown that it can be classified as a "strong CYP3A 
inhibitor" when a certain preparation was used (eg, high dose, double strength) or as a "moderate 
CYP3A inhibitor" when another preparation was used (eg, low dose, single strength).
Abbreviations: AUC = area under the concentration-time curve; CL = oral clearance.


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Example of CYP3A Inducers
CYP Enzyme
Strong inducers1 or ≥ 80% 
decrease in AUC
Moderate Inducers2 50 –
80% decrease in AUC
CYP3A
Carbamazepine, enzalutamide, 
mitotane, phenytoin, rifampin, 
St. John’s wort3
Bosentan, efavirenz, 
etravirine, modafinil
1 A strong inducer is a drug that decreases the AUC of sensitive index substrates of a given 
metabolic pathway by ≥80%.
2 A moderate inducer is a drug that decreases the AUC of sensitive index substrates of a given 
metabolic pathway by ≥50% to <80%.
3 The effect of St. John's wort varied widely and is preparation-dependent. 
Abbreviation: AUC = area under the concentration-time curve.
Example of CYP3A Substrates
CYP Enzymes
Sensitive Substrates1
Moderate Sensitive Substrates2
CYP3A
Alfentanil, avanafil, budesonide, 
buspirone, conivaptan, darifenacin, 
darunavir, dasatinib, dronedarone, 
ebastine, eletriptan, eplerenone, 
everolimus, felodipine, ibrutinib, 
indinavir, lomitapide, lovastatin, 
lurasidone, maraviroc, midazolam, 
naloxegol, nisoldipine, quetiapine, 
saquinavir, sildenafil, simvastatin, 
sirolimus, tacrolimus, ticagrelor, 
tipranavir, tolvaptan, triazolam, 
vardenafil
Alprazolam, aprepitant, atorvastatin, 
colchicine, eliglustat, pimozide, 
rilpivirine, rivaroxaban, tadalafil
1 Sensitive substrates are drugs that demonstrate an increase in area under the concentration-time 
curve (AUC) of ≥ 5-fold with strong index inhibitors of a given metabolic pathway in clinical 
drug-drug interaction studies.
2 Moderate sensitive substrates are drugs that demonstrate an increase in AUC of ≥ 2 to < 5fold 
with strong index inhibitors of a given metabolic pathway in clinical drug-drug interaction 
studies.


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Example of Inhibitors for P-gp and BCRP
Transporters
Gene
Inhibitor
P-gp1
ABCB1
Amiodarone, carvedilol, 
clarithromycin, dronedarone, 
itraconazole, lapatinib, lopinavir and 
ritonavir, propafenone, quinidine, 
ranolazine, ritonavir, saquinavir and 
ritonavir, telaprevir, tipranavir and 
ritonavir, verapamil
BCRP2
ABCG2
Curcumin, cyclosporine A, 
eltrombopag
1 P-gp: (1) AUC fold-increase of digoxin ≥2 with co-administration and (2) in vitro inhibitor.
2 BCRP: (1) AUC fold-increase of sulfasalazine ≥1.5 with co-administration and (2) in vitro 
inhibitor. Cyclosporine A and eltrombopag were also included, although the available DDI 
information was with rosuvastatin, where inhibition of both BCRP and OATPs may have 
contributed to the observed interaction.
Abbreviations: AUC = area under the concentration-time curve; BCRP = breast cancer resistance 
protein; P-gp = p-glycoprotein.
Example of Substrates for P-gp and BCRP
Transporters
Gene
Substrate
P-gp1
ABCB1
Dabigatran, digoxin, fexofenadine
BCRP2
ABCG2
Rosuvastatin, sulfasalazine
1 P-gp: (1) AUC fold-increase ≥2 with verapamil or quinidine co-administration and (2) in vitro 
transport by P-gp expression systems, but not extensively metabolized.
2 BCRP: (1) AUC fold-increase ≥2 with pharmacogenetic alteration of ABCG2 (421C>A) and 
(2) in vitro transport by BCRP expression systems.
Abbreviations: AUC = area under the concentration-time curve; BCRP = breast cancer resistance 
protein; P-gp = p-glycoprotein.


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APPENDIX D. SUPPLEMENTAL REQUIREMENTS FOR JAPAN
1. Sample Size for Japan
Expected sample size for Japan: approximately 22 patients
2. Clinical Study Period
Planned clinical study schedule: From December 2019 to April 2023
3. Effective Contraception During Study
In Section 5.5 of this protocol, the following drugs or devices for contraception (marked with 
asterisks [*]) are not approved in Japan:

combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation with an oral, intravaginal* or transdermal* form

progestogen-only hormonal contraception associated with inhibition of ovulation with 
an oral, injectable or implantable* form

In case that effective contraception methods are not general, patients should follow 
the authority regulations or use double-barrier method of contraception (eg, condom 
with pessary, condom with spermicidal jelly*, spermicide* or film*, pessary with 
spermicidal jelly*, spermicide *or film).

SAP_001.pdf: 
Official Title: Phase 3, Open-Label, Randomized Study of Futibatinib Versus Gemcitabine Cisplatin 
Chemotherapy as First-Line Treatment of Patients with Advance Cholangiocarcinoma Harboring FGFR2 
Gene Rearrangements
NCT Number: NCT04093362   
Document Date: SAP Version 1.0: 26 March 2021


Taiho Oncology, Inc. 
Statistical Analysis Plan 
TAS-120-301 
26 MAR 2021 
1 
STATISTICAL ANALYSIS PLAN 
VERSION: 1.0 
DATE OF PLAN: 26 MAR 2021 
STUDY DRUG: Futibatinib (TAS-120) 
PROTOCOL NUMBER: TAS-120-301 
IND Number: 121062 
STUDY TITLE: 
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 
SPONSOR: 
Taiho Oncology, Inc. 
101 Carnegie Center 
Princeton, NJ USA 08540 
+1 (609) 750-5300
This trial was conducted in accordance with the ethical principles of Good Clinical Practice 
(GCP), according to the International Conference on Harmonization (ICH) Harmonized 
Tripartite Guideline. 
Confidentiality Statement 
The information in this document contains trade secrets and commercial information that are privileged or 
confidential and may not be disclosed unless such disclosure is required by applicable law or regulations. 
In any event, persons to whom the information is disclosed must be informed that the information is privileged 
or confidential and may not be further disclosed by them. These restrictions on disclosure will apply equally to 
all future information supplied to you that is indicated as privileged or confidential. 


