Phase II Study of FGFR Inhibitor Futibatinib in Combination With Anti-PD-1 Antibody Pembrolizumab in Patients With Advanced or Metastatic Hepatocellular Carcinoma With FGF19 Expression After First Line Therapy
Phase: PHASE2
Conditions: Advanced Hepatocellular Carcinoma, BCLC Stage A Hepatocellular Carcinoma, BCLC Stage B Hepatocellular Carcinoma, BCLC Stage C Hepatocellular Carcinoma, Metastatic Hepatocellular Carcinoma
Sponsor: Mayo Clinic

MC200402 
Protocol Version Date: 20Jun2025 
Mayo Clinic Comprehensive Cancer Center 
MC200402 Phase II Study of FGFR Inhibitor Futibatinib in Combination with Anti-PD-1 Antibody 
Pembrolizumab in Patients with Advanced or Metastatic Hepatocellular Carcinoma  
with FGF19 Expression 
Sponsor/Principal Investigator: 
 
 
 
Co-Principal Investigator: 
 
Co-Investigators: 
 
 
 
 
 
Statistician: 
 
FDA IND #: 154038 
Trial Supported by:  
Funding: NCCN Oncology Research Program through a research grant provided by Taiho Oncology, Inc. 
Neither NCCN or Taiho Oncology, Inc. are sponsors. 
Drug Availability:  
Supplied Investigational Agents: futibatinib (TAS-120) 
Commercial Agents: pembrolizumab 
√Study contributor(s) not responsible for patient care 
 
Document History 
Approval 
Effective Date 
Activation 
 
07May2021 
MCCC Amendment 1 
06Aug2021 
11Aug2021 
MCCC Amendment 2 
01Oct2021 
06Oct2021 
MCCC Amendment 3 
22Apr2022 
27Apr2022 
MCCC Amendment 4 
02Aug2023 
10Aug2023 
MCCC Amendment 5 
22Dec2023 
04Jan2024 
MCCCC Amendment 6 
03Jul2025 
03Jul2025 
 

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Protocol Resources 
Questions: 
Contact Name: 
Patient eligibility*, test schedule, 
treatment delays/ interruptions/ 
adjustments, dose modifications, adverse 
events, forms completion and submission 
 
 
 
Lead Site Clinical Study Coordinator 
 
  
Lead Site Clinical Data Coordinator  
 
 
Protocol document, consent form, 
regulatory issues 
 
 
  
Laboratory Contacts for Correlative 
Studies 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
  
Serious Adverse Event Reporting 
 
 
*No waivers of eligibility allowed 

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Table of Contents 
MC200402 Phase II Study of FGFR Inhibitor Futibatinib in Combination with Anti-PD-1 Antibody 
Pembrolizumab in Patients with Advanced or Metastatic Hepatocellular Carcinoma with FGF19 
Expression ........................................................................................................................................ 1 
Protocol Resources ........................................................................................................................................ 2 
Table of Contents .......................................................................................................................................... 3 
Schema  ......................................................................................................................................................... 4 
1.0 
Background ......................................................................................................................... 5 
2.0 
Goals ................................................................................................................................. 10 
3.0 
Patient Eligibility .............................................................................................................. 11 
4.0  
Test Schedule .................................................................................................................... 15 
5.0 
Grouping Factor ................................................................................................................ 17 
6.0 
Registration Procedures .................................................................................................... 17 
7.0 
Protocol Treatment ........................................................................................................... 20 
8.0 
Dosage Modification Based on Adverse Events ............................................................... 22 
9.0 
Ancillary Treatment/Supportive Care ............................................................................... 26 
10.0 
Adverse Event (AE) Monitoring and Reporting ............................................................... 30 
11.0 
Treatment Evaluation/Measurement of Effect .................................................................. 40 
12.0 
Descriptive Factors ........................................................................................................... 46 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient .................................................. 46 
14.0 
Body Fluid Biospecimens ................................................................................................. 48 
15.0 
Drug Information .............................................................................................................. 51 
16.0 
Statistical Considerations and Methodology .................................................................... 57 
17.0  
Pathology Considerations/Tissue Biospecimens .............................................................. 61 
18.0 
Records and Data Collection Procedures .......................................................................... 64 
19.0 
Budget ............................................................................................................................... 65 
20.0 
References ......................................................................................................................... 66 
Appendix I 
ECOG Performance Status ............................................................................................... 70 
Appendix II 
Child Pugh Scores ............................................................................................................. 71 
Appendix III 
Barcelona Clinic Liver Cancer (BCLC) Staging Classification & Treatment Schedule .. 72 
Appendix IV 
Guidelines for Contraception ............................................................................................ 73 
Appendix V 
Patient Medication Diary .................................................................................................. 74 
Appendix VI 
Classification of Substrates, Inhibitors, & Inducers of CYP Enzymes & Transporters.... 75 
Appendix VII Patient Questionnaire Booklet .......................................................................................... 77 
.

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Schema 
 
 
Registration 
 
 
 
↓ 
 
 
 
Treatment with  
futibatinib  
Days 1-21 
and pembrolizumab 
Day 1 
for up to 2 years* 
Off protocol treatment 
for reasons other than 
disease progression 
and alternative therapy  
→ 
Clinical follow-up/ 
Observation 
 
↓ 
 
↓ 
 
Events at any time: 
Disease Progression 
Alternative therapy 
 
Events at any time: 
Disease Progression  
New anti-cancer therapy 
 
↓ 
 
 
 
Survival Follow-up/ 
Event Monitoring** 
 
 
*When patients complete Cycle 9, the cycle length can be increased to 6 weeks with imaging every other 
cycle (~12 weeks) 
**NOTE: Survival follow-up/Event Monitoring will cease for all patients as of 31Aug2025 
Cycle = 21 days ±3 days for Cycles 1-9 
Cycle = 42 days ±7 days for Cycles 10 and beyond 
 
Generic name: futibatinib (TAS-120) 
Brand name(s): n/a 
Availability: Supplied by Taiho Pharmaceuticals 
Generic name: pembrolizumab 
Brand name(s): Keytruda® 
Availability: Commercial 

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1.0 
Background  
1.1 
Hepatocellular Carcinoma 
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. It is 
the sixth most common cancer worldwide and the fourth leading cause of cancer death.1 
Between 1990 and 2015, the incidence of this specific disease has increased significantly 
owing mainly to changing age structure and population growth.1 Patients often present with 
advanced disease when first diagnosed. The natural history of untreated advanced HCC 
has a dismal 3-year survival of approximately 28%.2 Even with recent advances in systemic 
treatments, median overall survival (OS) ranges from 10.7 to 13.6 months.3,4 Since 2007, 
sorafenib, an oral multikinase inhibitor, has been established as first line systemic therapy 
for patients with advanced HCC. This is based on the results of a phase III clinical trial 
(SHARP) where Llovet and colleagues randomized 602 patients to sorafenib or placebo.3 
Patients on the sorafenib arm demonstrated an improvement in OS (10.7 versus 7.9 months; 
hazard ratio (HR), 0.69; 95% CI, 0.55-0.87; P<0.001). Kudo and colleagues demonstrated 
non-inferiority of lenvatinib, another oral multikinase inhibitor, in comparison to sorafenib 
in patients with untreated advanced HCC.4 In this phase III trial, 954 patients were 
randomly assigned to lenvatinib or sorafenib. The median OS were 13.6 and 12.3 months, 
respectively (HR 0.92, 95% CI 0.79-1.06). More recently, atezolizumab, an anti-PD-L1 
antibody, in combination with bevacizumab, a monoclonal anti-VEGF antibody, showed 
superior outcomes (67.2% OS at 12 months vs. 54.6% with sorafenib), which led to FDA 
approval of the combination as the first-line systemic treatment for advanced HCC. Second 
line treatments include multikinase inhibitors cabozantinib and regorafenib, the anti VEGF 
antibody ramucirumab, and the anti PD1 antibodies nivolumab and pembrolizumab.5 
However, toxicity often limits the use of these agents and responses with these therapies 
are often measured in months. Majority if not all of patients will progress. Thus, there is a 
large unmet need for novel tailored treatments in HCC. 
1.2 
FGF-19 expression and role of FGFR4 inhibitor in HCC 
Fibroblast growth factor (FGF) and fibroblast growth factor receptor (FGFR) signaling 
system is involved in broad biological processes including embryogenesis, angiogenesis, 
tissue homeostasis and cancer progression.6 The FGF family consists of 22 members with 
FGF-19 functioning as a secreted endocrine signal that regulates many metabolic processes 
such as phosphate, glucose, and lipid metabolism.7 Emerging data suggest FGF-19 is a 
potential HCC driver8,9 with exclusive binding to FGFR4 in the presence of co-receptor 
klotho-β.10 FGF-19 overexpression in HCC occurs via several mechanisms including 
amplification of the FGF19/CCND1 locus on chromosome 11q13.3 (5% of cases9,11,12) and 
epigenetic alterations13 (23%). Aberrant expression of FGF-19 in transgenic mice has been 
shown to promote liver proliferation, dysplasia and tumor formation by enhancing 
expression of α-fetoprotein(AFP).14 Furthermore, recombinant FGF-19 promotes 
proliferation and invasive ability of HCC cells while knockdown of FGF-19 or FGFR4 
inhibits proliferation and invasion as well as induces apoptosis of HCC cells.15 The binding 
of FGF-19 to FGFR4 form a homodimer receptor complex in the presence of klotho-β 
leading to downstream signaling pathways including Ras-Raf-ERK/2MAPK and PI3K-
Akt.16,17 Several studies have shown FGF-19 amplification was independently associated 
with shorter survival and higher risk of recurrence with poor prognostic factors including 
microvascular invasion and high AFP.12,18,19 
A number of pan-FGFR inhibitors are under development in different phases of clinical 
trials in different disease types including LY2874455 (NCT01212107), AZD4547 
(NCT02965378), infigratinib (NCT01004224), erdafitinib (NCT02365597), PRN1371 

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(NCT02608125), ASP5878 (NCT02038673). Kim and colleagues recently published 
results of the phase I trial using BLU-554 (fisogatinib) with accompanying IHC essay for 
FGF19 expression in advanced HCC.20 This drug showed an overall response rate of 17% 
with 1 complete response and 10 partial responses. This data was encouraging but the level 
of IHC positivity was not correlated with response or genomic amplification of the FGF19 
locus.  
Futibatinib is a novel and highly selective irreversible pan-FGFR inhibitor. In the phase I 
dose-escalation study, 460 patients with solid tumor harboring FGF amplifications or 
FGFR aberrations showed manageable toxicity and had reasonable clinical activity.21 The 
recommended phase 2 dose was 20mg daily. The most frequently reported treatment-
related adverse events include hyperphosphatemia, diarrhea, dry mouth, nausea, and 
stomatitis. Currently, there is no clinical data on the efficacy of futibatinib alone or the 
combination of futibatinib and immunotherapy in HCC. 
1.3 
Role of checkpoint inhibitors (CPI) in HCC 
The role of cytotoxic immune response against a tumor requires a complex and evolving 
interaction between several immune cells. T-cell activation requires antigen-specific 
receptor signaling in addition to a second costimulatory signal;22 the lack of this latter 
signal may lead to unresponsive state known as clonal anergy.23 The first signal involves 
the binding of T-cell receptor to a peptide presented by major histocompatibility complex 
(MHC) of antigen presenting cells (APCs). The second important costimulatory signal 
involves the interaction between B7 (CD80/86) on the APCs and CD28 on T cells. The 
combination of signaling leads to T-cell proliferation, cytokine release and upregulation of 
immune response. CD28, cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed 
death-1 (PD-1), inducible costimulator (ICOS) and BTLA (B and T lymphocyte attenuator) 
are homologous costimulatory receptors that regulate T-cell activation and tolerance.24 
Other costimulatory receptors include CD137, OX40, CD27, LAG3, TIM3.25 CTLA-4 
competes with CD28 for B7 binding with higher affinity. There are two PD-1 ligands, PD-
L1 and PD-L2 that bind PD-1 receptor. Whereas CD28 signaling leads to T-cell activation 
and survival, CTLA-4 and PD-1 signaling inhibit T-cell responses.24 
Preclinical work has demonstrated chronic inflammation in the liver as seen in viral 
hepatitis B (HBV), hepatitis C (HCV) and autoimmune hepatitis appears to promote a 
microenvironment that favors T cell exhaustion.26 Comparing to liver biopsies from normal 
individuals, patients with chronic inflammatory conditions contained increased numbers of 
PD-1 expressing lymphocytes, PD-L1 on intrahepatic Kupffer cells and liver sinusoidal 
endothelial cells. It is suggested that high antigen load and high frequencies of infected 
liver cells seen in HBV infected patients result in persistent antigen exposure and the 
expression of co-inhibitory molecules such as PD-1, CTLA-4, LAG-3, etc,27 leading to a 
less effective immune response capable of controlling the infection. Additionally, other 
factors seen in chronic inflammatory conditions include increased levels of IL-10, TGF-ß, 
increased frequency of Tregs as well as impaired antigen presentation.28–32 Altogether, 
these factors contribute to an immunosuppressive environment associated with chronic 
inflammation that fosters the development and growth of HCC. Multiple studies, both in 
vitro and in vivo, have shown by blocking the inhibitory receptor pathways, the function 
of specific CD8+ T cells can be restored.33–37 Using anti-PD-1 or anti-PD-L1 mAb in HBV 
murine models also showed clearance of HBV in vivo.33,35 
One of the first immunotherapies studied in HCC was tremelimumab, a human IgG2 
monoclonal antibody (mAb) that blocks CTLA-4, one of many inhibitory receptors that 
interfere with T cell activation. In a pilot phase II clinical trial involving 20 HCV-related 

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HCC patients with advanced tumor that had relapsed or progressed on at least one previous 
therapy, 3 of 17 evaluable patients had confirmed partial response with one patient having 
clinical benefit that lasted to 15.8 months.38 It was also notable that 3 patients had transient 
complete viral response during follow up. Adverse events included transient grade 3 
transaminitis occurring in 45% of patients after first dose. Since then, several clinical trials 
involving PD-1 inhibitors have shown clinical activity in HCC and are FDA approved for 
use.39,40 Pembrolizumab has been evaluated in the 2nd line in HCC in phase II and phase III 
clinical trials with common toxicities including increased AST (13.3%), bilirubin (7.5%), 
fatigue and pruritus, as well as immune-related (18.3%) adverse events. These include 
hypothyroidism, hyperthyroidism and pneumonitis. The FDA approved dose for 
pembrolizumab is 200mg IV every 3 weeks or 400mg IV every 6 weeks. 
1.4 
Rationale for combining FGFR4 inhibitor and PD-1 inhibitor 
Patients with advanced HCC have a dismal prognosis. Despite the recent approval of the 
combination atezolizumab and bevacizumab, this combination showed a confirmed 
response rate of only 27.3% by conventional RECIST 1.1 and 33.2% by mRECIST criteria. 
The median PFS is 6.8 months. There is currently no biomarker to predict response in these 
patients. Furthermore, the implementation of this combination as the new standard of care 
front line therapy has significantly changed the sequencing of treatments of HCC, as many 
of the currently approved therapies were not tested in ICP experienced patients. Thus, this 
poses the important question whether every patient with advanced HCC should receive this 
combination and whether there is a role for continuing ICP in combination with other 
agents in the second line setting. 
FGFR4 inhibitors appeared to have activity in HCC, however, duration of response is 
similar to that of single agent CPI in the second line setting, inclusive of patients with 
negative FGF19 expression.20 Combining FGFR inhibitors with CPI appeared synergistic. 
Previously, FGFR-altered cancers have been correlated with non-T-cell-inflamed 
microenvironment.42 Palakurthi and colleagues confirmed this finding in genetically 
engineered mice showing significant decrease in T and natural killer cells, increased 
regulatory T cells, and exhaustion marker-positive T cells.43 The combination of erdafitinib 
with anti-PD-1 leads to decrease infiltration of immunosuppressive TAMs, increased NK 
and B cells and higher proliferative, activated T and NK cells. Furthermore, the 
combination resulted in significant increase in both T-cell fraction and clonality resulting 
in improved survival. This provides a strong rationale for combining the use of futibatinib 
with anti-PD-1 antibody.  
As of Amendment 4, we have expanded this trial to allow most patients with metastatic 
hepatocellular carcinoma (HCC) regardless of FGF19 expression at baseline. Our rationale 
for including patients with no known FGF19 expression by IHC at registration (but will be 
tested retrospectively) is three-fold: 1) In the current study, of 36 patients screened for 
FGF19 by IHC, we observed no FGF19 expression in only 5 patients (13%); 2) single agent 
FGFR inhibitor has demonstrated activity in those with no FGF19 expression as evidenced 
by Kim and colleagues who noted stable disease in 16 patients (50%) out of 32 patients20; 
and 3) we have enrolled 11 patients with FGF19 expression with a total target goal of 
22 evaluable patients. 
The treatment landscape for HCC is rapidly evolving. Since the conception of this protocol, 
another regimen has been approved in the first line setting (tremelimumab and 
durvalumab), which demonstrated improvement in survival for patients with advanced 
unresectable HCC. Furthermore, recently, we have received matured data from the 
IMbrave150 regimen which showed that patients are staying on treatment longer than ever, 

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and little is known of their liver function at the end of treatment. In clinical practice, we 
are observing patients with worsening bilirubin levels above clinical trial criteria or rapid 
decompensation of their cirrhosis making it difficult to enroll patients in the second line 
and later.  
In an effort to improve recruitment to test our hypothesis, the protocol is being amended to 
reflect the changing treatment landscape. By adjusting the eligibility criteria, we hope to 
enroll advanced HCC patients in any line of systemic therapy who are not  eligible for the 
standard first line treatments (e.g., due to history of varices with bleeding risks, or having 
portal vein invasion of disease) including IMbrave150 or STRIDE regimens based on the 
criteria listed in the respective clinical trials. We will continue to test for FGF19 tissue 
retrospectively, which would allow us to explore the efficacy signal of this combination in 
patients with FGF19 expression. 
We therefore hypothesize that futibatinib in combination with anti-PD-1 antibody in 
patients with or without FGF19 expression will improve progression free survival in 
advanced HCC patients. This will be the first biomarker driven clinical trial combining CPI 
with pan-FGFR inhibitor. These results are expected to have an important positive impact 
because they will provide evidence guided understanding and indication of the use of 
FGFR inhibitor with a CPI in HCC. 
1.5 
Correlatives  
1.51 
Cell free DNA (cfDNA) 
Detection of cancer specific mutations from the peripheral blood is an area of active 
investigation in many different types of cancers. An accumulating body of literature 
confirms an excellent correlation between mutations found in cancer tissues and mutations 
detected in cfDNA from the same patients.47 Changes in cfDNA also correlate well with 
tumor marker dynamics in serial sampling, suggesting that cfDNA mutant allele fraction 
changes reflect changes in disease burden over time and treatment. Plasma based DNA 
mutation detection should therefore provide longitudinal changes in the representative 
genomic landscape of the malignancy in a non-invasive manner, overcoming the two major 
limitations of tissue based DNA mutation analysis (invasiveness and limited sampling from 
a genetically heterogeneous tumor).48–50 In this protocol we will explore the utility of 
cfDNA as a marker to assess treatment response in advanced HCC. 
1.52 
3-D cell cultures (organoids) and microfluidic device 
Preclinical tumor models are important tools to study cancer biology, develop novel 
therapeutics, and provide information for treatment decisions. However currently available 
tumor models such as cell lines, transgenic mice and patient-derived xenograft (PDX) 
models have inherent limitations that can adversely affect the translation of preclinical 
findings to the clinic. Patient-derived tumor organoids and microfluidic devices are 3-D 
cell cultures which enable the establishment of ex vivo tumor models from scant core-
needle biopsy specimen in a timely manner. These tumor organoids recapitulate both 
phenotypes and genotypes of the donor tumo.r67 The laboratory of 
 at our institution has successfully established such tumor 
organoids and device from core-biopsy tumor specimens donated by patients with 
metastatic hepatocellular carcinoma and hepatocytes, respectively. The established tumor 
organoids were ready for drug screening and related molecular studies within 4-6 weeks of 
the biopsy. Though the concordance between treatment effect in tumor organoids and the 
clinical benefit observed in the donor patients has been reported, the role of tumor 
organoids has not been prospectively evaluated in clinical trials of patients with advanced 
hepatocellular carcinoma. Here, we aim: 1) to determine if drug response from a parallel 

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ex vivo trial using patient-derived tumor organoids correlates with clinical response to 
futibatinib and pembrolizumab; and 2) to characterize the tumor microenvironment in 
antitumor immune response and resistance to this combination of therapy. 
1.53 
Patient Reported Outcomes/Quality of Life (PROQOL) 
To understand the quality of life changes while on study treatment, we will have patients 
complete an EORTC-QLQ-C30, a series of 30 items that has been previously validated. 
The EORTC-QLQ-C30 is used to assess patient quality of life for patients with cancer. 
This questionnaire will be completed prior to treatment on Day 1 of the first cycle and prior 
to treatment on Day 1 of the 4th cycle to correspond with imaging results. 
1.6 
Study Design 
This is a single-arm, two-stage, phase II trial to assess the efficacy of futibatinib plus 
pembrolizumab in advanced hepatocellular carcinoma for patients with FGF19 expression. 
Patients will receive futibatinib 20 mg daily Days 1-21 and will receive pembrolizumab 
200 mg Day 1 of each 21 day cycle per current clinical standard of care. Patient will receive 
treatment until disease progression or unacceptable toxicities. Patients will undergo 
restaging scans every 3 cycles. Subjects will be monitored for adverse events from the 
beginning of the study drug to 28 days after the last dose. We will collect blood samples 
for determination of cell free DNA at baseline, after 3 and 6 cycles, and at progression. We 
will collect tumor biopsy specimens before treatment initiation to develop patient derived 
tumor organoid. 
Once patient has completed 9 cycles of treatment, the cycle length can be extended to 
6 weeks with futibatinib daily Days 1-42 and pembrolizumab 400mg Day 1 of each 42 day 
cycle (as currently approved by FDA). Restaging will be done every other cycle 
(~12 weeks). Patient will continue to receive treatment until disease progression or 
unacceptable adverse events. 
 

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2.0 
Goals  
2.1 
Primary Goal 
Determine the efficacy of combination of futibatinib and pembrolizumab in patients with 
advanced HCC and high FGF19 expression using progression free survival (PFS) at 6 
months. 
2.2 
Secondary Goals 
2.21 
Assess the safety and tolerability of futibatinib and pembrolizumab combination 
through adverse event monitoring. 
2.22 
Determine the overall objective response rate (ORR) and overall survival (OS) of 
patients with advanced HCC treated with futibatinib and pembrolizumab 
combination. 
2.23 
Assess change in overall health-related quality of life, as measured by the global 
health domain of the European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire (EORTC-QLQ-C30) between baseline and 
at time of first-restaging scan. 
2.3 
Exploratory Objectives 
2.31 
To evaluate the prognostic effect of baseline cfDNA. 
2.32 
To determine whether the change in cfDNA at 2 months of treatment from 
baseline is associated with PFS and OS. 
2.33 
To correlate drug response in patient derived organoids with clinical response 
and characterize the tumor microenvironment. 
 
 

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3.0 
Patient Eligibility 
3.1 
Registration – Inclusion Criteria 
3.11 
Age ≥18 years 
3.12 
Adequate tissue for FGF19 testing by mRNA or IHC. 
3.13 
Disease characteristics: 
Radiologically or pathologically confirmed hepatocellular carcinoma (HCC) that 
is not eligible for curative resection, transplantation, or ablative therapies.  
NOTE: Prior radiation, chemoembolization, radioembolization, or other local 
ablative therapies or hepatic resection are permitted. 
3.14 
Measurable disease by any imaging modality as defined by RECIST 1.1 criteria 
(See Section 11.0) in at least one site not previously treated with radiation or 
liver directed therapy (including bland, chemo- or radio-embolization, or 
ablation) 
NOTE: Tumor lesions in a previously irradiated area are not considered 
measurable disease; disease that is measurable by physical examination only is 
not eligible. 
3.15 
ECOG Performance Status (PS) 0, 1 or 2 (Appendix I). 
3.16 
The following laboratory values obtained ≤15 days prior to registration:  
• 
Absolute neutrophil count (ANC) ≥1500/mm3 
• 
Hemoglobin ≥8.0 g/dL 
• 
Platelet count ≥75,000/mm3 
• 
Albumin ≥2.5 g/dL 
• 
Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤2.5 × 
ULN (or ≤5 × ULN for patients with liver metastasis) 
• 
Total bilirubin ≤2 × ULN 
• 
Phosphorus ≤1.5 × ULN 
• 
Calcium ≤1.5 × ULN 
• 
PT/INR/aPTT ≤1.5 × ULN OR if patient is receiving anticoagulant therapy 
then INR or aPTT is within target range of therapy 
• 
Calculated creatinine clearance ≥40 ml/min using the Cockcroft-Gault 
formula below: 
Cockcroft-Gault Equation: 
 
 
Creatinine clearance for males 
= 
(140 - age)(weight in kg) 
 
 
(72)(serum creatinine in mg/dL) 
Creatinine clearance for females 
= 
(140 - age)(weight in kg)(0.85) 
 
 
(72)(serum creatinine in mg/dL) 
3.17 
Child-Pugh scores of ≤7 (Child-Pugh A or B7) (See Appendix II) 
3.18 
BCLC stage A, B, or C (See Appendix III) 
3.19a 
Negative pregnancy test done ≤7 days prior to registration, for persons of 
childbearing potential only. 
3.19b Willing to use an adequate method of contraception (see Appendix IV) from 
Registration through 120 days after the last dose of study medication  
NOTE: Only for a) persons of childbearing potential or b) persons able to father a 
child with partners of childbearing potential) 

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3.19c 
Able to swallow oral medication. 
3.19d Provide written informed consent. 
3.19e 
Willingness to provide mandatory blood specimens for correlative research (see 
Section 14.0). 
3.19f 
Willingness to provide mandatory tissue specimens for correlative research (see 
Section 17.0). 
3.19g Willingness and the ability to comply with scheduled visits (including 
geographical proximity), treatment plans, laboratory tests, and other study 
procedures.  
3.19h Ability to complete questionnaires by themselves or with assistance. 
3.2 
Registration - Exclusion Criteria 
3.21 
Known standard therapy for the patient’s disease that is potentially curative or 
definitely capable of extending life expectancy. 
3.22 
Eligible for first-line treatment with IMbrave150 or STRIDE regimens. 
3.23 
Any of the following because this study involves an investigational agent whose 
genotoxic, mutagenic and teratogenic effects on the developing fetus and 
newborn are unknown: 
• 
Pregnant persons 
• 
Nursing persons 
• 
Persons of childbearing potential who are unwilling to employ adequate 
contraception 
3.24 
Any of the following prior therapies:  
• 
Surgery ≤4 weeks prior to registration 
• 
Radiotherapy for extended field ≤4 weeks prior to registration or limited field 
radiotherapy ≤2 weeks prior to registration 
• 
Systemic anticancer therapy ≤2 weeks prior to registration  
NOTE: Prior immunotherapy is allowed unless patient discontinued due to 
Grade 4 AE  
• 
Live vaccine ≤30 days prior to registration 
• 
Prior treatment with FGFR inhibitor 
• 
Received strong inhibitors and inducers and sensitive substrates of CYP3A4 
≤2 weeks prior to registration 
• 
Received a drug that has not received regulatory approval for any indication 
as follows: 
o ≤2 weeks prior to registration for nonmyelosuppressive agents or  
o ≤4 weeks prior to registration for myelosuppressive agents 
3.25 
History and/or current evidence of any of the following disorders: 
• 
Retinal or corneal disorder confirmed by retinal/corneal examination and 
considered clinically significant in the opinion of the Investigator 
• 
Pneumonitis or interstitial lung disease within ≤3 years prior to registration 
3.26 
Active CNS metastasis and/or carcinomatous meningitis.  
NOTE: Patients with previously treated brain metastases that are clinically and 
radiologically stable (for at least 4 weeks prior to enrollment) are eligible. 

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3.27 
Corrected QT interval using Fridericia’s formula (QTcF) >480 msec.  
NOTE: Patients with an atrioventricular pacemaker or other condition (for 
example, right bundle branch block) that renders the QT measurement invalid are 
an exception and the criterion does not apply. 
3.28 
Co-morbid systemic illnesses or other severe concurrent disease which, in the 
judgment of the investigator, would make the patient inappropriate for entry into 
this study or interfere significantly with the proper assessment of safety and 
toxicity of the prescribed regimens. 
3.29a 
Receiving any other investigational agent which would be considered as a 
treatment for the primary neoplasm. 
3.29b History or risk of autoimmune disease, including, but not limited to, systemic 
lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular 
thrombosis associated with antiphospholipid syndrome, Wegener’s 
granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple 
sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis. 
Notes: 
• 
Patients with a history of autoimmune hypothyroidism on a stable dose of 
thyroid replacement hormone are eligible. 
• 
Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen 
are eligible. 
• 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis would 
be excluded) are permitted provided that they meet the following conditions: 
o Must not have ocular manifestations 
o Rash must cover less than 10% of body surface area (BSA) 
o Disease is well controlled at baseline and only requiring low potency 
topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 
0.1%, flucinolone 0.01%, desonide 0.05%, aclometasone 
dipropionate 0.05%) 
o No acute exacerbations of underlying condition within the last 
12 months (not requiring psoralen plus ultraviolet A radiation 
[PUVA], methotrexate, retinoids, biologic agents, oral calcineurin 
inhibitors; high potency or oral steroids) 
3.29c 
Known active human immunodeficiency virus (HIV) infection (defined as 
patients who are not on anti-retroviral treatment and have detectable viral load 
and CD4+ <500/ml). 
NOTE: HIV-positive patients who are well controlled on anti-retroviral therapy 
are allowed to enroll. 
3.29d History and/or current evidence of any of the following disorders: 
a. Non-tumor related alteration of the calcium-phosphorus homeostasis that is 
considered clinically significant in the opinion of the Investigator 
b. 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  
c. Retinal or corneal disorder confirmed by retinal/corneal examination and 
considered clinically significant in the opinion of the Investigator.  

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3.29e 
Uncontrolled intercurrent illness including, but not limited to:  
• 
Ongoing or active severe infection 
NOTE: Must be afebrile >7 days to be eligible. Patient may be eligible if 
fever is present and infection has been ruled out or fever is related to tumor. 
• 
Psychiatric illness/social situations that would limit compliance with study 
requirements. 
3.29f 
Clinically significant or uncontrolled cardiac disease, including unstable angina, 
acute myocardial infarction within 6 months from Day 1 of study treatment 
administration, New York Heart Association Class III and IV congestive heart 
failure, and uncontrolled arrhythmia  
NOTE: Participants with pacemaker or with atrial fibrillation and well controlled 
heart rate are allowed. 
3.29g Other active malignancy <6 months prior to registration.  
EXCEPTIONS: Non-melanotic skin cancer, papillary thyroid cancer, or 
carcinoma-in-situ of the cervix, or others curatively treated and now considered 
to be at less than 30% risk of relapse are eligible. 
3.29h Prior organ transplantation. 
 