Taiho Oncology, Inc.
TAS-120-301
Statistical Analysis Plan 
26 MAR 2021
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SIGNATURE PAGE
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
Protocol TAS-120-301 
Prepared by:
 PhD 
 Biostatistics
Signature 
Date
Approved by: 
MD, PhD
Biostatistics 
Signature 
Date
 MD 
Clinical 
Development
Signature 
Date


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TABLE OF CONTENTS 
LIST OF TABLES ........................................................................................................................... 6 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .................................................. 7 
1.
INTRODUCTION ........................................................................................................ 9 
2.
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 10 
2.1. 
Study Objectives ......................................................................................................... 10 
2.1.1. 
Primary Objective ....................................................................................................... 10 
2.1.2. 
Secondary Objectives .................................................................................................. 10 
2.1.3. 
Exploratory Objectives................................................................................................ 10 
2.2. 
Study Endpoints .......................................................................................................... 10 
2.2.1. 
Primary Endpoint ........................................................................................................ 10 
2.2.2. 
Secondary Endpoints ................................................................................................... 11 
2.2.3. 
Exploratory Endpoints ................................................................................................ 11 
3.
STUDY DESCRIPTION ............................................................................................ 12 
3.1. 
Study Design ............................................................................................................... 12 
3.2. 
Randomization and Treatment Assignment ................................................................ 12 
3.3. 
Determination of Sample Size .................................................................................... 13 
4.
STUDY PERIODS, TREATMENT REGIMENS, AND POPULATIONS
FOR ANALYSIS ........................................................................................................ 14 
4.1. 
Study Periods for Analyses ......................................................................................... 14 
4.2. 
Populations for Analysis ............................................................................................. 14 
4.3. 
Timing of Analysis ...................................................................................................... 15 
5.
STATISTICAL METHODOLOGY ........................................................................... 16 
5.1. 
General Methods ......................................................................................................... 16 
5.2. 
Data Quality ................................................................................................................ 16 
5.3. 
Disposition and Baseline Characteristics .................................................................... 16 
5.3.1. 
Patient Disposition ...................................................................................................... 16 
5.3.2. 
Protocol Deviations ..................................................................................................... 17 
5.3.3. 
Demographic and Other Baseline Characteristics ....................................................... 17 
5.3.4. 
Medical History .......................................................................................................... 17 
5.3.5. 
Prior/Concomitant Therapy......................................................................................... 17 
5.4. 
Efficacy Analyses ....................................................................................................... 18 
5.4.1. 
Primary Efficacy Analyses .......................................................................................... 18 


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5.4.2. 
Secondary Efficacy Analyses ...................................................................................... 19 
5.4.2.1. 
Overall Response Rate (ORR) .................................................................................... 19 
5.4.2.2. 
Disease Control Rate (DCR) ....................................................................................... 19 
5.4.2.3. 
Overall Survival (OS) ................................................................................................. 19 
5.4.2.4. 
PFS per Investigator assessment ................................................................................. 20 
5.4.3. 
Exploratory Efficacy Analyses ................................................................................... 20 
5.4.3.1. 
Duration of response (DOR) ....................................................................................... 20 
5.4.3.2. 
Patient Reported Outcomes (PRO) ............................................................................. 20 
5.4.4. 
Subgroup Analyses ..................................................................................................... 22 
5.4.5. 
Handling of Missing Data ........................................................................................... 23 
5.4.6. 
Multiplicity Adjustment .............................................................................................. 23 
5.5. 
Pharmacokinetic Analysis ........................................................................................... 24 
5.6. 
Pharmacodynamic/Biomarker Analysis ...................................................................... 24 
5.7. 
Safety Analyses ........................................................................................................... 24 
5.7.1. 
Extent of Exposure ...................................................................................................... 25 
5.7.1.1. 
Administration of Study Drug ..................................................................................... 25 
5.7.1.2. 
Modification of Study Drug ........................................................................................ 25 
5.7.2. 
Adverse Events ........................................................................................................... 25 
5.7.2.1. 
Deaths ......................................................................................................................... 25 
5.7.2.2. 
Adverse Events ........................................................................................................... 25 
5.7.2.3. 
Serious Adverse Events .............................................................................................. 26 
5.7.2.4. 
Adverse Events Leading to Discontinuation of Study Drug ....................................... 27 
5.7.2.5. 
Adverse Events Leading to Dose Modification .......................................................... 27 
5.7.2.6. 
Multiple Events ........................................................................................................... 27 
5.7.3. 
Clinical Laboratory Evaluations ................................................................................. 27 
5.7.3.1. 
Hematology ................................................................................................................. 27 
5.7.3.2. 
Chemistry .................................................................................................................... 28 
5.7.3.3. 
Additional Analyses .................................................................................................... 28 
5.7.4. 
Vital Signs ................................................................................................................... 28 
5.7.5. 
Electrocardiograms ...................................................................................................... 28 
5.8. 
Interim Analyses ......................................................................................................... 29 
6.
CHANGES IN PLANNED ANALYSIS .................................................................... 30 
7.
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING .......................... 31 


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7.1. 
Baseline Period ........................................................................................................... 31 
7.2. 
Post-Baseline Period ................................................................................................... 31 
7.3. 
Other Missing Data Handling Rules ........................................................................... 31 
8.
REFERENCES............................................................................................................ 33


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LIST OF TABLES 
Table 1: 
Definition of Study Periods for Analysis ....................................................................14 
Table 2: 
Censoring Rules for Progression-Free Survival ..........................................................18 
Table 3: 
Censoring Rules for Overall Survival .........................................................................20 
Table 4: 
Censoring Rules for Duration of Response .................................................................20 
Table 5: 
Partial Date Imputation Rule for AE or Medication ...................................................32 
LIST OF FIGURES 
Figure 1: 
Study Schema ..............................................................................................................12 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
 Abbreviation 
Term 
 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ARP 
All randomized population 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
BCRP 
breast cancer resistance protein 
CCA 
cholangiocarcinoma 
CI 
confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CR 
complete response 
CSR 
clinical study report 
CT 
computed tomography 
ctDNA 
circulating tumor DNA 
CYP 
Cytochrome P450 
DCR 
disease control rate 
DMC 
Data Monitoring Committee 
DOR 
duration of response 
DRAE 
Drug-related adverse event 
eCCA 
extrahepatic cholangiocarcinoma 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
FGF 
fibroblast growth factor 
FGFR 
fibroblast growth factor receptor 
GCP 
Good Clinical Practice 
HR 
Hazard Ratio 
I.V. 
intravenous 
iCCA 
intrahepatic cholangiocarcinoma 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICR 
independent central review 
IEC 
independent ethics committee 
IRB 
institutional review board 
IXRS 
Interactive Voice/Web Response System 


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KM 
Kaplan-Meier 
MRI 
magnetic resonance imaging 
NCI-CTCAE 
National Cancer Institute – Common Terminology Criteria for Adverse Events 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival 
PFS2 
PFS on next-line therapy 
P-gp 
P-glycoprotein 
PI 
prescribing information 
PK 
pharmacokinetic(s) 
Pop PK 
population pharmacokinetics 
PP 
Per Protocol 
PR 
partial response 
PRO 
patient-reported outcomes 
PS 
performance status 
QD 
daily 
QTcF 
Fridericia's corrected QT interval 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors, Version 1.1 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
stable disease 
SOP 
standard operating procedure 
TEAE 
treatment-emergent adverse event 
TID 
three times per day 
TOI 
Taiho Oncology, Inc. 
ULN 
upper limit of normal 
TRAEs 
Treatment-related AEs (TRAEs) 
WBC 
white blood cell 
WOCBP 
woman/women of child-bearing potential 


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1. 
INTRODUCTION 
 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and data 
displays to be included in the Clinical Study Report (CSR) for Protocol TAS-120-301. The SAP 
is developed according to the Protocol TAS-120-301, dated 13 September 2019. 
Genomic aberrations in FGF or the FGFR are a reported genetic modification in CCA. In iCCA, 
FGFR2 gene rearrangements, including gene fusions, have been identified as an early driver of 
oncogenic events. Futibatinib, a selective small molecule FGFR inhibitor, has shown promising 
antitumor activity in preclinical studies and ongoing clinical studies against a variety of tumor 
types harboring FGFR aberrations. 
The Phase 3 study will evaluate the safety and efficacy of futibatinib to compare with the current 
standard of care (gemcitabine-cisplatin chemotherapy) in the first-line treatment of patients with 
advanced CCA harboring FGFR2 gene rearrangements (including gene fusions). 
 