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4.0  
Test Schedule 
4.1 
Test schedule for Hepatocellular Carcinoma (HCC) 
 
Screening 
Active Monitoring Phase 
Obs 
Tests and procedures1 
≤21 days 
prior to 
registration 
After Reg 
 prior to 
C1D1 Tx 
Cycle 1 
Days 8, 
15 
End of 
every 
cycle 
End of every 
3 cycles 
(Cycles 1-9)2 
End of every 
2 cycles 
(Cycles 10+)3 
End of 
treatment 
Safety follow-
up: 30 days 
post treatment 
Clinical 
follow-up4 
Window 
 
 
±3 days ±3 days 
±7 days 
±7 days 
±7 days 
±7 days 
±7 days 
History and exam, Wt, PS  
X 
 
X 
X 
 
 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
Adverse event assessment5 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy test6 
X 
 
 
 
 
 
 
 
 
Hematology group: CBC /w diff  
X7 
 
X 
X 
 
 
X 
X 
 
Chemistry group8 
X9 
 
X 
X 
 
 
X 
X 
 
TSH 
X 
 
 
X 
 
 
X 
X 
 
Ophthalmologic testing10 
X 
 
 
 
X11 
X12 
 
 
 
Nutrition consult13 
 
 
X 
 
 
 
 
 
 
FGF19 testingR 
 
X14 
 
 
 
 
 
 
 
AFP, AFP-L3 %15 
X 
 
 
 
X 
X 
 
 
 
 
Cycle = 21 days ±3 days for Cycles 1-9; Cycle = 42 days ±7 days for Cycles 10+; R= Research funded (See Section 19.0) 
1 All tests and procedures should be performed as needed for clinical care at treating physician’s discretion. 
2 End of Cycles 3, 6, 9 (NOTE: Imaging schedule may be adjusted by treating oncologist as necessary for clinical care.) 
3 End of Cycles 11, 13, 15, etc. (NOTE: Imaging schedule may be adjusted by treating oncologist as necessary for clinical care.) 
4 Observation: every 9 weeks until disease progression, new anti-cancer therapy, death, withdrawal from clinical follow-up, or a maximum of 18 month post registration. 
5 AEs must be assessed at every cycle; Baseline AE collection for eligibility should be done after patient signs main study consent 
6 For persons of childbearing potential only: Must be done ≤7 days prior to registration and repeated prior to C1D1 if >7 days between registration and treatment. 
7 Eligibility requires ≤15 days prior to Registration 
8 Chemistry: comprehensive metabolic panel (CMP) (80053) plus phosphorus (84100) 
9 Eligibility requires ≤15 days prior to Registration 
10 Must include external ocular exam; routine slit lamp biomicroscopy of anterior ocular structures include the anterior and posterior chambers; dilation of the pupil with 
direct/indirect fundoscopy per institutional guidelines; must be done ≤6 months prior to treatment and 2 months after first dose of futibatinib and every 2 months until 6 months 
after first dose, and every 3 months thereafter and urgently at any time for visual symptoms. 
11 Every 2 months for first 6 months and every 3 months until 3 months after last dose of futibatinib; Order at any time if clinically indicated. 
12 Every 3 months until 3 months after last dose of futibatinib; Order at any time if clinically indicated 
13 Nutrition consult may be done one time at anytime after starting treatment as needed. (This exam is part of expanded patient care.) 
14 Testing may be done on archived tissue at any time after registration – not required to be prior to C1D1 (see Section 17.0) 
15 Performed in all HCC patients at baseline 

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Screening 
Active Monitoring Phase 
Obs 
Tests and procedures1 
≤21 days 
prior to 
registration 
After Reg 
 prior to 
C1D1 Tx 
Cycle 1 
Days 8, 
15 
End of 
every 
cycle 
End of every 
3 cycles 
(Cycles 1-9)2 
End of every 
2 cycles 
(Cycles 10+)3 
End of 
treatment 
Safety follow-
up: 30 days 
post treatment 
Clinical 
follow-up4 
Clinical tumor genomic testing16 
 
X 
 
 
 
 
 
 
 
Tumor measurement17 
X18 
 
 
 
X19 
X20 
X 
 
X 
Tumor biopsy 
X21R 
 
 
 
 
 
 
 
 
Research blood specimens22R 
 
X 
 
 
X23 
 
X 
 
 
Research tissue specimens 24R 
X 
 
 
 
 
 
X 
 
 
Patient medication diary (Appendix V)25 
 
 
 
X 
 
 
X 
 
 
Patient questionnaire booklets (Appendix 
VII) 
 
X 
 
 
X26 
 
X 
 
 
Cycle = 21 days ±3 days for Cycles 1-9; Cycle = 42 days ±7 days for Cycles 10+; R= Research funded (See Section 19.0) 
 
 
16 Clinical testing – Note: Molecular analysis including next generation sequencing (NGS) to be done per clinical practice – should be ordered/tested any time prior to end of 
treatment and results should be uploaded in Medidata Rave® when available 
17 To be performed per Mayo Clinic Cancer Center guidelines – For HCC usually CT chest/abdomen/pelvis or CT chest and MRI abdomen/pelvis; NOTE: If pseudoprogression is 
suspected at any time, repeat imaging after two more cycles of treatment. 
18 Can be performed ≤28 days prior to registration 
19 To be performed about every 9 weeks (or 3 cycles), ≤7 days prior to planned Day 1 of Cycles 4, and 7 or as clinically indicated 
20 To be performed about every 12 weeks, ≤7 days prior to planned Day 1 of Cycles 10, 12, 14 etc., or as clinically indicated 
21 Research biopsy should be done after registration and prior to treatment on C1D1. Research biopsy may be omitted after discussion with PI, (e.g., if it is not medically feasible, 
or exceeds lab capacity, or other reason). 
22 Research blood specimens to be collected on Cycle 1 Day 1 (or any time between registration and Cycle 1 Day 1), end of Cycle 3 and end of treatment (see Section 14.0) 
23 End of Cycle 3 only 
24 Research tissue specimens to be collected during research biopsy any time between registration and prior to treatment on C1D1 (see Section 17.0). Biopsy can be omitted for 
patients for whom investigator deems it unsafe. 
25 The diary must begin the day the patient starts taking the medication, and must be completed per protocol and returned to the treating institution at each visit. 
26 End of Cycle 3, prior to C4 only. 

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4.2 
Survival Follow-up/Event Monitoring 
NOTE: Survival Follow-up/Event Monitoring on this study will cease as of 31Aug2025. 
NOTE: Timelines are approximate and not meant to represent exact dates. 
 
Survival Follow-up 
q. 6 months 
Death 
New Primary 
Survival Follow-up1 
X 
X 
At each occurrence 
1. If a patient is still alive 5 years after registration, no further follow-up is required. 
5.0 
Grouping Factor  
Enrollment Group: Safety run-in vs. phase II 
6.0 
Registration Procedures 
6. 
Registration (Step 1) 
To register a patient, access the Mayo Clinic Research Registration Application web page 
at 
 The registration application is available 24 hours a day, 7 
days a week. Back up and/or system support contact information is available on the 
website. If unable to access the website, contact Research Registration at  
between the hours of 8 a.m. and 4:30 p.m. Central Time (Monday 
through Friday). 
The instructions for the registration/randomization application are available on the Mayo 
Clinic Office of Clinical Trials web page
nd detail the process for completing and confirming patient 
registration. Prior to initiation of protocol treatment, this process must be completed in its 
entirety and an MCCC subject ID number must be available as noted in the instructions. 
It is the responsibility of the individual registering the patient to confirm the process has 
been successfully completed prior to release of the study agent. Patient registration via 
the registration/randomization application can be confirmed in any of the following ways: 
• 
Contact Mayo Clinic Research Registration Office 
 If 
the patient was fully registered, the Research Site Management staff can access 
the information from the centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section “Finding/Displaying 
Information about A Registered Subject.” 
6.2 
Verification of materials 
Prior to accepting the registration, registration/randomization application will verify the 
following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information  
6.3 
Documentation of IRB approval 
Documentation of IRB approval must be on file in the Research Site Management Office 
before an investigator may register any patients.  

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In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) with the Research Site 
Management Office 
 If the necessary 
documentation is not submitted in advance of attempting patient registration, the 
registration will not be accepted and the patient may not be enrolled in the protocol until 
the situation is resolved. 
When the study has been permanently closed to patient enrollment, submission of annual 
IRB approvals to the Research Site Management Office is no longer necessary. 
6.4 
Patient Permissions 
At the time of registration, the following will be recorded: 
• 
Patient is or is not willing to complete questionnaires as part of this study 
• 
Patient has/has not given permission for Mayo Clinic to have access to his/her 
recurrence/progression clinical sample(s) for research testing as part of this study. 
6.5 
Correlative Research 
6.51 
Mandatory 
A mandatory correlative research component is part of this study, the patient will 
be automatically registered onto this component (see Sections 3.1, 17.0). 
6.52 
Banking 
At the time of registration, the following will be recorded: 
• 
Patient has/has not given permission to store and use his/her sample(s) for 
future research on cancer at Mayo Clinic. 
• 
Patient has/has not given permission to store and use his/her sample(s) for 
future research to learn, prevent, or treat other health problems. 
• 
Patient has/has not given permission for MCCC to give his/her sample(s) to 
researchers at other institutions. 
• 
Patient has/has not given permission for Mayo Clinic to place coded genetic 
and medical information in secure databases for future research 
• 
Patient has/has not given permission for Mayo Clinic to contact him/her for 
future research opportunities 
6.6 
Treatment on protocol 
Treatment on this protocol must commence at Mayo Clinic under the supervision of a 
medical oncologist. 
6.7 
Treatment start 
Treatment cannot begin prior to registration and must begin ≤7 days after registration. 
6.8 
Pretreatment 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified on the test schedule. 
6.9a 
Baseline symptoms 
All required baseline symptoms (see Section 10.6) must be documented and graded. 
6.9b 
Ophthalmology consult required 
An ophthalmologist has seen the patient and confirms the patient is a suitable candidate 
for this study. 

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6.9c 
Study drug 
Study drug is available on site. 
6.9d 
Blood draw kits 
Blood draw kit is available on site for sites outside of Rochester, MN. 
6.9e 
Study Conduct 
The clinical trial will be conducted in compliance with regulations (21 CFR 312, 50, and 
56), guidelines for Good Clinical Practice (ICH Guidance E6), and in accordance with 
general ethical principles outlined in the Declaration of Helsinki; informed consent will 
be obtained from all participating patients; the protocol and any amendments will be 
subject to approval by the designated IRB prior to implementation, in accordance with 
21 CFR 56.103(a); and subject records will be stored in a secure location and subject 
confidentiality will be maintained. The investigator will be thoroughly familiar with the 
appropriate use of the study drug as described in the protocol and Investigator’s 
Brochure. Essential clinical documents will be maintained to demonstrate the validity of 
the study and the integrity of the data collected. Master files should be established at the 
beginning of the study, maintained for the duration of the study and retained according to 
the appropriate regulations. 
 
 

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7.0 
Protocol Treatment 
7.1 
Treatment Schedule 
Patients may receive treatment on this trial for up to 2 years until disease progression, 
unacceptable adverse events, or patient refusal. 
7.11 
Treatment medication table – Cycles 1-9 
Agent 
Dose Level 
Route 
Day 
ReRx 
futibatinib 
20 mg* 
oral 
Once daily on Days 1-21 
Q3w 
pembrolizumab 
200 mg 
IV 
1 
Q3w 
Cycle length = 21 days ±3 days  
*Investigator may start patients at lower dose (16mg) if clinically indicated (e.g., 
patient history of diarrhea) after discussion with PI 
Once patients have completed Cycle 9, the cycle length can be increased to 
6 weeks with imaging every other cycle (~12 weeks). 
7.12 
Treatment medication table – Cycles 10 and beyond 
Agent 
Dose Level 
Route 
Day 
ReRx 
futibatinib 
20 mg 
oral 
Once daily on Days 1-42 
Q6w 
pembrolizumab 
400 mg 
IV 
1 
Q6w 
Cycle length = 42 days ±7 days 
7.13 
Futibatinib 
Futibatinib is an oral agent taken once daily by mouth with water with or without 
food. Futibatinib should be taken at the same time every day. 
On Day 1 of each cycle, the futibatinib dose should be held until at least 30 
minutes after pembrolizumab infusion. 
Futibatinib is supplied as 4 mg tablets and will be taken orally at a dose of 20 mg 
daily until the patient meets any of the administration discontinuation criteria.  
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. 
7.14 
Pembrolizumab 
Pembrolizumab is given by IV infusion over 30 minutes (-5 or +10) 
Pembrolizumab should be administered according to institutional guidelines for 
premedication and standard clinical care. 
Pembrolizumab should be administered prior to futibatinib dose on Day 1. 
7.2 
Biopsies 
If research biopsy material has already been obtained under IRB 17-003174 for this 
patient, then no additional research biopsy is needed specifically for this trial. 
Tissue for FGF-19 testing can be from archived tissue or clinical biopsy as needed. 

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7.3 
Return to consenting institution 
For this protocol, the patient must return to the consenting institution for evaluation at 
least every 21 days ±3 days during treatment for first 9 cycles. Beginning with Cycle 10 
patients must return at least every 42 days ±7 days. 
7.4 
Treatment by local medical doctor (LMD) 
Treatment with futibatinib by a local medical doctor (LMD) is not allowed. 
7.5 
Safety Run-in for first six patients 
Patients will receive futibatinib and pembrolizumab combination. The safety profile of 
both agents has been previously evaluated individually21,40. To ensure the safety of this 
combination, we will perform a safety run-in with 6 patients. If there are 2 or more 
patients out of 6 who developed excessive toxicity during first cycle, the trial will be 
temporarily closed for enrollment to allow the study team to convene and discuss the best 
next steps. 
7.51 
For this protocol, excessive toxicity will be defined as follows: 
Adverse event at least possibly related to 
the study medication 
Definition using CTCAE v5.0 
Any* 
Grade 3 resulting in treatment interruption of 
both drugs for more than 21 days 
Blood and lymphatic system disorders: 
Anemia 
Grade 3 lasting >3 days 
Any* 
Grade 4 
Investigations: 
Absolute neutrophil count decreased 
Grade 4 lasting >7 days 
Any 
Grade 5 
Gastrointestinal disorders 
• 
Diarrhea 
• 
Nausea 
• 
Vomiting 
Grade 3 lasting >3 days with optimal 
supportive care 
*Exceptions for: anemia, absolute neutrophil count; transient laboratory values without 
clinical manifestation; bowel obstruction resulting in hospitalization as a 
consequence of disease; which will not count as excessive toxicity 
 
 

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8.0 
Dosage Modification Based on Adverse Events  
Strictly follow the modifications in this table for the first two cycles, until individual treatment 
tolerance can be ascertained. Thereafter, these modifications should be regarded as guidelines to 
manage mild-to-moderate, but not debilitating, side effects. If multiple adverse events are seen, 
administer dose based on greatest reduction required for any single adverse event observed. 
Reductions or increases apply to treatment given in the preceding cycle and are based on adverse 
events observed since the prior dose. 
Special Considerations 
• 
The treating investigator may reduce/withhold/discontinue a patient’s dose for an AE of any 
grade/duration where s/he believes it to be in the best interests of the patient. 
• 
In patients who have met the criteria for permanent discontinuation, resumption of futibatinib 
may be considered if the patient is deriving clinical benefit and has fully recovered from the 
related event after consulting with PI. 
• 
Any consideration to modification of the above dose modification guidelines should be 
discussed with the Principal Investigator for approval or disapproval in advance. 
→ ALERT: 
ADR reporting may be required for some adverse events (See Section 10.0) ← 
8.1 
Dose Levels (Based on Adverse Events in Tables 8.2 and 8.3) 
Dose 
Level 
Futibatinib (TAS-120) 
Pembrolizumab 
Cycles 1-9 
Pembrolizumab 
Cycles 10+ 
1* 
20 mg 
200 mg q3w 
400mg q6w 
-1 
16 mg 
-- 
-- 
-2 
12 mg 
-- 
-- 
*Dose level 1 refers to the starting dose. 
Patients may be started at dose -1 if clinically indicated after discussion with PI 
NOTE: If either of futibatinib or pembrolizumab is discontinued, the patient can continue 
on the other drug, unless specified otherwise in the dose modification tables. If both are 
discontinued, the patient will go to survival follow-up (Section 4.2). 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
current version 5.0* unless otherwise specified   
 
 
 

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8.2 
Dose Modifications for Futibatinib 
8.21 
Dose Modifications for Futibatinib for Expected Adverse Events 
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
ACTION** 
Blood and lymphatic 
system disorders 
Anemia 
Grade 3 
Omit 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 
Omit dose until resolved to ≤Grade 1 or baseline 
Blood and lymphatic 
system disorders 
Febrile neutropenia 
Omit dose until resolved, then reduce 1 dose level  
Eye disorders 
Eye disorders - Other, 
specify - retinal 
pigment epithelial 
detachment (RPED) 
Continue at current dose and continue periodic ophthalmic 
evaluation: 
• If resolved ≤14 days to ≤Grade 1, then maintain dose level 
• If resolved >14 days to ≤Grade 1, then omit dose until 
resolved, then resume at same dose level or a lower dose 
Gastrointestinal 
disorders 
Diarrhea 
Grade 2 
Omit futibatinib dose until resolved to ≤Grade 1 or baseline 
 