Study measurements and assessments, planned statistical methods, and derived variables are 
summarized in this plan. Planned tables, figures, and listings are specified. All decisions 
regarding final analyses, as defined in this SAP document, will be made prior to locking the 
database. Any deviations from these guidelines will be documented in the CSR. 


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objective 
The primary objective of the study is to compare futibatinib (TAS-120) monotherapy relative to 
the current standard of care (gemcitabine-cisplatin chemotherapy) in the first-line treatment of 
patients with advanced iCCA harboring FGFR2 gene rearrangements (including gene fusions) 
with respect to progression free survival as assessed by independent review committee. 
2.1.2. 
Secondary Objectives 
The secondary objectives of this study are: 
• To compare the objective response rate (ORR) of patients treated with futibatinib versus 
current standard of care (gemcitabine-cisplatin chemotherapy); 
• To compare the disease control rate (DCR) of patients treated with futibatinib versus 
current standard of care (gemcitabine-cisplatin chemotherapy); 
• To compare overall survival (OS) of patients treated with futibatinib versus current 
standard of care (gemcitabine-cisplatin chemotherapy); 
• To compare PFS per Investigator assessment, of patients treated with futibatinib versus 
current standard of care (gemcitabine-cisplatin chemotherapy); 
• To compare the safety and tolerability of treatment with futibatinib versus current 
standard of care (gemcitabine-cisplatin chemotherapy); 
2.1.3. 
Exploratory Objectives 
• To compare PFS on next-line therapy (PFS2) of patients treated with futibatinib versus 
current standard of care (gemcitabine-cisplatin chemotherapy); 
• To compare duration of response (DOR) of patients treated with futibatinib versus current 
standard of care (gemcitabine-cisplatin chemotherapy); 
• To compare patient-reported outcomes (PRO) of patients treated with futibatinib versus 
current standard of care (gemcitabine-cisplatin chemotherapy); 
• To assess the population pharmacokinetics (Pop PK) of futibatinib and to explore the 
relationship between PK and efficacy or toxicity. 
 
2.2. 
Study Endpoints 
2.2.1. 
Primary Endpoint 
The primary endpoint of the study is progression-free survival (PFS) as assessed by independent 
central review (ICR), defined as the time from the date of randomization to the date of the first 
documentation of disease progression using RECIST 1.1 criteria or death due to any cause. PFS 
censoring rules will follow the FDA guidance of 2007 (FDA 2007). 


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2.2.2. 
Secondary Endpoints 
The secondary efficacy endpoints are: 
• ORR, defined as the proportion of patients who have best overall response of CR or PR 
as determined by ICR using RECIST 1.1. 
• DCR, defined as the proportion of patients experiencing a best overall response of stable 
disease (SD), PR, or CR (per RECIST 1.1), based on ICR. 
• OS, defined as the time from the date of randomization to the date of death from any 
cause. Patients who are lost to follow-up and those who are alive at the date of data cut- 
off will be censored at the date the subject was last known alive, or date of data cut-off. 
• 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. 
The secondary safety and tolerability endpoints are: 
• Treatment-emergent adverse events (TEAEs), including serious adverse events (SAEs), 
clinical 
laboratory 
tests, 
vital 
signs, 
ophthalmological 
exams, 
and 
12-lead 
electrocardiogram (ECG). 
2.2.3. 
Exploratory Endpoints 
• DOR, defined as the time from the first documentation of response (per RECIST 1.1 and 
based on central assessment of radiologic images) to the first documentation of objective 
tumor progression or death due to any cause, whichever occurs first. 
• PRO, the European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30 (EORTC QLQ-C30) and the Cholangiocarcinoma and Gallbladder 
Cancer module (EORTC QLQ-BIL21). 
• PFS on next-line therapy (PFS2), defined as the time from randomization to subsequent 
disease progression per ICR after initiation of next-line therapy or death from any cause 
(whichever occurs first). 
• Population pharmacokinetics (Pop PK) of futibatinib. 


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3. 
STUDY DESCRIPTION 
3.1. 
Study Design 
Study TAS-120-301 is an open-label, multinational, parallel two-arm, randomized Phase 3 study 
evaluating the efficacy and safety of futibatinib versus gemcitabine-cisplatin chemotherapy as 
first-line treatment in patients with advanced, metastatic, or recurrent unresectable iCCA 
harboring FGFR2 gene rearrangements. Approximately 216 patients will be centrally 
randomized in a 1:1 ratio to receive futibatinib or gemcitabine-cisplatin chemotherapy (control 
arm). 
Patients in the experimental arm may continue to receive 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. Patients who discontinue gemcitabine-cisplatin for 
other reasons (eg, safety, withdrawal of consent, Investigator decision) are eligible for crossover 
following subsequent ICR-confirmed PD. 
The study design is summarized in Figure 1. 
 
Figure 1: 
Study Schema 
 
 
3.2. 
Randomization and Treatment Assignment 
Randomization will occur centrally using an Interactive Voice/Web Response System (IXRS). 
Patients will be assigned randomly in a 1:1 ratio to the treatment arms as follows: 
a. Experimental Arm: futibatinib (20 mg QD) 
b. Control Arm: gemcitabine-cisplatin (I.V. infusion) 
• 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 


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• 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. 
Randomization will be stratified according to the following factors: 
• Prior surgical excision of the primary tumor (yes vs. no). 
• Geographic region (Asia vs. rest of the world). 
• Locally advanced vs. metastatic disease. 
 
3.3. 
Determination of Sample Size 
Calculations are done with EAST 6.4 software. 
Assuming median PFS of 10 months in the Experimental Arm and 6 months in the Control Arm, 
a total of 162 PFS events will be required for the primary analysis to detect a hazard ratio of 0.60 
with 90% power using a log-rank test at a two-sided 5% level of significance. 
Based on the assumption that enrolment will continue for about 32 months, and that about 
10%/year of the patients will drop out, a total of approximately 216 patients randomized in a 1:1 
ratio will be needed to observe at least 162 PFS events approximately 8 months after the last 
patient randomization. 


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4. 
STUDY PERIODS, TREATMENT REGIMENS, AND 
POPULATIONS FOR ANALYSIS 
4.1. 
Study Periods for Analyses 
For each patient, the Study Duration is defined as the time from day of ICF signature to the last 
day of Disease Assessment Follow-up/Survival Follow-up. 
Study periods are defined in Table 1. 
Table 1: 
Definition of Study Periods for Analysis 
 
Period 
Definition 
Baseline 
Up to 3 days before the date of the first dose of study drug. 
On-Treatment 
From the date of the first dose of study drug to 30 days after the last 
dose of study drug. Unless otherwise specified, the on-treatment period 
will be the basis for the summaries of safety. 
Safety Follow-Up 
From the date of last dose of study drug through 30 days (±3 days) 
following the last dose of study drug or until the start of new anticancer 
therapy, whichever comes first. 
Survival Follow-up 
From disease progression or new anticancer therapy, whichever occurs 
first, survival follow-up every 12 weeks (±2 weeks) until withdrawal of 
consent, death, or loss to follow up, or study completion. 
Study Completion 
The study will be considered complete 12 months after the last event 
has been observed for the primary analysis of efficacy or the trial is 
halted early for any reason. 
Abbreviations: ICF=informed consent form. 
 
 
 
4.2. 
Populations for Analysis 
• All Enrolled Population: All patients who signed an informed consent form and were 
registered into the IVRS. 
• All Randomized Population (AR): All patients who were randomized to any treatment 
group in the study. This is the primary population for analyses of demography, protocol 
deviations, baseline characteristics and efficacy. 
• All Treated Population (AT) : All patients who received at least one dose of study drug. 
This is the primary population for dosing and safety analyses. 
• Per-Protocol Population (PP): All randomized patients who have no relevant protocol 
deviations. Relevant protocol deviation will be identified prior to unblinding of the study. 
For patients who have a relevant deviation during the study, data collected before the 
point of deviation can be included in the analysis preformed for this population. 


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• Pharmacodynamic / Biomarker Evaluable Set: All patients in the All Treated 
Population who have evaluable pharmacodynamic/biomarker data for analyses. 
• Pharmacokinetic Evaluable Set: All patients who received futibatinib and have 
evaluable plasma data for analysis 
 
 
4.3. 
Timing of Analysis 
The primary analysis will be performed when approximately 162 PFS events are accumulated. 
There is no planned interim analysis for efficacy or futility. Interim analyses for safety 
monitoring will occur when approximately 25%, 50%, and 75% of the planned total number of 
patients have been treated. A Data Monitoring Committee (DMC) will meet to assess the 
cumulative safety data and recommend study continuation, discontinuation, or study 
modification. A description of the roles and responsibilities of the DMC and details of the review 
processes are provided in a separate DMC charter. 


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5. 
STATISTICAL METHODOLOGY 
5.1. 
General Methods 
All recorded data will be presented in listings. 
Unless otherwise stated, descriptive statistics and summaries will be presented by treatment arm 
and overall using All Randomized Population (ARP). 
Descriptive statistics will be provided for selective demographics, safety, PD and biomarker 
data. Descriptive statistics on continuous data will include non-missing observations (n), means, 
medians, standard deviations and ranges, while categorical data will be summarized using 
frequency count and percentage. Graphical summaries of the data may also be provided. 
Confidence interval (CI) for proportions will be estimated using an exact method proposed by 
Clopper-Pearson (Clopper and Pearson, 1934). 
Time to event endpoints will be estimated using the Kaplan–Meier method. The number of 
events and censorings will be reported. When appropriate, the median along with the 
corresponding log-log transformed 95% CI will be estimated. Survival rates at fixed time points 
(eg, PFS at 6 months) will be derived from the Kaplan–Meier estimate and the corresponding CI 
will be derived based on the Greenwood formula (Kalbfleisch and Prentice, 1980). 
All the analyses for this study will be performed using SAS®, Version 9.3 or a higher version. 
5.2. 
Data Quality 
The sponsor will ensure that the clinal trial is conducted with a quality management system that 
will define quality tolerance limits in order to ensure human subject protection and reliability of 
study results. Data will be generated, documented, and reported in compliance with the protocol, 
ICH GCP, and applicable regulatory requirements. 
Although this trial is being conducted as an open-label study, analyses or summaries generated 
by randomized treatment assignments, actual treatment received, and biomarker status will be 
limited and documented. 
 
5.3. 
Disposition and Baseline Characteristics 
5.3.1. 
Patient Disposition 
The total number of patients enrolled by treatment group will be summarized along with the reason 
for not being randomized. The table will include the number that withdrew prior to completing the 
study, and the primary reasons for withdrawal. The number of patients completing treatment, and 
the primary reasons for treatment discontinuation will also be summarized. 
A list of all randomized patients will be provided showing each patients study/treatment 
completion information, including first and last dosing date, off study date and reason for going 
off-study, the reason for premature study withdrawal/treatment discontinuation, if applicable, will 
be presented. A listing for patients not randomized will also be provided, showing each patient’s 
race, gender, age, consent date and reason for not being included. 
A listing of analysis populations will be provided. 


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5.3.2. 
Protocol Deviations 
Important protocol deviation (ICH E3 Q&A (R1)) is defined as a subset of protocol deviations 
that may significantly impact the completeness, accuracy, and/or reliability of the study data or 
that may significantly affect the patient’s rights, safety or well-being. These include important 
informed consent form (ICF) issues, inclusion/exclusion criteria not met, withdrawal criteria not 
followed; wrong treatment, incorrect dose/overdose based on protocol definitions, important 
deviations based on protocol design, and other important Good Clinical Practice (GCP) 
deviations. 
Important protocol deviations will be summarized and listed in the Clinical Study Report (CSR). 
According to US Food and Drug Administration (FDA) guidance on conduct of clinical trials of 
medical products during COVID-19 public health emergency, updated on March 2020 and 
updated on January 27, 2021, protocol deviations related to COVID-19 will be listed in the CSR. 
5.3.3. 
Demographic and Other Baseline Characteristics 
All demographic and other baseline characteristic summary statistics and analyses are based on 
the latest one collected prior to the first dose of study drug or date of randomization for untreated 
patients. Baseline characteristics data including age, sex, race, ethnicity, height (cm), weight (kg) 
and baseline ECOG performance status will be listed individually by patient and summarized 
overall and by treatment arm. 
Disease characteristics at initial diagnosis (primary tumor location, histology type, tumor grade, 
TNM classification, AJCC staging), Extent of disease at baseline (locally advanced or 
metastatic) will be summarized and listed. 
5.3.4. 
Medical History 
Medical history will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA). The actual version of the MedDRA coding dictionary will be noted in the statically 
tables and clinical study report. The number and percentage of patients in each medical history 
category (by MedDRA system organ class and preferred term) will be summarized overall and 
by treatment arm. The system organ class (SOC) will be presented in alphabetical order, and the 
preferred terms will be presented in alphabetical order within each SOC. Patients reporting more 
than one condition/diagnosis will be counted only once in each row (SOC or preferred term). 
General medical history will be listed by patient, and pre-treatment events will be tabulated. 
5.3.5. 
Prior/Concomitant Therapy 
A medication is considered prior if the medication stop date is before treatment start date. 
Concomitant therapy includes all medications/therapies administered from the time ICF is signed 
through 30 days after the last dose of TAS0120 or until the start of new anticancer therapy. 
Prior/concomitant non-study medication will be classified by anatomic and therapeutic classes. 
Agents and medication will be reported using the generic name. A listing by patient will also be 
provided. Prior medications will be flagged in the listing. Medication terms will be coded using 
WHO drug dictionary (WHODDE B2). 