Grade 3 
Omit dose until further evaluation and cause is determined 
If resolved within 21 days, and deemed related to futibatinib, 
then reduce 1 dose level 
Gastrointestinal 
disorders 
Mucositis oral 
Grade 3 
If AE persists despite optimal supportive care: Omit futibatinib 
dose until resolved to ≤Grade 1 or baseline 
Gastrointestinal 
disorders 
Nausea 
Grade 3 
If AE persists despite optimal supportive care (See 
Section 9.0): Omit futibatinib dose until resolved to ≤Grade 1 
or baseline 
Gastrointestinal 
disorders 
Vomiting  
Grade 3 
If AE persists despite optimal supportive care (See 
Section 9.0): Omit futibatinib dose until resolved to ≤Grade 1 
or baseline 
Investigations 
Alanine 
aminotransferase 
increased >5 x ULN 
AND 
Aspartate 
aminotransferase 
increased >5 x ULN  
AND 
Blood bilirubin 
increased ≥3 x ULN 
Omit futibatinib for up to 14 days until resolved to ≤Grade 1 or 
baseline, then restart at same dose level 
If related to futibatinib then reduce 1 dose level 
Investigations 
For ALT >20 x ULN, 
and 
AST >20 x ULN,  
or  
Blood bilirubin 
increased >10 x ULN 
Permanently discontinue futibatinib 

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CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
ACTION** 
Investigations 
Hyperphosphatemia 
Grade 3  
Serum phosphorus level 
>7 - ≤10 mg/dL 
Dose reduce futibatinib to the next lower dose level and initiate 
or intensify phosphate lowering therapy (See Section 9.0 for 
management suggestions) 
Re-assess serum phosphate within 7 days and at least once a 
week. 
If the serum phosphorus level has resolved to ≤Grade 2 within 
14 days after dose reduction, continue futibatinib at the 
reduced dose level. 
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), omit dosing with futibatinib until it is 
resolved to ≤Grade 2 before resuming futibatinib at the 
reduced dose prior to dose interruption. 
Investigations 
Hyperphosphatemia 
Grade 4  
Serum phosphate 
>10 mg/dL 
Omit futibatinib until it is 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 
Investigations 
Neutrophil count 
decreased 
Grade 4 
Omit 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 
Investigations 
Platelet count 
decreased 
Grade 3 
Omit 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 
Omit dose until resolved to ≤Grade 1 or baseline, then reduce 
1 dose level 
Skin and subcutaneous 
tissue disorders 
Palmar-plantar 
erythrodysesthesia 
syndrome 
Grade 3 
Omit dose until resolved to ≤Grade 1 or baseline 
• If resolved ≤21days, then maintain dose level  
• If resolved >21 days, then reduce 1 dose level 
 
Rash, maculopapular 
Omit dose until resolved to ≤Grade 1 or baseline 
• If resolved ≤21 days, then maintain dose level  
• If resolved >21 days, then reduce 1 dose level 
All others not 
specified above and at 
least possibly related 
to futibatinib 
Grade 3 
Omit dose until resolved to ≤Grade 1 or baseline 
Reduce by 1 dose level from the previous level 
 
Grade 4 (nonlab) 
Discontinue futibatinib 

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CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
ACTION** 
 
Grade 4 lab 
abnormalities 
Omit dose until resolved to ≤Grade 1 or baseline 
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 continue 
treatment at a reduced dose level 
**  Use the following to describe actions in the Action column: 
 Omit = The current dose(s) for the specified drug(s) during a cycle is skipped. The 
patient does not make up the omitted dose(s) at a later time. 
 Hold/Delay = The current dose(s) of all drugs during a cycle is delayed. The patient does 
make up the delayed dose(s) when the patient meets the protocol criteria to restart drugs. 
 Discontinue = The specified drug(s) are totally stopped. 
NOTE: Interrupt futibatinib if any adverse events are intolerable, regardless of the grade (including 
Grade 1 and 2). If or when the adverse event resolves to a tolerable state, consideration can be given to 
resuming futibatinib at the same dose if deemed appropriate or reduced by one dose level if needed  
NOTE: If the patient experiences a significant adverse event requiring a dose reduction at the start of the 
next cycle, then the dose will remain lowered for that entire subsequent cycle. If that cycle is completed 
with no further adverse events >Grade 2, then the dose may be increased, at the investigator’s discretion, 
one level at a time, in the following cycles.  
8.3 
Dosage Modifications for Pembrolizumab 
There are no dose reductions for pembrolizumab. 
Holding and discontinuation of pembrolizumab should follow clinical practice and most 
current product information. 
 
 

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9.0 
Ancillary Treatment/Supportive Care 
9.1 
Full supportive care  
Patients should receive full supportive care while on this study. This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions. All blood products and concomitant medications such as 
antidiarrheals, analgesics, and/or antiemetics received from the first day of study treatment 
administration until 30 days after the final dose will be recorded in the medical records. 
9.2 
Blood products and growth factors 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations. The use of growth factors should 
follow published guidelines of the Journal of Clinical Oncology, Volume 33, No 28 
(October 1), 2015: pp. 3199-3212 (WBC growth factors) AND Journal of Clinical 
Oncology, Volume 37, No 15 (May 20), 2019: pp. 1336-1351 (darbepoetin/epoetin). 
9.3 
Antiemetics 
Antiemetics may be used at the discretion of the attending physician. 
9.4 
Diarrhea/Colitis 
All events of diarrhea or colitis should be thoroughly evaluated for more common 
etiologies other than immune-induced effects.  
NOTE: Futibatinib can cause non-immune-related diarrhea which can be managed 
clinically. 
• 
For events of significant duration or severity or associated with signs of systemic 
inflammation or acute-phase reactants, check for immune-related colitis. 
9.41 
Grade 1- without abdominal pain/or blood in stool and symptoms. 
Infectious etiologies should be ruled out. Discontinue medications that 
may exacerbate colitis (e.g., NSAIDS) while investigating etiology. 
Patients may be managed symptomatically (e.g., loperamide). Instruct 
patients to report any increase in stools. 
9.42 
Grade 2- without abdominal pain/or blood in stool and symptoms 
<1 week, and resolve to Grade 0 or 1. Continue to monitor. Infectious 
etiologies should be ruled out. Discontinue medications that may 
exacerbate colitis (e.g., NSAIDS) while investigating etiology. Patients 
may be managed symptomatically (e.g., loperamide). Instruct patients to 
report any increase in stools. 
9.43 
Grade 2- with symptoms >1 week despite optimal supportive care, 
considersteroid therapy –first choice is budesonide at 12 mg once daily 
(if unable to obtain budesonide and/or patent continues to have diarrhea 
after 72 hours of use start systemic steroids at 0.5 mg/kg/day prednisone 
or equivalent- can be given in two doses- especially for patients that have 
nocturnal diarrhea). 
 ** Infectious etiologies should be ruled out. Discontinue medications 
that may exacerbate colitis (e.g., NSAIDS) while investigating etiology.  
9.44  
Grade 3 or greater- despite optimal supportive care including loperamide, 
and with other etiologies ruled out consider systemic steroids at 1-
2 mg/kg/day prednisone or equivalent (may be given in two daily doses-
especially for patients that have nocturnal diarrhea). 
** Assess for dehydration. Patients may require hospitalization for IV 

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steroids (1-2 mg/kg/day methylprednisolone). Discontinue medications 
that may exacerbate colitis (e.g., NSAIDS) while investigating etiology.  
** Once patients have improvement of symptoms to Grade 0 or 1 taper 
of steroids should occur over at least 1 month. If patients have been 
started on budesonide in addition to systemic steroids, start tapering the 
prednisone FIRST.  
Do NOT administer loperamide in patients with ≥Grade 3 diarrhea until 
etiology is known as it may cause toxic megacolon and/or perforation. 
If at any time patients experience diarrhea with the following symptoms: 
fever or abdominal pain patients should have a CT scan of the abdomen to 
rule out perforation. Emergent surgical evaluation should be performed if 
perforation is found. If a patient has bloody diarrhea, a Gastroenterology 
consult should be obtained. A Gastroenterology consult should be obtained 
if provider is considering infliximab for treatment of colitis. 
For all patients- assess hydration status and monitor electrolytes, including 
magnesium. 
9.5 
Hyperphosphatemia Management Recommendations 
Serum Phosphorus Resulta  
(mg/dL and mmol/L)b 
Management Suggestionsd,e,f 
ULN <P <5.5 mg/dL 
ULN <P <1.78 mmol/L 
If not already done, implement dietary restrictions and consider 
consultation with nutritionist. 
Re-assess serum phosphate within 7 days  
5.5 mg/dL ≤P ≤7.0 mg/dL 
1.78 ≤P ≤2.26 mmol/L 
 
Consider phosphate binder (monotherapy or in combination)g 
Start with sevelamer monotherapy (range from 800 mg TID to 
2400 mg TID). 
Re-assess serum phosphate within 7 days 
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 titration,h if phosphate level continues to increase 
7.0 <P ≤10.0 mg/dL 
2.26<P ≤3.23 mmol/L 
Dose reduce futibatinib to the next lower dose level and intensify 
phosphate lowering therapy 
Re-assess serum phosphate within 7 days and at least once a week 
If the serum phosphorus level has resolved to ≤Grade 2 within 14 
days after dose reduction, continue futibatinib at the reduced dose 
level 
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 
Omit 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 

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Serum Phosphorus Resulta  
(mg/dL and mmol/L)b 
Management Suggestionsd,e,f 
serum phosphorus level has not resolved to ≤Grade 2 after 14 
days, permanently discontinue futibatinib 
a. Serum phosphorus will be tested 4 days (± 24 hours) after Day 1 of Cycle 1 to initiate early intervention 
for hyperphosphatemia if indicated.  
b. mmol/L=mg/dL x 0.3229 (conversion factor)  
d. Interrupt futibatinib if any toxicities are intolerable, regardless of the grade (including Grade 1 and 2). If 
or when the toxicity resolves to a tolerable state, consideration can be given to resuming futibatinib at the 
same dose if deemed appropriate or reduced by one dose level if needed.  
e. Serum calcium levels should be assessed at the same time.  
f. Futibatinib will be permanently discontinued if ectopic mineralization or calcification associated with 
hyperphosphatemia and considered clinically significant is observed  
g. 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 quite big, but can be cut if required. No dose adjustments are 
needed in patients with renal or hepatic impairment  
h. Titrate the dose every 2-3 weeks until an acceptable serum phosphate level is reached.  
9.6 
Ocular Toxicity 
9.61 
Retinal Pigment Epithelial Detachment (RPED) 
Futibatinib can cause RPED, which may cause symptoms such as blurred vision. 
Median time to first onset of RPED is generally 40days. 
Perform a comprehensive ophthalmological examination, including OCT of the 
macula,prior to initiation of therapy, every 2 months for the first 6 months, and 
every 3 months thereafter. For onset of visual symptoms, refer patients for 
ophthalmologic evaluation urgently, with follow-up every 3 weeks until 
resolution or discontinuation of futibatinib. 
Withhold or reduce the dose of futibatinib if not resolved to ≤Grade 1 within 
14 days of symptom onset. 
9.62 
Dry Eye/Corneal Keratitis 
Per standard clinical care, treat patients with ocular demulcents as needed. 
9.7 
Liver considerations 
9.71 
Hepatobiliary disorders 
In an integrated data analysis (as of 01 October 2020), treatment-related AEs of 
ALT increased, AST increased, and blood bilirubin increased were observed in 
patients who received futibatinib at a dose of 20 mg QD. 
If any of the following parameters are reported, testing should be repeated at least 
twice a week until resolution to National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) Grade ≤1 or baseline before 
initiation of treatment, and then at least weekly until either initiation of re-
treatment or until stabilization: 
• 
Bilirubin >2 × ULN 
• 
NCI CTCAE Grade ≥3 ALT or AST elevation 
• 
NCI CTCAE Grade >2 bilirubin and any NCI CTCAE Grade ≥2 ALT or 
AST elevation 

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9.72 
Hepatic impairment 
Futibatinib PK was evaluated in subjects with mild, moderate, and severe hepatic 
impairment and healthy matched control subjects following administration of 
20mg futibatinib. While exposure was higher in subjects with hepatic 
impairment, the magnitude of exposure change did not correspond with severity 
of impairment and was not considered clinically relevant. No dose modification 
is needed in patients with impaired hepatic function.  
Patients with existing hepatic impairment should be monitored per standard 
clinical care while taking futibatinib. 
9.8 
Side effect management for immune-related adverse events 
These are to be regarded as guidelines for managing adverse events that occur with therapy 
and should not replace clinical judgement (e.g., patients with Grade 1 rash may require 
systemic steroids). Follow clinical standard of care for all events related to pembrolizumab. 
General recommendations. 
Symptomatic and topical therapy should be considered for low-grade (Grade 1 or 2, 
unless otherwise specified) events.  
For persistent (>3 to 5 days) low-grade (Grade 2) or severe (Grade ≥3) events, promptly 
start prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
Some events with high likelihood for morbidity and/or mortality – e.g., myocarditis, or 
other similar events even if they are not currently noted in the guidelines – should 
progress rapidly to high dose IV corticosteroids (methylprednisolone at 2 to 4 mg/kg/day) 
even if the event is Grade 2, and if clinical suspicion is high and/or there has been clinical 
confirmation. Consider, as necessary, discussing with the study physician, and promptly 
pursue specialist consultation. 
If symptoms recur or worsen during corticosteroid tapering (28 days of taper), increase 
the corticosteroid dose (prednisone dose [e.g., up to 2 to 4 mg/kg/day PO or IV 
equivalent]) until stabilization or improvement of symptoms, then resume corticosteroid 
tapering at a slower rate (>28 days of taper). 
More potent immunosuppressives such as TNF inhibitors (e.g., infliximab) should be 
considered for events not responding to systemic steroids. Progression to use of more 
potent immunosuppressives should proceed more rapidly in events with high likelihood 
for morbidity and/or mortality – e.g., myocarditis, or other similar events when these 
events are not responding to systemic steroids.  
With long-term steroid and other immunosuppressive use, consider need for 
Pneumocystis jirovecii pneumonia (PJP, formerly known as Pneumocystis carinii 
pneumonia) prophylaxis, gastrointestinal protection, and glucose monitoring. 
Discontinuation of study drug/study regimen is not mandated for Grade 3/Grade 4 
inflammatory reactions attributed to local tumor response (e.g., inflammatory reaction at 
sites of metastatic disease and lymph nodes). Continuation of study drug/study regimen 
in this situation should be based upon a benefit-risk analysis for that patient. 
9.9a 
Concomittant Medications 
Consider more frequent monitoring for adverse reactions associated with concomitantly 
administered drugs that are sensitive substrates of P-gp or BCRP and reduce the dose of 
these drugs per their Prescribing Information. 
Futibatinib may increase exposure of drugs that are substrates of P-gp or BCRP as an 
inhibitor of P-gp and BCRP. 
 