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5.4. 
Efficacy Analyses 
Unless otherwise specified, all efficacy analyses will be based on All Randomized Population. 
5.4.1. 
Primary Efficacy Analyses 
The primary efficacy endpoint of this study is ICR-assessed PFS, which is defined as the time 
from randomization to the first occurrence of progression as assessed by ICR or death from any 
cause, whichever comes first. The primary analysis of the study will test the equality of PFS 
distribution in the futibatinib (experimental arm) and in the gemcitabine-cisplatin (GC, control 
arm), as follows: 
H0: PFSfutibatinib = PFSGC vs. H1: PFSfutibatinib ≠ PFSGC 
The treatment comparison will be performed using a two-sided log-rank test at 0.05 significant 
level stratified by prior surgical excision of the primary tumor (yes or no), geographic region 
(Asia or rest of the world) and locally advanced or metastatic disease. If the null hypothesis is 
rejected and the observed hazard ratio (HR) is favorable for the fubibatinib arm, it is showed that 
fubibatinib treatment arm has statistically significant longer PFS than that of the GC arm. 
The HR and the corresponding 95% CIs will be estimated using the Cox regression model 
stratified by the same stratification factors. The median PFS, and the PFS rates at 6, 12 and 18 
months, will be calculated using the KM product-limit estimates for each treatment arm, and 
presented with two-sided 95% CIs. The Kaplan-Meier plot will be used to provide a visual 
description of the differences in duration of PFS across treatment arms. The investigator- 
assessed PFS will also be analyzed using the same models. Agreement/Disagreement between 
investigator assessment and assessment by the ICR will be summarized. 
The PFS censoring rules in this SAP and definition of progression date follow the Food and Drug 
Administration (FDA) “Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer 
Drugs and Biologics (2007)”. The detail event definition and censoring rule are described in 
Table 2. 
Table 2:    Censoring Rules for Progression-Free Survival 
 
No. 
Situation 
End Date 
Outcome 
1 
Documented PD between scheduled visits 
Date of the first assessment that 
determined PD 
PFS event 
2 
Death during the study with no prior PD 
Date of death 
PFS event 
3 
Patients still on treatment without PD as of 
data cut-off a 
Date of the last tumor assessment b 
Censored 
4 
Treatment discontinuation for reasons other 
than PD or death, and no post baseline tumor 
assessments 
Date of the first dose 
Censored 
5 
Treatment discontinuation for reasons other 
than PD or death with post baseline tumor 
assessments 
Date of the last tumor assessment 
Censored 
6 
New anticancer treatment started 
Date of the last tumor assessment 
before start of new treatment 
Censored 


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No. 
Situation 
End Date 
Outcome 
7 
Death or PD after two or more missed tumor 
assessments c 
Date of the last tumor assessment 
before missed assessments 
Censored 
8 
No baseline or unreadable baseline 
assessment but readable post baseline 
assessments 
Date of the first dose 
Censored 
a. This refers to patients who were still receiving study treatment at time of data cutoff. 
b. For PFS analysis, the date of last tumor assessment refers to the date of last adequate tumor assessment. 
c. Two or more missed tumor assessments is defined as having either one of the following two durations being 
longer than for the first 12 weeks, or thereafter 3: 
Duration between two consecutive tumor assessments 
Duration between the last tumor assessment and death or PD 
 
The following sensitivity analyses will be performed. 
• PFS will be compared between treatment groups using unstratified log-rank test. 
• To investigate impact of informative censoring on study outcomes, PFS will be analyzed 
using different censoring rules, such as: 
o Counting patients who lost to follow-up and those who started new anticancer 
therapy as events. 
o Using the actual reported date of progression by IRC or death to define PFS 
regardless of missing assessments, treatment discontinuation, or use of new anti- 
cancer therapy. 
• PFS will be compared using the primary censoring rules based on per-protocol population. 
 
5.4.2. 
Secondary Efficacy Analyses 
5.4.2.1. 
Overall Response Rate (ORR) 
ORR will be calculated for each treatment arm with exact 95% CIs using the method of Clopper 
and Pearson. The analysis of ORR for comparison between the two arms will be performed at the 
two-sided significant level of 0.05 by using a stratified Cochran-Mantel-Haenszel (CMH) test 
with the stratification factors in it. 
5.4.2.2. 
Disease Control Rate (DCR) 
DCR will be calculated for each treatment arm with exact 95% CIs using the method of Clopper 
and Pearson. The analysis of DCR for comparison between treatment arms will be performed 
using the CMH test stratified by the stratification factors used in the randomization. 
5.4.2.3. 
Overall Survival (OS) 
Time to event endpoint OS will be analyzed using the same log-rank tests as described in the 
primary analysis of PFS. The detail event definition and censoring rule of OS are described in 
Table 3. 


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Table 3: 
Censoring Rules for Overall Survival 
 
Situation 
End Date 
Outcome 
Death before cut-off 
Date of death 
Death 
Death after data cut-off 
Date of data cut-off 
Censored event 
Patient still alive at data cut-off 
Date of data cut-off 
Censored event 
Patient discontinued treatment due to any 
reason before data cut-off 
Date last known to be alive 
Censored event 
 
5.4.2.4. 
PFS per Investigator assessment 
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. The similar approach for analysis of primary endpoint PFS per ICR descried in 5.4.1 
will be used. 
 
5.4.3. 
Exploratory Efficacy Analyses 
5.4.3.1. 
Duration of response (DOR) 
DOR is defined as the time from first documented response (CR or PR), as assessed by the 
investigator or local radiologist, to the date of first documented disease progression or death due 
to underlying cancer. Analysis of the DOR will incorporate data only from the subset of patients 
in both treatment arms that achieved a CR/PR. Censoring rules for DOR are summarized in 
Table 4. 
Table 4: 
Censoring Rules for Duration of Response 
 
Situation 
Date of Progression or Censoring 
Outcome 
No progression nor death, no new 
anticancer therapy initiated 
Last adequate disease assessment 
Censor 
(non-event) 
No progression nor death, new anti-cancer 
therapy initiated 
Last adequate disease assessment before new 
anti-cancer therapy initiated 
Censor 
(non-event) 
Death or progression after ≥ 2 missed 
adequate disease assessments 
Last adequate disease assessment prior to 
the after ≥ 2 missed adequate disease 
assessments 
Censor 
(non-event) 
Death or progression after ≤ 1 missed 
adequate disease assessments 
PD or death 
End of response 
(Event) 
DOR (months) = ([Date of progression/death due to underlying cancer – date of first response] + 
1) / 30.5 
As there is no expectation for treatment arm balance, analyses of DOR will not incorporate 
stratification factors and will not produce a p-value but only be summarize the treatment arm 
estimates and confidence intervals. 
 
5.4.3.2. 
Patient Reported Outcomes (PRO) 
The following PRO assessments will be performed as exploratory analyses: 


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 European Organization for Research in the Treatment of Cancer – Quality of Life 
Questionnaire (EORTC-QLQ-C30) 
 The Cholangiocarcinoma and Gallbladder Cancer module (EORTC QLQ-BIL21). 
The PRO instruments will be completed by patients using paper-based questionnaires. All 
assessments should be completed without assistance from anyone. The PRO questionnaires will 
be administered on the days specified in the Schedule of Events. 
Patients who discontinued treatment due to toxicity should continue the PRO assessments. PRO 
data collection will be discontinued due to patient withdrawal of consent, initiation of subsequent 
anti-cancer therapy, study completion, or early study termination by the Sponsor. 
5.4.3.2.1. EORTC QLQ-C30 
The EORTC QLQ-C30 was developed to be an “integrated, modular approach for evaluating the 
quality of life of patients participating in international [oncology] clinical trials.” It is comprised 
of 5 functional scales (physical, role, cognitive, emotional, and social), three symptom scales 
(fatigue, pain, and nausea and vomiting), a global health status scale, a number of single items 
assessing additional symptoms commonly reported by cancer patients (dyspnea, loss of appetite, 
insomnia, constipation, and diarrhea), and perceived financial impact of the disease. Validation 
experience documents that the scales assess distinct components of the health-related quality of 
life construct. 
Functional scales: 
• Physical functioning: (1 - ((Q1+Q2+Q3+Q4+Q5)/5 -1)/3) * 100 
• Role functioning: (1 - ((Q6+Q7)/2-1)/3) * 100 
• Emotional functioning: (1 - ((Q21+Q22+Q23+Q24)/4-1)/3) * 100 
• Cognitive functioning: (1 - ((Q20+Q25)/2-1)/3) * 100 
• Social functioning: (1 - ((Q26+Q27)/2-1)/3) * 100 
Global health status: 
• Global health status/QoL: ((Q29+Q30)/2-1)/6 * 100 
Symptom scales/items: 
• Fatigue: ((Q10+Q12+Q18)/3-1)/3 * 100 
• Nausea and vomiting: ((Q14+Q15)/2-1)/3 * 100 
• Pain: ((Q9+Q19)/2-1)/3 * 100 
• Dyspnea: ((Q8-1)/3 * 100 
• Insomnia: (Q11-1)/3 * 100 
• Appetite loss: (Q13-1)/3 * 100 
• Constipation: (Q16-1)/3 * 100 
• Diarrhea: (Q17-1)/3 * 100 
• Financial difficulties: (Q28-1)/3 * 100 
Baseline and change from baseline in EORTC QLQ-C30 global health status/quality of life 
(QoL) composite scale data and the remaining EORTC QLQ-C30 scale data will be summarized 
by time point using descriptive statistics. In addition, the percentage of patients demonstrating a 