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10.0 
Adverse Event (AE) Monitoring and Reporting  
The site principal investigator is responsible for reporting any/all serious adverse events to the 
sponsor as described within the protocol, regardless of attribution to study agent or treatment 
procedure. 
Adverse events are collected from the time the patient signs the main study consent until a 
minimum of 30 days after the last dose of study drug. 
The sponsor/sponsor-investigator is responsible for notifying FDA and all participating 
investigators in a written safety report of any of the following: 
• 
Any suspected adverse reaction that is both serious and unexpected. 
• 
Any findings from laboratory animal or in vitro testing that suggest a significant risk for 
human subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity. 
• 
Any findings from epidemiological studies, pooled analysis of multiple studies, or 
clinical studies, whether or not conducted under an IND and whether or not conducted by 
the sponsor, that suggest a significant risk in humans exposed to the drug 
• 
Any clinically important increase in the rate of a serious suspected adverse reaction over 
the rate stated in the protocol or Investigator’s Brochure (IB). 
10.01 Summary of SAE Reporting for this study  
(please read entire section for specific instructions): 
WHAT form: 
WHERE to send: 
 
  
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
  
 
 
 
 
 
 

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Definitions 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether or 
not considered drug related.  
Serious Adverse Event 
An adverse event is considered serious if it results in ANY of the following outcomes:  
• 
Death 
• 
A life-threatening adverse event  
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours  
• 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions  
• 
A congenital anomaly/birth defect.  
• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition 
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the adverse 
event. 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team becoming aware 
of the event. 
Routine Reporting 
Events reported to sponsor via case report forms 
Events of Interest 
Events that would not typically be considered to meet the criteria for expedited reporting, but 
that for a specific protocol are being reported via expedited means in order to facilitate the 
review of safety data (may be requested by the FDA or the sponsor).  
10.1 
Adverse Event Characteristics 
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0 A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site: 
 
• 
Identify the grade and severity of the event using the CTCAE version 5.0. 
• 
Determine whether the event is expected or unexpected (see Section 10.2). 
• 
Determine if the adverse event is related to the study intervention (agent, treatment or 
procedure) (see Section 10.3). 
• 
Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4).  
• 
Determine if other reporting is required (see Section 10.5). 
NOTE: All AEs reported via expedited mechanisms must also be reported via the routine 
data reporting mechanisms defined by the protocol (see Sections 10.6 and 18.0). 
NOTE: A severe AE is NOT the same as a serious AE, which is defined in Section 10.4. 

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10.2 
Expected vs. Unexpected Events  
Expected events - are those described within Section 15.0 of the protocol, the study 
specific consent form, package insert (if applicable), and/or the investigator brochure, (if 
an investigator brochure is not required, otherwise described in the general 
investigational plan).  
Unexpected adverse events or suspected adverse reactions are those not listed in Section 
15.0 of the protocol, the study specific consent form, package insert (if applicable), or in 
the investigator brochure (or are not listed at the specificity or severity that has been 
observed); if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan. 
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 
An investigational agent/intervention might exacerbate the expected AEs associated with a 
commercial agent. Therefore, if an expected AE (for the commercial agent) occurs with a 
higher degree of severity or specificity, expedited reporting is required. 
NOTE: *The consent form may contain study specific information at the discretion of the 
Principal Investigator; it is possible that this information may NOT be included in the 
protocol or the investigator brochure. Refer to protocol or IB for reporting needs. 
10.3 
Attribution to agent(s) or procedure 
When assessing whether an adverse event (AE) is related to a medical agent(s) medical or 
procedure, the following attribution categories are utilized: 
Definite - The AE is clearly related to the agent(s)/procedure. 
Probable - The AE is likely related to the agent(s)/procedure. 
Possible - The AE may be related to the agent(s)/procedure. 
Unlikely - The AE is doubtfully related to the agent(s)/procedure. 
Unrelated - The AE is clearly NOT related to the agent(s)/procedure. 
10.31 AEs Experienced Utilizing Investigational Agents and Commercial Agent(s) on 
the SAME (Combination) Arm 
NOTE: When a commercial agent(s) is (are) used on the same treatment arm as 
the investigational agent/intervention (also, investigational drug, biologic, 
cellular product, or other investigational therapy under an IND), the entire 
combination (arm) is then considered an investigational intervention for 
reporting. 
• An AE that occurs on a combination study must be assessed in accordance with the 
guidelines for investigational agents/interventions.  
• An AE that occurs prior to administration of the investigational agent/intervention 
must be assessed as specified in the protocol. In general, only Grade 4 and 5 AEs 
that are unexpected with at least possible attribution to the commercial agent require 
an expedited report, unless hospitalization is required. Refer to Section 10.4 for 
specific AE reporting requirements or exceptions. 
An investigational agent/intervention might exacerbate the expected AEs associated 
with a commercial agent. Therefore, if an expected AE (for the commercial agent) 
occurs with a higher degree of severity or specificity, expedited reporting is 
required. 

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• An increased incidence of an expected adverse event (AE) is based on the 
patients treated for this study at their site. A list of known/expected AEs is 
reported in the package insert or the literature, including AEs resulting from a 
drug overdose. 
10.32 EXPECTED Serious Adverse Events: Protocol Specific Exceptions to Expedited 
Reporting 
For this protocol only, the following Adverse Events/Grades are expected to occur 
within this population and do not require Expedited Reporting. These events must still 
be reported via Routine Reporting (see Section 10.6).* 
*Report any clinically important increase in the rate of a serious suspected 
adverse reaction (at your study site) over that which is listed in the protocol or 
investigator brochure as an expedited event.  
*Report an expected event that is greater in severity or specificity than expected 
as an expedited event. 
*Specific protocol exceptions to expedited reporting should be reported 
expeditiously by investigators ONLY if they exceed the expected grade of the 
event. 
CTCAE 
System Organ Class 
(SOC) 
Adverse event/ Symptoms 
CTCAE Grade at which the 
event will not be reported in 
an expedited manner1 
Blood and lymphatic 
system disorders 
Anemia 
≤Grade 4 
Gastrointestinal disorders 
Diarrhea 
≤Grade 3 
 
Nausea 
≤Grade 3 
 
Vomiting 
≤Grade 3 
General disorders and 
administrations site 
conditions 
Fatigue 
≤Grade 3 
Malaise 
≤Grade 3 
Investigations 
Lymphocyte count decreased 
≤Grade 4 
 
Neutrophil count decreased 
≤Grade 4 
 
Platelet count decreased 
≤Grade 4 
 
White blood cell count decreased 
≤Grade 4 
1 These exceptions only apply if the adverse event does not result in hospitalization. If the 
adverse event results in hospitalization, then the standard expedited adverse events 
reporting requirements must be followed.  
The following hospitalizations are not considered to be SAEs because there is no 
“adverse event” (i.e., there is no untoward medical occurrence) associated with the 
hospitalization: 
● Hospitalization prior to signing main study consent 
● Hospitalizations for respite care 
● Planned hospitalizations required by the protocol 
● Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration) 
● Hospitalization for elective procedures unrelated to the current disease and/or 
treatment on this trial 
● Hospitalization for administration of study drug or insertion of access for 
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● Hospitalization for routine maintenance of a device (e.g., battery replacement) that 
was in place before study entry 
● Hospitalization, or other serious outcomes for signs and symptoms of progression of 
the cancer. 
10.4 
Expedited Reporting Requirements for IND Agents  
10.41 Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for 
Adverse Events that Occur on Studies under an IND within 30 Days of the Last 
Administration of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:  
• Death 
• A life-threatening adverse event  
• An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for  
≥ 24 hours  
• A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
• A congenital anomaly/birth defect.  
• Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may 
be considered serious when, based upon medical judgment, they may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 
CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the sponsor within 
the timeframes detailed in the table below.  
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization 
≥24 hrs 
7 Calendar Days 
24-Hour 3 Calendar 
Days 
Not resulting in 
Hospitalization 
≥24 hrs 
Not required 
Expedited AE reporting t timelines are defined as: 
• 
“24-Hour; 3 Calendar Days” - The AE must initially be reported within 24 hours of learning of the AE, 
followed by a complete expedited report within 3 calendar days of the initial 24-hour report. 
• 
“7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days of 
learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered. Footnote “1” above 
applies after this reporting period. 
Effective Date: May 5, 2011 
NOTE: Refer to Section 10.32 for exceptions to Expedited Reporting 
 
 

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10.42 General reporting instructions 
The Mayo IND and/or MCCC Compliance will assist the sponsor-investigator in 
the processing of expedited adverse events and forwarding of suspected 
unexpected serious adverse reactions (SUSARs) to the FDA and IRB. 
Use Mayo Expedited Event Report form 
 for investigational agents or 
commercial/investigational agents on the same arm.  
Submit to NCCN via email 
 
AND 
Submit to Taiho Oncology Inc. Pharmacovigilance contact information for IIT 
sites to report SAEs (email preferred): 
 
 
 
 
10.43 Reporting of re-occurring SAEs 
ALL SERIOUS adverse events that meet the criteria outlined in Table10.41 
MUST be immediately reported to the sponsor within the timeframes detailed in 
the corresponding table. This reporting includes, but is not limited to SAEs that 
re-occur again after resolution. 
10.5 
Other Required Reporting 
10.51 Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) in 
general, include any incident, experience, or outcome that meets all of the 
following criteria: 
• 
Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
• 
Related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 
involved in the research); and 
• 
Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
Some unanticipated problems involve social or economic harm instead of the 
physical or psychological harm associated with adverse events. In other cases, 
unanticipated problems place subjects or others at increased risk of harm, but no 
harm occurs. 
Note: If there is no language in the protocol indicating that pregnancy is not 
considered an adverse experience for this trial, and if the consent form does not 
indicate that subjects should not get pregnant/impregnate others, then any 
pregnancy in a subject/patient or a male patient’s partner (spontaneously 

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reported) which occurs during the study or within 120 days of completing the 
study should be reported as a UPIRTSO. 
Mayo Clinic Cancer Center (MCCC) Institutions: 
If the event meets the criteria for IRB submission as a Reportable 
Event/UPIRTSO, provide the appropriate documentation and use the Mayo 
Clinic Cancer Center Expedited Event Report form 
 
he Mayo Clinic Compliance Unit will 
review and process the submission to the Mayo Clinic IRB and work with the 
IND Coordinator for submission to FDA. 
10.52 Death 
Note: A death on study requires both routine and expedited reporting 
regardless of causality, unless as noted below. Attribution to treatment or 
other cause must be provided. 
Any death occurring within 30 days of the last dose, regardless of attribution to 
an agent/intervention under an IND requires expedited reporting within 24-
hours. 
Any death occurring greater than 30 days with an attribution of possible, 
probable, or definite to an agent/intervention under an IND requires expedited 
reporting within 24-hours. 
Reportable categories of Death  
1. Death attributable to a CTCAE term. 
2. Death Neonatal: A disorder characterized by cessation of life during the 
first 28 days of life.  
3. Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5. 
4. Sudden death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
5. Death due to progressive disease that cannot be attributed to a CTCAE 
term associated with Grade 5 should be reported as Grade 5 “Disease 
progression” under the system organ class (SOC) of General disorders 
and administration site conditions. Evidence that the death was a 
manifestation of underlying disease (e.g., radiological changes suggesting 
tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted. 
10.53 Secondary Malignancy 
• 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation 
or chemotherapy). A secondary malignancy is not considered a metastasis of 
the initial neoplasm. 
• 
All secondary malignancies that occur following treatment with an agent under 
an IND will be reported. Three options are available to describe the event: 
o Leukemia secondary to oncology chemotherapy (e.g., Acute Myeloctyic 
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o Myelodysplastic syndrome (MDS) 
o Treatment-related secondary malignancy 
• 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
10.54 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy). Second malignancies require ONLY 
routine reporting unless otherwise specified. 
10.55 Pregnancy and Lactation, Paternal Drug Exposure, Fetal Death, and Death 
Neonatal  
If a female subject (or female partner of a male subject) taking investigational 
product becomes pregnant, the subject taking should notify the Investigator, and 
the pregnant female should be advised to call her healthcare provider 
immediately. The patient should have appropriate follow-up as deemed necessary 
by her physician. If the baby is born with a birth defect or anomaly, a second 
expedited report is required. 
Prior to obtaining private information about a pregnant woman and her infant, the 
investigator must obtain consent from the pregnant woman and the newborn 
infant’s parent or legal guardian before any data collection can occur. A consent 
form will need to be submitted to the IRB for these subjects if a pregnancy 
occurs. If informed consent is not obtained, no information may be collected. 
In cases of fetal death, miscarriage or abortion, the mother is the patient. In cases 
where the child/fetus experiences a serious adverse event other than fetal death, 
the child/fetus is the patient. 
NOTE: When submitting Mayo Expedited Adverse Event Report reports for 
“Pregnancy”, “Pregnancy loss”, or “Neonatal loss”, the potential risk of exposure 
of the fetus to the investigational agent(s) or chemotherapy agent(s) should be 
documented in the “Description of Event” section. Include any available medical 
documentation.  
Include this form: 
10.551 
Pregnancy 
Pregnancy should be reported in an expedited manner as Grade 3 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC. Pregnancy should be followed until the outcome is 
known. 
10.552 
Fetal Death 
Fetal death is defined in CTCAE as “A disorder characterized by death 
in utero; failure of the product of conception to show evidence of 
respiration, heartbeat, or definite movement of a voluntary muscle after 
expulsion from the uterus, without possibility of resuscitation.” 
Fetal loss at any gestational age should be reported expeditiously, as 
Grade 4 “Pregnancy loss” under the SOC of “Pregnancy, 

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puerperium and perinatal conditions”” under the Pregnancy, 
puerperium and perinatal conditions SOC. 
10.553 
Death Neonatal 
Neonatal death, defined in CTCAE as “Newborn death occurring 
during the first 28 days after birth” that is felt by the investigator to be 
at least possibly due to the investigational agent/intervention.  
A neonatal death should be reported expeditiously as Grade 4 “Death 
neonatal” under the SOC of General disorders and administration 
site conditions.  
10.56 Overdose 
An overdose is defined as the accidental or intentional use of the drug in an 
amount higher than the dose being studied. An overdose or incorrect 
administration of study treatment is not itself an AE, but it may result in an AE. 
An overdose that results in an AE should be reported using the Mayo Expedited 
Event Report form 
  
and to Taiho Pharmacovigilance or designee within 24 hours from the time the 
Investigator first becomes aware of its occurrence.  
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. 
10.6 
Required Routine Reporting  
10.61 Baseline and Adverse Events Evaluations 
Pretreatment symptoms/conditions to be graded at baseline and adverse events to be 
graded at each evaluation.  
Grading is per CTCAE v5.0 unless alternate grading is indicated in the table below: 
CTCAE  
System/Organ/Class 
(SOC) 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Eye disorders 
Dry eye 
X 
X 
 
Blurred vision 
X 
X 
 
Eye disorders – Other, 
specify (retinal pigment 
epithelial detachment RPED) 
X 
X 
Gastrointestinal disorders 
# of stools at baseline 
X 
 
 
Diarrhea 
 
X 
 
Mucositis oral 
X 
X 
General disorders and 
administration site 
conditions 
Fatigue 
X 
X 
Investigations 
Alanine aminotransferase 
increased (ALT)  
X 
X 
 
Aspartate aminotransferase 
increased (AST) 
X 
X 
 
Blood bilirubin increased 
X 
X 
 
Hyperphosphatemia 
X 
X 

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CTCAE  
System/Organ/Class 
(SOC) 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Skin and subcutaneous 
tissue disorders  
Nail changes 
X 
X 
 
Palmar-plantar 
erythrodysesthesia syndrome 
X 
X 
 
Rash maculopapular 
X 
X 
10.62 All other AEs 
Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.6: 
10.621 
Grade 2 AEs deemed possibly, probably, or definitely related to the 
study treatment or procedure. 
10.622 
Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
10.623 
Grade 5 AEs (Deaths) 
10.6231 
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 
10.6232 
Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, 
with a CTCAE type and attribution assigned. 
10.624 
Outcome of Adverse Events 
Record the outcome of AEs as follows: 
• 
Resolved 
• 
Not resolved/ Ongoing 
• 
Fatal/ Death 
10.625 
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 
• 
Start of new antitumor therapy 
• 
Withdrawal of consent  
• 
Death  
• 
Other (eg, transfer to another hospital)  
10.7 
Late Occurring Adverse Events 
Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion of the 
Active Monitoring Phase (i.e., compliance with Test Schedule in Section 4.0). 
 