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clinically meaningful deterioration (defined as a 10-point change from baseline) will be 
presented for each scale at each assessment time point. Percentages will be based on number 
patients assessed at each assessment time point. 
A linear mixed effect regression model with an appropriate covariate structure will be used to fit 
the longitudinal data. In the linear mixed regression model, stratification factors used in the 
randomization will be included as fixed factors. The model will also include time, study arm, and 
study arm by time interaction. The following covariance structure will be explored: Unstructured 
(TYPE=UN), compound symmetry structure (TYPE=CS) and first-order autoregressive 
(TYPE=AR(1)). The covariance structure resulting in model convergence and the lowest 
Bayesian Information Criterion (BIC) will be used for analysis. Change from baseline scores 
from all post-baseline visits will be compared between the two study arms based on the linear 
mixed effects model. Subjects without baseline score or any post-baseline score will be excluded 
from the linear mixed effects regression analysis.` 
 
5.4.3.2.2. EORTC QLQ-BIL21 
 
The EORTC QLQ-BIL21 is a validated tool for the assessment of QoL in patients with CCA and 
cancer of the gallbladder. It has five multi-item scales: eating (four items); jaundice (three 
items); tiredness (three items); pain (four items) and anxiety (four items) and three single items 
about treatment side effects, drainage tubes/bags and worried about losing weight. 
Multi-item scales: [Need EORTC BIL21 Scoring Manual; scoring algorithm below are based on 
EORTC QLQ-C30 Scoring methods with 0-to-100 linear transformation] 
• Eating: (1 - ((Q1+Q2+Q3+Q4)/4 -1)/3) * 100 
• Jaundice: (1 - ((Q5+Q6+Q7)/2-1)/3) * 100 
• Tiredness: (1 - ((Q8+Q9+Q10)/3-1)/3) * 100 
• Pain: (1 - ((Q11+Q12+Q13+Q14)/4-1)/3) * 100 
• Anxiety: (1 - ((Q15+Q16+Q17+Q18)/4-1)/3) * 100 
 
Baseline and change from baseline in EORTC QLQ-BIL21 will be summarized by time point 
using descriptive statistics for each cohort. In addition, the percentage of patients demonstrating 
a clinically meaningful deterioration (defined as a 10-point change from baseline) will be 
presented for each scale at each assessment time point. Percentages will be based on number 
patients assessed at each assessment time point. The changes values from baseline to post- 
baseline and shift evaluation from baseline to post-baseline will be summarized. 
 
The changes values from baseline to post-baseline and shift evaluation from baseline to post- 
baseline will be summarized. The similar mixed linear mixed effect regression model descried in 
5.4.3.2.1 will be used. 
 
5.4.4. 
Subgroup Analyses 
To evaluate of the impact of demographics and baseline characteristics on efficacy, subgroup 
analyses on efficacy endpoints including, but not limited to, PFS, OS, ORR and DOR will be 
performed for subgroups including, but not limited to, those defined below: 


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• Geographic Region (Asia vs. rest of the world). 
• Age categorization (< 65, ≥65). 
• Gender (male, female). 
• Race (White, African American, Asian, Other). 
• Baseline ECOG PS (0 vs. 1). 
For PFS/OS, estimate of hazard ratio along with its two-sided 95% CI will be presented for 
subgroups defined above. 
For ORR, the proportion of patients with response along with the treatment difference will be 
summarized for subgroups defined above along with its 95% exact CI. 
The consistency of the treatment difference among these sub-populations will be examined by 
forest plots. 
 
5.4.5. 
Handling of Missing Data 
For time to event endpoints such as PFS and OS, detail event definition and censoring rule are 
described in Table 2 and Table 3, respectively. 
For response endpoints such as ORR and DCR, patients without any post-baseline assessment 
will be considered non-responders. 
For DOR, patients with no documented progression after CR/PR will be censored at the last date 
of adequate assessment. Patients who have never responded will not be included in this analysis. 
For PRO instruments, missing values will be imputed for missing items by “assuming that the 
missing items have values equal to the average of those items which are present” for any scale in 
which at least half the items are completed. A scale in which less than half of the items are 
completed will be treated as missing. A questionnaire will be considered as received if at least 
one of the 15 scales is non-missing (after imputation). All scales and single items are scored on a 
categorical scale and linearly transformed to 0-to-100 scales with higher scores for a functional 
scale representing higher levels of functioning, higher scores for the global health status/quality 
of life representing higher levels of global health status/quality of life, and higher scores for a 
symptom scale representing higher level of symptoms. 
 
5.4.6. 
Multiplicity Adjustment 
To adjust for multiple testing of the secondary endpoints, a fixed sequence testing procedure will 
be used. The following endpoints will be tested in the order listed below: 
• ORR 
• DCR 
• OS 
• PFS per Investigator assessment 


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If the study meets its primary efficacy endpoint of prolonged PFS in the treatment arm, a formal 
statistical test of ORR between the two arms will be performed. After achieving statistical 
significance at α = 0.05 (2-sided) with primary endpoint PFS, the secondary endpoint ORR will 
be compared. If the study does not meet its primary endpoint, this test will not be performed. 
If the ORR comparison achieves statistical significance, DCR will be tested at a two-sided 
significant level of 0.05. OS and PFS per investigator will also be tested sequentially if the 
previous comparison reaches its statistical significance. 
The p-values generated from other analyses outside this hierarchical testing procedure are not 
inferential, for descriptive purpose only. 
 
5.5. 
Pharmacokinetic Analysis 
The concentration vs. time data obtained in this study will be combined with data from other 
studies in the clinical development program to develop a Pop PK model. This model will be used 
to evaluate the effects of intrinsic and extrinsic covariates on the PK of futibatinib and to 
estimate measures of individual exposure (such as steady-state peak, trough and area under the 
plasma drug concentration-time curve). Model estimated exposures will be used for exposure- 
response analyses of selected efficacy and safety endpoints. 
The analysis procedure of the PopPK and exposure-response analyses will be detailed in a 
separate analysis plan, and the results of the analyses will be reported separately. 
 
The list of futibatinib plasma concentrations will be provided. 
 
5.6. 
Pharmacodynamic/Biomarker Analysis 
There is no PD biomarkers for this study except, probably, circulating CA19.9 data which will be 
collected from local results. If enough data is collected, % change of on-treatment levels from 
baseline will be calculated as a patient monitoring biomarker. 
Tissue FGFR2 rearrangement status reported to sites will be collected from the EDC but will be 
also obtained from the central lab. Correlation of clinical outcome with different types of FGFR2 
rearrangements/fusions will be assessed. 
Other tissue NGS results will be collected from the central lab for exploratory statistical analysis 
which can be handled outside this formal SAP. 
Data from circulating free DNA (cfDNA), if analyzed, will be collected from the central lab for 
exploratory statistical analysis which can be handled outside this formal SAP. 
 
5.7. 
Safety Analyses 
All safety analyses will be performed on the all treated population. No inferential statistics are 
planned. 
The safety analysis will be performed by treatment arms and overall on the as-treated patients 
(all treated population). 


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AEs will be coded according to the MedDRA (Version 23.1 or later) terminology and the 
severity of the toxicities will be graded according to NCI CTCAE Version 5.0, where applicable. 
 
5.7.1. 
Extent of Exposure 
5.7.1.1. 
Administration of Study Drug 
The following parameters will be summarized by treatment group: 
• Duration of treatment 
• Number of doses received 
• Cumulative dose 
• Relative dose intensity 
Duration of treatment will be calculated as: (Date of last dose – Date of first dose + 1). 
Cumulative dose is sum of the doses administered to a subject during the treatment period. 
Relative dose intensity will be calculated as cumulative dose (dose received) divided by dose 
planned (taking the dosing cycle into consideration) 
A by-patient listing of dosing of study medication and a listing of batch number will be also 
provided. 
 
5.7.1.2. 
Modification of Study Drug 
The number and percentage of patients with at least one dose interruption along with reason for 
the interruptions will be summarized by treatment group. 
The number and percentage of patients with at least one dose reduction and reason for the dose 
reduction will be summarized by treatment group. 
By-patient listings of dose interruptions and dose reductions will be also provided. 
 
5.7.2. 
Adverse Events 
5.7.2.1. 
Deaths 
Deaths and reasons for death will be summarized by treatment group for all deaths on treatment 
or within 30 days of last dose received. 
A by-patient listing of all deaths will be provided. 
 
5.7.2.2. 
Adverse Events 
An AE is any untoward medical condition that occurs in patients while participating in this clinical 
trial. A treatment-emergent AE (TEAE) is defined as an AE that is starting or worsening at the 
time of or after the first dose of study drug administration and within 30 days after the last dose of 
study drug, and does not necessarily have a causal relationship to the use of the study drug. 
Treatment-related AEs (TRAEs) will be reported in the table. 


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The following summary tables will be generated: 
1. Summary of AEs with the number and percentage of patients reporting AEs, serious 
AEs, grade ≥ 3 AEs, AEs leading to study drug discontinuation, interruption and dose 
modification, and AEs with the outcome of death. 
2. Summary of TEAEs with the number and percentage of patients reporting TEAEs, 
serious TEAEs, grade ≥ 3 TEAEs, TEAEs leading to study drug discontinuation, 
interruption and dose modification, and TEAEs with outcome of deaths. 
3. Summary of TRAEs with the number and percentage of patients reporting TRAEs, 
serious TRAEs, grade ≥ 3 TRAEs, TRAEs leading to study drug discontinuation, 
interruption and dose modification, and TRAEs with outcome of deaths. 
4. Summary of AEs by worst CTC Grade (grade 1, 2, 3, 4, 5, any grade, Grade ≥ 3) 
presented by SOC and Preferred Term (PT). 
5. Summary of TEAEs by worst CTC grade (Grade 1, 2, 3, 4, 5, any grade, Grade ≥ 3) 
presented by SOC and PT. 
6. Summary of TRAEs by worst CTC grade (Grade 1, 2, 3, 4, 5, any grade, Grade ≥ 3) 
presented by SOC and PT. 
7. Grade ≥ 3 AEs by worst CTC Grade (grade 3, 4, 5, 3-5) presented by SOC and PT. 
8. Grade ≥ 3 TEAEs by worst CTC Grade (grade 3, 4, 5, 3-5) presented by SOC and PT. 
9. Grade ≥ 3 TRAEs by worst CTC Grade (grade 3, 4, 5, 3-5) presented by SOC and PT. 
10. Summary of AEs leading to death by SOC and PT. 
11. Summary of TEAEs leading to death by SOC and PT. 
12. Summary of TRAEs leading to death by SOC and PT. 
13. Summary of the most common AEs (≥10% incidence) and median time to first AE by 
SOC and PT. 
14. Summary of the most common TEAEs (≥10% incidence) and median time to first 
TEAE by SOC and PT. 
15. Summary of the most common TRAEs (≥10% incidence) and median time to first 
TRAE by SOC and PT. 
 
5.7.2.3. 
Serious Adverse Events 
Serious adverse events (SAEs) will be summarized: 
• Summary of SAEs by worst CTC Grade (grade 1, 2, 3, 4, 5, any grade, Grade ≥ 3) 
presented by SOC and PT 
• Summary of treatment-related SAEs by worst CTC Grade (grade 1, 2, 3, 4, 5, any grade, 
Grade ≥ 3) presented by SOC and PT 
A by-patient listing of SAEs will also be provided. 


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5.7.2.4. 
Adverse Events Leading to Discontinuation of Study Drug 
AEs leading to discontinuation will be summarized by treatment group: 
• Overall summary of AEs leading to discontinuation by worst CTC Grade (grade 1, 2, 3, 
4, 5, any grade, Grade 3-5) presented by SOC/PT 
• Overall summary of drug-related AEs leading to discontinuation by worst CTC grade 
(Grade 1, 2, 3, 4, 5, any grade, Grade 3-5) presented by SOC/PT 
A by-patient listing of AEs leading to discontinuation will also be provided. 
 
5.7.2.5. 
Adverse Events Leading to Dose Modification 
AEs leading to dose modification (including dose interruption or reduction) will be summarized 
by treatment group: 
• Overall summary of AEs leading to modification by worst CTC Grade (grade 1, 2, 3, 4, 5, 
any grade, Grade 3-5) presented by SOC/PT 
• Overall summary of drug-related AEs leading to discontinuation by worst CTC grade 
(Grade 1, 2, 3, 4, 5, any grade, Grade 3-5) presented by SOC/PT 
A by-patient listing of AEs leading to modification will also be provided. 
 
5.7.2.6. 
Multiple Events 
The following summary tables will be provided: 
• A table showing the total number and rate (exposure adjusted) of occurrences for all AEs. 
In addition, the rate (exposure adjusted) and its 95% CI evaluated for different time intervals will 
be displayed graphically for each treatment group. This analysis will be limited to the rate of all 
AEs and all drug-related AEs. No formal comparisons will be made between treatment groups. 
Listing displaying the unique instances of all AEs (that is, after duplicates have been eliminated 
and overlapping and contiguous occurrences of the same event (same PT) have been collapsed) 
will be provided. 
 
5.7.3. 
Clinical Laboratory Evaluations 
5.7.3.1. 
Hematology 
The following will be summarized by treatment group as worst CTC grade on-treatment per patient 
and as shift table of worst on-treatment CTC grade compared to baseline CTC grade per patient: 
hemoglobin (HB), platelets, white blood counts (WBC), absolute neutrophils count (ANC) and 
lymphocyte count (LYMPH). 
A by- patient listing of these laboratory parameters will be provided. 