 
 

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11.0 
Treatment Evaluation/Measurement of Effect  
NOTE: This study uses protocol RECIST v1.1 template dated 2/16/2011. See the footnote for the 
table regarding measureable disease in Section 11.44, as it pertains to data collection and 
analysis. 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines 
(version 1.1)27. Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the short axis measurements in the case of lymph nodes are used in the RECIST 
guideline. 
11.1 
Schedule of Evaluations 
For the purposes of this study, patients should be reevaluated every 9 weeks.  
In addition to a baseline scan, confirmatory scans should also be obtained 4-6 weeks 
following initial documentation of objective response. 
11.2 
Definitions of Measurable and Non-Measurable Disease 
11.21  Measurable Disease 
11.211 A non-nodal lesion is considered measurable if its longest diameter can 
be accurately measured as ≥2.0 cm with chest x-ray, or as ≥1.0 cm with 
CT scan, CT component of a PET/CT, or MRI.  
11.212 A superficial non-nodal lesion is measurable if its longest diameter is 
≥1.0 cm in diameter as assessed using calipers (e.g. skin nodules) or 
imaging. In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is 
recommended. 
11.213 A malignant lymph node is considered measurable if its short axis is 
>1.5 cm when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  
NOTE: Tumor lesions in a previously irradiated area are not considered 
measurable disease.  
11.22 Non-Measurable Disease 
All other lesions (or sites of disease) are considered non-measurable disease, 
including pathological nodes (those with a short axis ≥1.0 to <1.5 cm). Bone 
lesions, leptomeningeal disease, ascites, pleural/ pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable as well. 
Note: ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. In addition, lymph nodes that have a short axis 
<1.0 cm are considered non- pathological (i.e., normal) and should not be 
recorded or followed. 
 
27 Eisenhauer EA, Therasse P, Bogaert J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, 
Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria 
in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer 45(2): 228-247, 2009. 

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11.3 
Guidelines for Evaluation of Measurable Disease 
11.31 Measurement Methods: 
• 
All measurements should be recorded in metric notation (i.e., decimal 
fractions of centimeters) using a ruler or calipers. 
• 
The same method of assessment and the same technique must be used to 
characterize each identified and reported lesion at baseline and during 
follow-up. For patients having only lesions measuring at least 1 cm to less 
than 2 cm must use CT imaging for both pre- and post-treatment tumor 
assessments. 
• 
Imaging-based evaluation is preferred to evaluation by clinical examination 
when both methods have been used at the same evaluation to assess the 
antitumor effect of a treatment.  
11.32 Acceptable Modalities for Measurable Disease: 
• 
Conventional CT and MRI: This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 mm 
or less. If CT scans have slice thickness greater than 5 mm, the minimum 
size for a measurable lesion should be twice the slice thickness.  
• 
As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and 
site of disease. The lesions should be measured on the same pulse sequence. 
Ideally, the same type of scanner should be used and the image acquisition 
protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible. 
• 
PET-CT: If the site can document that the CT performed as part of a PET-CT 
is of identical diagnostic quality to a diagnostic CT (with IV and oral 
contrast), then the CT portion of the PET-CT can be used for RECIST 
measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.  
• 
Chest X-ray: Lesions on chest x-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung. However, CT 
scans are preferable. 
• 
Physical Examination: For superficial non-nodal lesions, physical 
examination is acceptable, but imaging is preferable, if both can be done. In 
the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended. 
• 
FDG-PET: FDG-PET scanning is allowed to complement CT scanning in 
assessment of progressive disease [PD] and particularly possible 'new' 
disease. A ‘positive’ FDG-PET scanned lesion is defined as one which is 
FDG avid with an update greater than twice that of the surrounding tissue on 
the attenuation corrected image; otherwise, an FDG-PET scanned lesion is 
considered ‘negative.’ New lesions on the basis of FDG-PET imaging can be 
identified according to the following algorithm: 
a. Negative FDG-PET at baseline with a positive FDG-PET at follow-up is 
a sign of PD based on a new lesion. 

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b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  
i. 
If the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is PD.  
ii. If the positive FDG-PET at follow-up is not confirmed as a new site 
of disease on CT at the same evaluation, additional follow-up CT 
scans (i.e., additional follow-up scans at least 4 weeks later) are 
needed to determine if there is truly progression occurring at that 
site. In this situation, the date of PD will be the date of the initial 
abnormal PDG-PET scan.  
iii If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the 
anatomic images, it is not classified as PD. 
11.33 Measurement at Follow-up Evaluation:  
• 
A subsequent scan must be obtained not less than 4 weeks following initial 
documentation of an objective status of either complete response (CR) or 
partial response (PR).  
• 
In the case of stable disease (SD), follow-up measurements must have met 
the SD criteria at least once after study entry at a minimum interval of not 
less than 6 weeks (see Section 11.44). 
• 
The 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 stable disease is mandatory to differentiate between 
response or stable disease (an effusion may be a side effect of the treatment) 
and progressive disease. 
• 
Cytologic and histologic techniques can be used to differentiate between PR 
and CR in rare cases (e.g., residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain.) 
11.4 
Measurement of Effect 
11.41 Target Lesions & Target Lymph Nodes 
• 
Measurable lesions (as defined in Section 11.21) up to a maximum of 
5 lesions, representative of all involved organs, should be identified as “Target 
Lesions” and recorded and measured at baseline. These lesions can be non-
nodal or nodal (as defined in 11.21), where no more than 2 lesions are from 
the same organ and no more than 2 malignant nodal lesions are selected.  
Note: If fewer than 5 target lesions and target lymph nodes are identified (as 
there often will be), there is no reason to perform additional studies beyond 
those specified in the protocol to discover new lesions.  
• 
Target lesions and target lymph nodes should be selected on the basis of their 
size, be representative of all involved sites of disease, but in addition should 
be those that lend themselves to reproducible repeated measurements. It may 
be the case that, on occasion, the largest lesion (or malignant lymph node) 
does not lend itself to reproducible measurements in which circumstance the 
next largest lesion (or malignant lymph node) which can be measured 
reproducibly should be selected.  
• 
Baseline Sum of Dimensions (BSD): A sum of the longest diameter for all 
target lesions plus the sum of the short axis of all the target lymph nodes will 

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be calculated and reported as the baseline sum of dimensions (BSD). The 
BSD will be used as reference to further characterize any objective tumor 
response in the measurable dimension of the disease.  
• 
Post-Baseline Sum of the Dimensions (PBSD): A sum of the longest 
diameter for all target lesions plus the sum of the short axis of all the target 
lymph nodes will be calculated and reported as the post-baseline sum of 
dimensions (PBSD). If the radiologist is able to provide an actual measure 
for the target lesion (or target lymph node), that should be recorded, even if it 
is below 0.5 cm. If the target lesion (or target lymph node) is believed to be 
present and is faintly seen but too small to measure, a default value of 0.5 cm 
should be assigned. If it is the opinion of the radiologist that the target lesion 
or target lymph node has likely disappeared, the measurement should be 
recorded as 0 cm. 
• 
The minimum sum of the dimensions (MSD) is the minimum of the BSD 
and the PBSD. 
11.42 Non-Target Lesions & Non-Target Lymph Nodes 
Non-measurable sites of disease (Section 11.22) are classified as non- target 
lesions or non-target lymph nodes and should also be recorded at  
baseline. These lesions and lymph nodes should be followed in accord with 
Section 11.433. 
11.43 Response Criteria 
11.431 
Measurement 
All target lesions and target lymph nodes followed by CT/MRI/PET-
CT/Chest X-ray/physical examination must be measured on re-
evaluation at evaluation times specified in Section 11.1. Specifically, a 
change in objective status to either a PR or CR cannot be done without 
re-measuring target lesions and target lymph nodes.  
Note: Non-target lesions and non-target lymph nodes should be 
evaluated at each assessment, especially in the case of first response or 
confirmation of response. In selected circumstances, certain non-target 
organs may be evaluated less frequently. For example, bone scans may 
need to be repeated only when complete response is identified in target 
disease or when progression in bone is suspected. 
Note: Pseudoprogression is a term describing an initial increase in 
tumor burden caused by immune-cell infiltration in the setting of T cell 
response. This phenomenon is observed in many solid malignancies. 
This study will allow all patients to continue their assigned therapy 
after apparent radiographic progression per RECIST v1.1, with close 
observation (e.g., 4 to 8 week intervals), provided the benefit is judged 
to be favorable by the investigator and repeat scans in 6 weeks do not 
show progression per RECIST v1.1. If subsequent imaging studies 
and/or clinical observations demonstrate that progression in fact has 
occurred, the date of confirmed progression should be noted as the 
scan at which the potential progression was first identified. 
11.432 
Evaluation of Target Lesions 
o Complete Response (CR):All of the following must be true: 
a. Disappearance of all target lesions. 

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b. Each target lymph node must have reduction in short axis to 
<1.0 cm. 
c. Normalization of tumor biomarkers. 
o Partial Response (PR): At least a 30% decrease in PBSD (sum of 
the longest diameter for all target lesions plus the sum of the short 
axis of all the target lymph nodes at current evaluation) taking as 
reference the BSD (see Section 11.41). 
o Progression (PD): At least one of the following must be true: 
a. At least one new malignant lesion, which also includes any 
lymph node that was normal at baseline (<1.0 cm short axis) 
and increased to ≥1.0 cm short axis during follow-up.  
b. At least a 20% increase in PBSD (sum of the longest diameter 
for all target lesions plus the sum of the short axis of all the 
target lymph nodes at current evaluation) taking as reference 
the MSD (Section 11.41). In addition, the PBSD must also 
demonstrate an absolute increase of at least 0.5 cm from the 
MSD.  
c. See Section 11.32 for details in regards to the requirements for 
PD via FDG-PET imaging. 
o Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, 
nor sufficient increase to qualify for PD taking as reference the 
MSD. 
11.433 
Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
Complete Response (CR): All of the following must be true: 
a. 
Disappearance of all non-target 
lesions. 
b. 
Each non-target lymph node must 
have a reduction in short axis to 
<1.0 cm. 
c. 
Normalization of tumor biomarkers 
Non-CR/Non-PD: 
Persistence of one or more non-target 
lesions or non-target lymph nodes, and/or 
maintenance of tumor marker level above 
the normal limits. 
Progression (PD): 
At least one of the following must be true: 
a. At least one new malignant lesion, 
which also includes any lymph node 
that was normal at baseline (<1.0 cm 
short axis) and increased to ≥1.0 cm 
short axis during follow-up.  
b. Unequivocal progression of existing 
non-target lesions and non-target 
lymph nodes. (NOTE: Unequivocal 
progression should not normally 
trump target lesion and target lymph 
node status. It must be representative 
of overall disease status change.)  

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c. See Section 11.32 for details in 
regards to the requirements for PD via 
FDG-PET imaging. 
11.44 Overall Objective Status 
The overall objective status for an evaluation is determined by combining the 
patient’s status on target lesions, target lymph nodes, non-target lesions, non-
target lymph nodes, and new disease as defined in the following tables:  
11.441 
Objective Status Table for Patients with Measurable Disease 
Target Lesions & 
Target Lymph Nodes 
Non-Target Lesions & 
Non-Target Lymph 
Nodes 
New 
Sites of Disease 
Overall Objective 
Status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
CR 
Non-CR/Non-PD 
No 
PR 
CR/PR 
Not All Evaluated* 
No 
PR** 
SD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
SD 
Not all Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
Not Evaluated (NE) 
PD 
Unequivocal PD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
Unequivocal PD 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes 
PD 
*See Section 11.431 
** NOTE: This study uses the protocol RECIST v1.1 template dated 2/16/2011. For data collection 
and analysis purposes the objective status changed from SD to PR in the MCCC protocol RECIST 
v1.1 template as of 2/16/2011 and to match RECIST v1.1 requirements. 
11.45 Symptomatic Deterioration 
Patients with global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time, and not 
either related to study treatment or other medical conditions, should be reported as 
PD due to “symptomatic deterioration.” Every effort should be made to document 
the objective progression even after discontinuation of treatment due to 
symptomatic deterioration. A patient is classified as having PD due to 
“symptomatic deterioration” if any of the following occur that are not either related 
to study treatment or other medical conditions: 
• 
Weight loss >10% of body weight. 
• 
Worsening of tumor-related symptoms. 
• 
Decline in performance status of >1 level on ECOG scale. 
 
 

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12.0 
Descriptive Factors  
12.1 
Prior lines of treatment: 0 vs. 1 vs. 2 vs. 3+ 
12.2 
Extrahepatic spread of disease: Yes vs. No 
12.3 
Macrovascular invasion: Yes vs. No 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient  
13.1 
Continuation of treatment 
Patients who are CR, PR, or SD will continue treatment per protocol. 
13.2 
Progressive disease (PD) 
Patients who develop PD while receiving therapy will go to the survival follow-up phase. 
13.3 
Off protocol treatment 
Patients who go off protocol treatment for reasons other than PD will go to the clinical 
follow-up/observation phase per Section 4.0. Participants will be required to return to the 
consenting site for follow-up until disease progression, new anti-cancer therapy, death, 
withdrawal of consent for clinical followup, or a maximum of 18 months from 
Registration. 
13.4 
Duration of therapy for CR 
Patients who achieve a CR will receive a maximum total of 35 cycles (i.e., 2 years). After 
35 cycles, they will go to survival follow-up/event monitoring. Subsequent treatment is at 
the discretion of their attending physician. 
13.5 
Duration of therapy for PR or SD 
Patients who are in PR or SD will continue on therapy for a total of 35cycles (i.e., 
2 years). After 35 cycles, they will go to survival follow-up/event monitoring. 
Subsequent treatment is at the discretion of their attending physician. 
13.6 
Ineligible 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry. If 
the patient received treatment, the patient may continue treatment at the discretion of the 
physician as long as there are not safety concerns. The patient will continue in the Active 
Monitoring/Treatment phase of the study, per Section 4.0 of the protocol.  
• 
If the patient never received treatment, on-study material must be submitted. Survival 
follow-up/event monitoring will be required per Section 4.0 of the protocol. 
13.7 
Major violation 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
Cycle 1 of the initial therapy are severely violated that evaluability for primary endpoint 
is questionable. If the patient received treatment, the patient may continue treatment at 
the discretion of the physician as long as there are not safety concerns. The patient will 
continue in the Active Monitoring/Treatment phase of the study, per Section 4.0 of the 
protocol. 

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13.8 
Cancel 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given. On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted. No further data submission is necessary. 
13.9a 
Subsequent Anti-Cancer Therapy Status  
The investigator or qualified designee will review all new anti-neoplastic therapy 
initiated after the last dose of trial treatment. If a participant initiates a new anti-cancer 
therapy within 30 days after the last dose of trial treatment, the 30-day Safety Follow-up 
visit must occur before the first dose of the new therapy. Once new anti-cancer therapy 
has been initiated the participant will move into survival follow-up/event monitoring per 
Section 4.0. 
 

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14.0 
Body Fluid Biospecimens 
14.1  
Summary Table of Research Blood and Body Fluid Specimens to Be Collected for this Protocol 
Research (Section for 
more information) 
Specimen 
Purpose  
(check all that 
apply) 
Mandatory 
or Optional 
Blood or 
Body Fluid 
being 
Collected 
Type of 
Collection 
Tube (color 
of tube top) 
Volume to 
collect per 
tube (# of 
tubes to be 
collected) 
Baseline 
prior to 
Cycle 1, 
Day 1 
Prior to 
Cycle 4 
Day 1 
End of 
treatment 
Process 
at site? 
(Yes or 
No) 
Temperature 
Conditions 
for Storage 
/Shipping 
cfDNA based studies  
(Section 14.2 and 
14.3) 
☒ Correlative Mandatory 
Whole 
blood for 
platelet poor 
plasma 
Streck 
cfDNA 
BCT 
10 mL 
(2) 
X 
X 
X 
Yes 
Frozen 
Immune profiling 
☒ Correlative Mandatory 
Whole 
blood 
EDTA tube 
(purple top) 
10 mL 
(1) 
X 
X 
X 
No 
Ambient - 
Send 
immediately 
to 
 
Banking  
☒ Banking 
Mandatory 
Whole 
blood for 
DNA, buffy 
coat and 
plasma 
EDTA tube 
(purple top) 
10 mL 
(1) 
X 
X 
X 
Yes 
Frozen 
Banking 
☒ Banking 
Mandatory 
Whole 
blood for 
DNA 
EDTA tube 
(purple top) 
4 mL 
(1) 
X 
 
 
Yes 
Frozen 
 
 
 

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14.2 
Collection and Processing  
14.21 Sample collection should be restricted to Monday – Thursday. However, if the 
subject can only be seen on a Friday, please contact the laboratory of 
 
and the Biospecimen Accessioning and Processing (BAP) Service Center for 
additional instructions (see protocol resource pages for contact information). 
14.22 Specimen tube(s) must be labeled with the protocol number, study patient ID 
number, and the time and date of the blood draw. 
14.23  Blood/blood products must be collected and shipped according to specific 
instructions provided in the kit and the table above. 
14.3 
Shipping (AZ/FL only) 
14.31 Verify that ALL sections of the Blood Specimen Submission Form (see Forms 
Packet), BAP Requisition Form (provided in kit), and specimen collection labels 
are completed and filled in correctly. Enter information from the Blood Specimen 
Submission Form into the remote data entry system within 7 days after specimen 
collection (see Forms Packet). 
14.32 Specimens collected in the Streck cfDNA BCT and AccuCyte tubes should be 
shipped at ambient temperature on the same day they are drawn. 
14.33 Specimens collected in EDTA tubes should be processed for DNA from whole 
blood, a buffy coat back up and plasma aliquots then stored frozen.  
NOTE: DNA extraction may be done at site where it's collected. 
14.34 Samples should be shipped to BAP Freezer Mondays – Thursdays according to 
kit instructions. Samples should not be sent on weekends or just prior to federal 
holidays. (If samples can only be shipped on Fridays, please contact the 
Biospecimen Resource Manager for additional instructions.) 
14.4 
Processing 
NOTE: BAP Shared Resource will process the specimens. 
14.41 Double spun, platelet poor plasma will be derived from the Streck cfDNA BCT 
tubes using established laboratory processes, and stored at ≤-65ºC by BAP. 
14.42 DNA will be extracted from whole blood, and white blood cells and plasma will 
be derived from remaining blood from the EDTA tubes, divided into aliquots, 
and stored at ≤-65ºC by BAP according to patient consent information. 
14.43 One EDTA should be delivered immediately to 
 
Immunology, Guggenheim 4-06. 
14.44 As part of ongoing research at the Mayo Clinic, we will retain residual whole 
blood, white blood cells, DNA, and plasma for future research studies, according 
to patient consent information. Samples will be stored until specific analyses are 
identified and may be used for exploratory biomarker analyses, validation 

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studies, or potential diagnostic development. As protocols are developed, they 
will be presented for IRB review and approval. 
14.5 
Methodology 
14.51 cfDNA 
10 mL whole blood samples will be collected in Streck cfDNA BCT tubes. These 
specimens will be shipped immediately at ambient temperature to Mayo Clinic 
Rochester and then processed to aliquots of platelet poor plasma within 7 days of 
collection using standard protocols. Samples will be stored until we are ready for 
DNA extraction and mutational analysis. Mutation analysis will be performed on 
the baseline cfDNA samples. Selected mutations identified at baseline will be 
verified and quantified in all cfDNA samples using ultrasensitive digital droplet 
PCR based assays. 
 

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15.0 
Drug Information 
15.1 
Futibatinib (TAS-120) 
15.11 Background 
Futibatinib is a novel and selective small molecule irreversible, covalent kinase 
inhibitor of fibroblast growth factor receptor (FGFR) 1–4. Futibatinib equally 
inhibited all 4 subtypes of FGFR and showed high selectivity for FGFR when 
tested against a panel of 296 kinases. Futibatinib was highly active against cancer 
cell lines with FGFR gene abnormalities including cancer cell lines that acquired 
resistance to other adenosine triphosphate (ATP) competitive FGFR tyrosine 
kinase inhibitors (TKIs).  
15.12 Formulation 
Futibatinib (TAS-120) is available as 4 mg tablets in dose pak blister cards 
containing 28 tablets/card. The 4 mg tablet is a round, white or light yellow, film 
coated tablet. 
15.13 Preparation and storage 
Store at room temperature between 15-30° Celsius.  
15.14 Administration 
Futibatinib is taken orally at a starting dose of 20 mg daily at the same time each 
day. Futibatinib may be taken with or without food. 
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.  
15.15 Pharmacokinetic information 
PK parameters of futibatinib at a dose of 20 mg daily (Study TAS-120-101): 
Cmax (CV%): 50% 
Tmax: 2 hours 
AUClast: 790 ng*hr/mL 
T1/2: 3hours 
Protein Binding: 95% 
Metabolism: The primary cytochrome P450 enzyme is CYP3A 
(minor: glutathione S-transferase [GST]) 
15.16 Potential drug interactions 
To date, three clinical drug-drug interaction studies and one PK model analysis 
have been conducted in humans. These studies have shown that strong inhibitors 
or inducers of CYP3A and dual P-gp have potential clinical drug-drug 
interactions with futibatinib. Such inihibitors may increase futibatinib exposure 
and thus increase the incidence and severity of AEs associated with futibatinib. 
And such inducers may decrease futibatinib exposure and thus reduce the 
efficacy of futibatinib. 
Effect of Other Drugs on Futibatinib 
Futibatinib is a substrate of CYP3A and P-gp. 
Dual P-gp and Strong CYP3A Inhibitors: Avoid concomitant use of drugs that 
are dual P-gp and strong CYP3A inhibitors with futibatinib. Concomitant use of 
drugs that are dual P-gp and strong CYP3A inhibitors with futibatinib may 

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increase futibatinib exposure, which may increase the incidence and severity of 
adverse reactions.  
Dual P-gp and Strong CYP3A Inducers: 
Avoid concomitant use of dual P-gp and strong CYP3A inducers with futibatinib. 
Concomitant use of drugs that are dual P-gp and strongCYP3A inducers may 
decrease futibatinib exposure, which may reduce the efficacy of futibatinib. 
Effect of Futibatinib on Other Drugs 
Futibatinib is an inhibitor of P-gp and BCRP. 
P-gp or BCRP Substrates: 
Consider more frequent monitoringfor adverse reactions associated with 
concomitantly administered drugs that are sensitivesubstrates of P-gp or BCRP 
and reduce the dose of these drugs per their Prescribing Information. 
Futibatinib may increase exposure of drugs that are substrates of P-gp or BCRP. 
15.17 Known potential adverse events 
Reported from daily dosing schedule (Study 10059010) 
Most common adverse events (≥15%):  
Hyperphosphatemia, decreased appetite, constipation, diarrhea, nausea, vomiting, 
ALT and AST increased, anemia, stomatitis 
Reported from daily dosing schedule (Study TPU-TAS-120-101) 
Most common adverse events (≥15%):  
Hyperphosphatemia, diarrhea, constipation, nausea, dry mouth, ALT and AST 
increased, fatigue, vomiting, alopecia, decreased appetite, anemia, stomatitis, 
abdominal pain, dry skin, palmar-plantar erythrodysesthesia syndrome, blood 
creatinine increased, hypercalcemia, back pain, dry eye, pyrexia, arthralgia, 
dysgeusia, urinary tract infection, weight decreased, nail disorder, hyponatremia, 
onycholysis, onychomadesis 
Reported from daily dosing schedule (Study TAS-120-201) 
Most common adverse events (≥15%):  
Hyperphosphatemia, constipation, ALT and AST increased, decreased appetite, 
diarrhea, dry mouth, nausea, alopecia, fatigue, anemia, asthenia, rash, vomiting 
15.18 Drug procurement: 
Futibatinib will be supplied by the Taiho Oncology, Inc. 
Outdated or remaining drug is to be destroyed on-site per procedures in place at 
each institution. 
15.19 Nursing guidelines 
15.191 
Assess patient’s concomitant medications as there are many drug-drug 
interactions.  
15.192 
Gastrointestinal side effects are common, including diarrhea, 
constipation, nausea, vomiting and abdominal pain. Treat 
symptomatically and monitor for effectiveness. 
15.193 
Monitor LFTs. 
15.194 
Patients may experience dermatologic side effects including, dry skin, 
and palmar-plantar erythrodysesthesia (PPE aka hand-foot syndrome). 
Instruct patients to report any skin changes to the study team. For PPE, 
encourage frequent moisturizing of the hands and feet, with a urea 
based cream if possible.  

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15.195 
Patients may experience pyrexia. Instruct patients to report fever to the 
study team.  
15.196 
Instruct patients to report all side effects to the study team.  
15.197 
Eye problems are common. Instruct patient to report any changes in 
their eyes or vision to the study team. 
15.2 
Pembrolizumab (MK-3475, SCH 900475, Keytruda®) 
15.21 Background 
Pembrolizumab is a potent humanized IgG4 monoclonal antibody with high 
specificity of binding to the PD-1 receptor, thus inhibiting its interaction with 
PD-L1 and PD-L2. Based on preclinical in vitro data, pembrolizumab has high 
affinity and potent receptor blocking activity for PD-1. 
15.22 Formulation 
Pembrolizumab is available as a liquid 25 mg/mL, 100 mg/vial. 
15.23 Preparation and storage 
Vials should be stored in the refrigerator at temperatures between 2-8°C. 
Drug concentrate is further diluted with normal saline (or 5% dextrose in the 
concentration range of 1 to 10 mg/mL) in IV containers made of polyvinyl 
chloride (PVC) or non-PVC material. The infusion solution in the IV bag should 
be immediately administered. Diluted pembrolizumab solutions may be stored at 
room temperature for a cumulative period of up to 4 hours. This includes room 
temperature storage of admixture solutions in the IV bags and the duration of 
infusion. In addition, IV bags may be stored at 2-8°C for up to a cumulative time 
of 20 hours. This 24-hour total hold time from dilution may include up to 6 hours 
at room temperature 
15.24 Administration 
Pembrolizumab is administered by intravenous infusion over 30 minutes via a 
0.22 micron in-line filter. The final infusion volume must be between 1 and 10 
mg/mL. Maximum rate of infusion should not exceed 6.7 mL/minute through a 
peripheral or indwelling catheter. Flush the line with 0.9% NaCL following the 
completion of the infusion. 
15.25 Pharmacokinetic information 
a) Absorption – Because pembrolizumab is administered intravenously, it is 
immediately and completely bioavailable. Steady-state concentrations of 
pembrolizumab are reached by16 weeks of repeated dosing with a Q3W 
regimen, and the systemic accumulation is 2.1-fold. The peak concentration, 
trough concentration, and area under the plasma concentration versus time 
curve at steady state of pembrolizumab increased dose proportionally in the 
dose range of 2 to 10 mg/kg Q3W.  
b) Distribution – Pembrolizumab has a limited volume of distribution.  
c) Excretion – CL is approximately 23% lower after achieving maximal change 
at steady state compared with the first dose. The terminal elimination half-
life (t½) is estimated to be 22 days at steady state. 
d) Metabolism - Pembrolizumab is catabolized through non-specific pathways; 
metabolism does not contribute to its CL. 

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15.26 Potential Drug Interactions: There are no known significant drug interactions. 
15.27 Known potential adverse events:  
Very common known potential adverse events, ≥10%: 
Skin and subcutaneous tissue disorders: Pruritus, skin rash 
Gastrointestinal disorders: Diarrhea, nausea, abdominal pain 
General disorders and administration site conditions: fatigue 
Common known potential adverse events, >10%: 
Blood and lymphatic system disorders: anemia 
Immune system disorders: infusion related reaction 
Endocrine disorders: hyperthyroidism, hypothyroidism 
Metabolism and nutrition disorders: decreased appetite 
Nervous system disorders: headache, dizziness, dysgeusia 
Respiratory, thoracic, and mediastinal disorders: pneumonitis, dyspnea, cough 
Gastrointestinal disorders: colitis, vomiting, constipation, dry mouth 
Skin and subcutaneous tissue disorders: severe skin reactions, vitiligo, dry skin, 
erythema 
Musculoskeletal and connective tissue disorders: arthralgia, myositis, 
musculoskeletal pain, arthritis, pain in extremity 
General disorders and administration site conditions: asthenia, edema, pyrexia, 
influenza like illness, chills 
Investigations: alanine aminotransferase increased, aspartate aminotransferase 
increased, blood alkaline phosphatase increased, blood creatinine increased 
Uncommon known potential adverse events, 1% - 10%: 
Infusion related reactions 
Blood and lymphatic system disorders: neutropenia, thrombocytopenia, 
leukopenia, lymphopenia, eosinophilia 
Endocrine disorders: hypophysitis, adrenal insufficiency, thyroiditis, 
hypopituitarism 
Metabolism and nutrition disorders: type I diabetes mellitus, hyponatremia, 
hypokalemia, hypocalcemia 
Psychiatric disorders: insomnia, confusional state 
Nervous system disorders: epilepsy, lethargy, peripheral neuropathy 
Eye disorders: uveitis, dry eye 
Cardiac disorders: myocarditis, atrial fibrillation 
Vascular disorders: hypertension 
Gastrointestinal disorders: pancreatitis 
Hepatobiliary disorders: hepatitis 
Skin and subcutaneous tissue disorders: lichenoid keratosis, psoriasis, alopecia, 
dermatitis, dermatitis acneiform, eczema, hair color changes, papule 
Musculoskeletal and connective tissue disorders: tenosynovitis 
Renal and urinary disorders: nephritis, acute kidney injury 
Investigations: blood bilirubin increased, amylase increased, hypercalcemia 
Rare known potential adverse events, <1% (Limited to important or life-
threatening): 
Blood and lymphatic system disorders: immune thrombocytopenic purpura, 
hemolytic anemia 
Immune system disorders: sarcoidosis 
Nervous system disorders: Guillain-Barre syndrome, myasthenic syndrome 
Gastrointestinal disorders: small intestinal perforation 

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Skin and subcutaneous tissue disorders: toxic epidermal necrolysis, Stevens-
Johnson syndrome, erythema nodosum 
The risk profile for pembrolizumab also includes two important potential risks: a) 
myasthenic syndrome, and b) an increased risk of severe complications (such as 
early severe graft versus host disease and veno-occlusive disease) of allogeneic 
transplant in patients with hematologic malignancies who have previously been 
treated with PD-1 inhibitors. 
15.28 Drug procurement 
Commercial supply. 
15.29 Nursing Guidelines 
15.291 
Pembrolizumab side effects vary greatly from those of traditional 
chemotherapy and can vary in severity from mild to life threatening. 
Instruct patients to report any side effects to the study team 
immediately. Side effects may be immediate or delayed up to months 
after discontinuation of therapy. Most side effects are reversible with 
prompt intervention of corticosteroids. 
15.292 
Diarrhea can be seen, however is less common than that seen with anti-
CTLA-4 agents. However it can be severe, leading to colonic 
perforation. Instruct patients to report ANY increase in the number of 
stools and/or change in baseline, blood in the stool, abdominal pain to 
the study team immediately.  
15.293 
Rash/pruritis/dermatitis is seen. Patients should report any rash to the 
study team. Treat per Section 9.0 and monitor for effectiveness.  
15.294 
Monitor LFTs closely as elevations in these levels could indicate early 
onset autoimmune hepatitis. Patients should also be instructed to report 
any jaundice, or right upper quadrant pain to the study team 
immediately. 
15.295 
Pneumonitis can be seen and may be mild (only seen on imaging) to 
severe. Patients should be instructed to report any SOB, dyspnea, 
cough, chest pain, etc. to the study team immediately. Patients 
reporting these symptoms should have a pulse ox checked and consider 
immediate imaging per the treating MD. 
15.296 
Endocrinopathies (including hypopituitarism, hypothyroidism, 
hypophysitis, and adrenal insufficiency) are seen with this agent. Patients 
may present only with the vague sense of fatigue and “not feeling well.” 
Additional symptoms may be that of nausea, sweating and decreased 
activity tolerance. Instruct patients to report these signs or symptoms 
immediately and obtain appropriate labs as ordered by MD. 
15.297 
Patients who are started on steroid therapy for any side effects of 
pembrolizumab toxicity should be instructed to take the steroids as 
ordered, and not to discontinue abruptly as symptoms may return and 
be severe. Patients may be on steroid therapy for weeks. Instruct 
patients to report any increase or change in side effects with any 
dosage decrease as patients may need a slower taper. 
15.298 
Fatigue is common and may or may not be associated with immune 
related side effects. Assess patient’s fatigue level prior to each cycle of 
therapy and report any changes to the study team. 