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5.7.3.2. 
Chemistry 
The following will be summarized by treatment group as worst CTC grade on-treatment per patient 
and as shift table of worst on-treatment CTC grade compared to baseline CTC grade per patient: 
ALT, AST, alkaline phosphatase (ALP), inorganic phosphorus glucose, total bilirubin, creatinine. 
sodium (high and low), potassium (high and low), calcium (high and low) and magnesium (high 
and low). 
A by- patient listing of these laboratory parameters will be provided. 
5.7.3.3. 
Additional Analyses 
The number of patients with the following laboratory abnormalities from on-treatment 
evaluations will be summarized by treatment group: 
• ALT or AST > 3 x ULN, > 5 x ULN, > 10 x ULN and > 20 x ULN 
• Total bilirubin > 2 x ULN 
• Concurrent (within 1 day) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN 
• Concurrent (within 30 days) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN 
• ALT or AST >3 x ULN and total bilirubin >2 x ULN bilirubin and alkaline phosphatase 
<2 x ULN or missing 
• ALT or AST >3xULN total bilirubin >2 x ULN bilirubin and alkaline phosphatase <2 x 
ULN 
Scatterplots will be produced for the following hepatic laboratory parameters: 
• Total bilirubin peak vs. AST peak 
• Total bilirubin peak vs. ALT peak 
On-treatment peak total bilirubin and on-treatment peak AST/ALT may or may not happen on 
the same day of liver testing. A by-patient listing of these specific abnormalities will be 
provided. 
 
5.7.4. 
Vital Signs 
Descriptive statistics for vital signs parameters (diastolic and systolic blood pressure, pulse, 
respiration rate, temperature, <weight (if collected> and changes from baseline will be presented 
by visit and treatment group (and/or dose). 
 
5.7.5. 
Electrocardiograms 
Descriptive statistics for ECG parameters and changes from baseline will be presented by visit and 
treatment group (and/or dose). 
Shift tables will present changes from baseline in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) to end of treatment (or 
end of phase or by visit). 


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In addition, the number (percentage) of patients with at least 1 post-baseline abnormal ECG result 
in QTc Fridericia (and/or QTc Bazett) during the on-treatment period will be summarized. 
Clinically abnormal ECG results in QTc Fridericia (and/or QTc Bazett) will be categorized as 
follows: 
Absolute QTc interval prolongation: 
• QTc interval > 450 ms 
• QTc interval > 480 ms 
• QTc interval > 500 ms 
Change from baseline in QTc interval: 
• QTc interval increases from baseline > 30 ms 
• QTc interval increases from baseline > 60 ms 
 
5.8. 
Interim Analyses 
No interim analysis of efficacy is planned. An independent Data Monitoring Committee (DMC) 
will be established prior to the first interim analysis to monitor data on an ongoing basis to 
ensure the continuing safety of the patients enrolled in this study. Interim analyses for safety 
monitoring will occur when approximately 25%, 50%, and 75% of the planned total number of 
patients have been treated. DMC will meet to assess the cumulative safety data and recommend 
study continuation, discontinuation, or study modification. A description of the roles and 
responsibilities of the DMC and details of the review processes are provided in a separate DMC 
charter. 
Prior to final study unblinding, the Sponsor and external unblinded statistician will not be 
involved in any discussions regarding modifications to the protocol, statistical methods, 


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6. 
CHANGES IN PLANNED ANALYSIS 
There have been no changes to the initially planned analyses as of the finalization of this SAP. 


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7. 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
This section should contain detailed definitions and conventions, including data handling rules that 
will be used to perform statistical analyses. 
7.1. 
Baseline Period 
Baseline evaluations or events will be defined as evaluations or events that occur before the date 
and time of the first dose of study drug. Evaluations on the same date and time of the first dose of 
study drug will be considered as baseline evaluations. 
In cases where the time (onset time of event or evaluation time and dosing time) is missing or not 
collected, the following definitions will apply: 
• Pre-treatment AEs will be defined as AEs with an onset date prior to but not including the 
day of the first dose of study drug 
• Baseline evaluations (laboratory tests, pulse oximetry and vital signs) will be defined as 
evaluations with a date on or prior to the day of first dose of study drug 
If there are multiple valid assessments, the assessment that is closest to day (and time if collected) 
of the first dose of study drug will be used as the baseline in the analyses. If multiple assessments 
are collected on the same date (and time, if collected), the assessment with the latest database entry 
date (and time, if collected) will be considered as baseline. 
7.2. 
Post-Baseline Period 
On-treatment AEs will be defined as AEs with an onset date and time on or after the date and time 
of the first dose of study drug (or with an onset date on or after the day of first dose of study drug 
if time is not collected or is missing). For patients who are off study drug, AEs will be included if 
event occurred within a safety window of 30 days after the last dose of study drug. No “subtracting 
rule” will be applied when an AE occurs both pre-treatment and post-treatment with the same 
preferred term and grade. 
On-treatment evaluations (laboratory tests, pulse oximetry and vital signs) will be defined as 
evaluations taken after the day (and time, if collected and not missing) of first dose of study drug. 
For patients who are off study drug, evaluations should be within a safety window of 30 days after 
the last dose of study drug. 
7.3. 
Other Missing Data Handling Rules 
Missing data will not be imputed in listings. The listings will only present the data recorded on 
the original Case Report Form. 
If an AE has a completely missing onset date, then the AE will be considered a TEAE. A 
medication with a completely missing start date is considered a prior medication. A medication 
with a completely missing stop date is considered a concomitant medication. 
If an AE or a medication has a partial missing start date or stop date, the following rules in Table 
5 will be used to determine whether it is a TEAE, or a prior or concomitant medication. The rules 
are also used for determining the cycle of AE and concomitant medication. The derived date is 
used for determining TEAEs, the cycle of AE, and concomitant medication. 


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Table 5: 
Partial Date Imputation Rule for AE or Medication 
 
Partial Missing Start or Stop Date 
Derived Start Date 
Imputed Stop Date 
Missing month and day, and the 
year is present 
January 1 of that year or first dose 
date if the year is the same as the year 
of first dose date 
December 31 of that 
year 
Missing day, but year and month 
are present 
First day of that month or first dose 
date if the year and month are the 
same as the year and month of first 
dose date 
Last day of that month 
Missing month, but year and day are 
present 
Missing month derived as January or 
same as first dose month if the year is 
same as the year of first dose. 
Missing month 
imputed as December 
 
For the medical history, prior surgery, prior radiotherapy, and prior systemic cancer therapies: 
• A partial missing start dates will be imputed as below 
o Missing year- no imputation, data left missing 
o Missing day and month - January 1 will be assigned to the missing fields. 
o Missing month only - Treat day as missing and replace both month and day 
according to the above procedure. 
o Missing day only - Assign first of the month to the missing day 
• A partial missing stop dates will be imputed as below 
o Missing year: no imputation, date left missing 
o Month is missing and year is prior to year of first dose of study drug: impute 
'December'. 
o Month is missing and year is the same as the year of the first dose of study drug: 
impute same month as in first dose date of study drug. 
o Day is missing: impute 'last day of that month'. If results in a date ≥ the date of the 
first dose of study drug impute day as the day prior to date of first dose of study 
drug 


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8. 
REFERENCES 
 
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