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15.299a Patients should avoid receiving live vaccines within 30 days of study 
drug administration or per other study guidelines.  
15.299b Patients who have undergone an allogenic bone marrow transplant, 
have an increased risk of severe complications including early GVHD, 
and veno-occlusive disease, if they have previously been treated with 
pembrolizumab 
15.299c Myocarditis has been reported and associated with pembrolizumab. 
Instruct patients to report chest pain, SOB, or dyspnea to study team 
immediately and/or seek emergency medical attention. 
15.299d Autoimmune hematologic disorders including ITP and hemolytic 
anemia have been reported. Monitor blood counts closely and report 
any abnormalities to the study team. 
15.299e Rare neurologic disorders including Guillain-Barre syndrome and 
myasthenia gravis have been reported. Instruct patients to report any 
neurologic symptoms including weakness, paresthesias or numbness, 
tingling to the study team immediately. 
 

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16.0 
Statistical Considerations and Methodology  
16.1 
Primary Endpoint 
The primary endpoint is progression-free survival (PFS) at 6 months (PFS6) after 
registration. Six months is defined as 27 weeks. 
16.2 
Secondary Endpoints  
Secondary endpoints include: overall response rate (ORR), overall survival (OS), 
incidence of adverse events, and quality of life. 
16.3 
Sample Size 
We plan to accrue 22 evaluable patients. Evaluable patient is defined as those who are 
eligible, consented, are positive for FGF19, received any protocol treatment, and are 
without major violation. With 22 evaluable patients, we have 80% power to detect PFS6 
from 25% (historical control) to 47%, assuming a 1-sided significance level of 0.1 and an 
accrual rate of 2 patients per month.  
The trial has a single interim analysis for futility and the overall type I error rate is 
controlled. The interim analysis will be considered non-binding. The accrual will not be 
halted for the interim analysis. 
We anticipate accruing an additional 3 patients to account for ineligibility, cancellation, 
major treatment violation, or other reasons. Therefore, maximum accrual is projected to be 
25 patients. Sample size calculation was based on simulation using R. 
16.4 
Statistical Analysis 
Interim analysis will be conducted around 6 months after the 11th evaluable patient has 
been enrolled and the data from the third re-staging scan, if available, has been entered into 
the electronic database. The PFS6 rate will be calculated using the Kaplan-Meir method. 
The study may temporarily close to accrual if the PFS6 rate is ≤ 30% at the interim analysis. 
Final analysis will be conducted around 6 months after the 22nd evaluable patient has been 
enrolled and the data from the third re-staging scan, if available, has been entered into the 
electronic database. The PFS6 rate will be calculated using the Kaplan-Meir method and 
80% confidence interval will be calculated using Greenwood’s formula with logit 
transformation. The combination therapy will be declared as promising for future study if 
the lower bound of the 80% confidence interval is greater than 25%. 
16.5 
Operation Characteristics 
The probability of declaring that this regimen warrants further studies (i.e., statistical 
power) under various success proportions can be tabulated as a function of the true success 
proportion as shown in the following table.  
If the true success proportion is: 
25% 
47% 
then the probability of stopping early is:  
0.4597 0.0037 
and the probability of declaring that the regimen 
warrants further studies is: 
0.0651 0.7923 
The operation characteristics were calculated using simulation with 10,000 replications. 
PFS6 of 25% is generated using Weilbul distribution (scale=0.3, shape=0.6667) 
PFS6 of 47% is generated using Weilbul distribution (scale=0.73, shape=0.8850) 

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16.6 
Analysis Plan for Secondary Outcome and Translational Endpoints 
The below analyses will be done on FGF19 positive patients. The analyses will also be 
performed on FGF19 negative patients as exploratory analyses.  
16.61 Objective Response 
Objective response by RECIST v1.1 criteria will be estimated using objective 
response rate (ORR) where ORR is defined as the number of evaluable patients 
achieving a response (PR or CR per RECIST v1.1) during treatment with study 
therapy divided by the total number of evaluable patients. Point estimates will be 
generated for objective response rates along with 95% binomial confidence 
intervals28. 
16.62 Overall Survival 
Overall survival time is defined as the time from registration to death due to any 
cause. Patients who are alive will be censored at last follow-up for overall 
survival. The distribution of survival time will be estimated using the method of 
Kaplan-Meier29. OS medians will be estimated along with 95% confidence 
intervals. 
16.63 Incidence of Adverse Events (AEs) 
Adverse events will be evaluated, per CTCAE v5.0, for each patient. Grade 3+ 
AEs, at least possibility related, which occur more than 10% of patients will be 
reported by grade. 
16.64  Quality of Life (QoL) Outcomes 
To assess overall health-related quality of life, as measured by the global health 
domain of the European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire (EORTC-QLQ-C30). The raw score will be 
calculated per scoring manual30 and transformed to scores raning from 0 to 100. 
Change in score between baseline and first re-staging will be calculated for each 
individual. The median QOL change from baseline along with a 95% CI will be 
estimated using the Hodges-Lehmann method.31 
16.65 Prognostic effect of baseline cfDNA 
Cox proportional hazard model will be used to evaluate the prognostic effect of 
baseline cfDNA. 
16.66 The association between change in cfDNA and PFS/OS 
Patients will be categorized as increase vs. other in cfDNA. Cox proportional 
hazard model will be used to evaluate the prognostic effect of change in cfDNA 
(increase vs. other). 
 
28 Clopper, C.J. and E.S. Pearson, The Use of Confidence or Fiducial Limits Illustrated in the Case of the Binomial. 
Biometrika, 1934. 26(4): p. 404-413. 
29 Kaplan, E.L. and P. Meier, Nonparametric Estimation from Incomplete Observations. Journal of the American 
Statistical Association, 1958. 53(282): p. 457-481. 
30 Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A on behalf of the EORTC Quality of 
Life Group. EORTC QLQ-C30 Scoring Manual (3rd edition). Brussels: EORTC, 2001. 
31 Hodges, J. L.; Lehmann, E. L. (1963). "Estimation of location based on ranks". Annals of Mathematical Statistics. 
34 (2): 598–611. 

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16.67 Correlation of drug response in patient derived organoid with clinical response 
The correlation of drug response in patient derived organoid with clinical 
response will be tested using Chi-square test. 
16.7 
Data & Safety Monitoring 
16.71 Safety review 
The principal investigator(s) and the study statistician will review the study 
monthly to identify accrual, adverse events, and any endpoint problems that 
might be developing. The Mayo Clinic Cancer Center (MCCC) Data Safety 
Monitoring Board (DSMB) is responsible for reviewing accrual and safety data 
for this trial at least biannually, based on reports provided by the MCCC 
Statistical Office. 
16.72 Adverse Event Stopping Rules  
The stopping rules specified below are based on the knowledge available at study 
development. We note that the Adverse Event Stopping Rule may be adjusted in 
the event of either (1) the study re-opening to accrual or (2) at any time during 
the conduct of the trial and in consideration of newly acquired information 
regarding the adverse event profile of the treatment(s) under investigation. The 
study team may choose to suspend accrual because of unexpected adverse event 
profiles that have not crossed the specified rule below.  
Accrual will be temporarily suspended to this study if at any time, we observe 
events considered to be at least possibly related to study treatment (i.e., an 
adverse event with attribute specified as “possible”, “probable”, or “definite”) 
that satisfy the following:  
• 
If at any time, 4 of the initial 10 treated patients or 40% or more of all 
patients (i.e., when accrual is greater than 10 patients) have experienced a 
Grade 4+ adverse event at least possibly related to study treatment. per NCI 
Common Terminology Criteria for Adverse Events v.5.0,  
excluding the following: 
• 
Grade 4 white blood cell decreased lasting ≤3 days 
• 
Grade 4 platelet count decreased lasting ≤3 days 
• 
Grade 4 electrolyte alteration* lasting ≤3 days 
*Electrolyte alterations include the following events in SOC 
“Metabolism and nutrition disorders” 
• 
Hyperglycemia or Hypoglycemia 
• 
Hyperkalemia or Hypokalemia 
We note that we will review Grade 4 and 5 adverse events deemed “unrelated” or 
“unlikely to be related”, to monitor the emergence of a previously unrecognized 
treatment-related adverse event.  
16.8 
Subset Analyses for Minorities 
16.81 Study availability 
This study will be available to all eligible patients, regardless of gender, race or 
ethnic origin.  

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16.82 Statistical analysis by subset 
There is no information currently available regarding differential effects of this 
regimen in subsets defined by race, gender, or ethnicity, and there is no reason to 
expect such differences to exist. Therefore, although the planned analyses will 
look for differences in treatment effect based on racial groupings, the sample size 
is not increased in order to provide additional power for subset analyses.  
16.83 Regional population 
The geographical region served by MCCC has a population which includes 
approximately 3% minorities. Expected sizes of racial by gender subsets are 
shown in the following table: 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
1 
1 
2 
Not Hispanic or Latino 
11 
12 
23 
Ethnic Category: Total of all subjects 
12 
13 
25 
Racial Category 
American Indian or Alaskan Native 
1 
0 
1 
Asian 
0 
1 
1 
Black or African American 
1 
0 
1 
Native Hawaiian or other Pacific Islander 
0 
1 
1 
White 
10 
11 
21 
Racial Category: Total of all subjects 
12 
13 
25 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa.  
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 

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17.0  
Pathology Considerations/Tissue Biospecimens 
17.1  
Summary Table of Research Tissue Specimens to be Collected for this Protocol 
Research Study  
(Section for more 
information) 
Specimen Purpose 
 (check all that apply) 
Mandatory 
or Optional 
Type of 
Tissue to 
Collect 
Block, Slides, 
Core, etc.  
(# of each to 
submit) 
At any 
time 
after 
Reg* 
At time of 
disease 
progression 
Process 
at site? 
(Yes or 
No) 
Temperature 
Conditions 
for Storage 
/Shipping 
FGF-19 Testing, and 
correlative studies 
including 
Immunohistochemistry 
(Section 17.2 and 17.3) 
☒ Eligibility 
☒ Correlative 
Mandatory 
Formalin 
Fixed 
Paraffin 
Embedded 
2 cores  
(or archived 
5 unstained 
slides)* 
X 
 
No 
Ambient 
Patient-derived tumor 
organoid culture and 
studies  
(Section 17.2 and 17.3) 
Rochester ONLY 
☒ Correlative  
Mandatory 
Fresh 
Tissue 
4-6 cores or  
pieces of 
tissue 
X 
 
No 
Cold, ice 
pack 
Tumor tissue at disease 
progression** 
☒ Banking 
Optional 
Formalin 
Fixed 
Paraffin 
Embedded 
3 cores or  
10 unstained 
slides 
 
X 
No 
Ambient 
*All patients should have baseline biopsy for FGF-19 testing and correlative studies. If archived tissue is available and used for FGF-19 testing, 
then eligible patients will still need a baseline biopsy to collect correlative tissue unless already collected under IRB 17-003174. If baseline 
biopsy cannot be done (e.g., because not medically feasible or lack of lab capacity), and PI agrees, patient is still eligible if archived tissue is 
available for FGF-19 screening. 
**If biopsy or surgery is done at time of disease progression for clinical reasons, a sample of tumor tissue is requested for comparison with 
baseline sample 
17.2 
Tissue Collection  
17.21 Tissue Kits will not be provided for this protocol. 
All patients should have baseline biopsy for FGF-19 testing and correlative studies after Preregistration. 
If archived tissue is available and used for FGF-19 testing, then eligible patients will still need a baseline biopsy to collect 
correlative tissue prior to starting treatment unless already collected under IRB 17-003174. 

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If baseline biopsy cannot be done (e.g., because not medically feasible or lack of 
lab capacity), and PI agrees, patient is still eligible if archived tissue is available 
for FGF-19 screening. 
17.23 Fresh Tissue 
17.231 Six cores of fresh tumor tissue will be collected after registration and prior to 
Cycle 1 Day 1 of treatment. 
17.232 Tissue must be labeled with the protocol number, study patient ID number, and 
the time and date of the biopsy. 
17.233 Fresh tissue must be collected according to the table above. 
17.234 
A portion of the fresh tissue should be routed and made into formalin-
fixed, paraffin-embedded (FFPE) blocks 
17.234 Fresh tissue must be stored in tissue media on cold ice pack (~0ºC) until delivery 
to the lab 
17.24 Paraffin Embedded Tissue 
17.241 
One block of HCC tumor tissue from research biopsy will be submitted 
after registration and prior to Cycle 1 Day 1 of treatment.  
17.242 
Paraffin embedded tissue must be labeled with the protocol number, 
study patient ID number, and the time and date of the biopsy.  
17.243 
Paraffin embedded tissue must be collected and shipped according to 
specific instructions provided in the table above. 
17.244 
Paraffin embedded tissue can be stored at ambient temperature. 
17.25 Submission/Shipping 
17.251  
Verify that ALL sections of the Tissue Specimen Submission Form 
(see Forms Packet), BAP Requisition Form (provided in kit), and 
specimen collection labels are completed and filled in correctly. Enter 
information from the Tissue Specimen Submission Form into the 
remote data entry system within 7 days after specimen collection (see 
Forms Packet). 
17.252  
Rochester ONLY: Fresh tissue specimens collected in tissue media 
should be placed on cold ice pack (~0ºC) and immediately delivered to 
the following laboratories at Mayo Clinic in Rochester, MN: 
  
 
17.26 Processing 
17.261 
Paraffin embedded tissue block 
DLMP or BAP/PRC Shared Resource will process the paraffin 
embedded tissue specimens according to routine protocols.  
Study Coordinator will route blocks to 
 
 that sample is on the way by email 
  
Rochester internal address: 
 

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From outside of Rochester ship ambient and include room temperature 
cool pack if needed, to: 
 
 
 
17.262 
Fresh tissue cores – Rochester ONLY 
17.2621 The laboratory of 
will process 
half of the fresh tissue specimens.  
Email 
 and copy 
 
when you have a potential patient for the study (include 
patient name, MCN, diagnosis, biopsy location, and 
date/time of procedure, as well as study coordinator contact 
info) and then send a second email to confirm once the 
patient has consented. 
On the day of the procedure, study coordinator will 
display/digital page the lab at 
(do not priority page) 
when the procedure is about to start so the lab can send staff 
to collect tissue. Also contact lab directly at 
to make 
sure the page is not missed. 
17.2622 The laboratory of 
 will process half of 
the fresh tissue specimens.  
Email 
 
when you have a potential patient for the study 
(include patient name, MCN, diagnosis, biopsy location, and 
date/time of procedure, as well as study coordinator contact 
info) and then send a second email to confirm once the 
patient has consented. 
On the day of the procedure, study coordinator will 
display/digital page 
(do not priority 
page) when the procedure is about to start so the lab can 
send staff to collect tissue. Also contact lab directly 
 to make sure the page is not missed. 
17.3 
Background and Methodology 
17.31 Patient-derived tumor organoid 
Preclinical tumor models are important tools to study cancer biology, develop 
novel therapeutics, and provide information for treatment decisions. However 
currently available tumor models such as cell lines, transgenic mice and patient-
derived xenograft (PDX) model have inherent limitations that can adversely 
affect the translation of preclinical findings to the clinic. Patient-derived tumor 
organoid is a 3-D cell culture which enables the establishment of ex vivo tumor 
model from scant core-needle biopsy specimen in a timely manner. These tumor 
organoids recapitulate both phenotypes and genotypes of the donor tumor. 
(Vlachogiannis et al. 2018) The laboratory of 
at 
our institution has successfully established such tumor organoids from core-
biopsy tumor specimens donated by patients with metastatic cholangiocarcinoma. 

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The established tumor organoids were ready for drug screening and related 
molecular studies within 4-6 weeks of the biopsy. Though the concordance 
between treatment effect in tumor organoids and the clinical benefit observed in 
the donor patients have been reported, the role of tumor organoids has not been 
prospectively evaluated in clinical trials of patients with advanced HCC. Here, 
we aim to 1) determine if drug response from a parallel ex vivo trial using 
patient-derived tumor organoid correlates with clinical response to futibatinib 
plus pembrolizumab and 2) to evaluate the role of thymidine kinase 1 in 
predicting the clinical response to treatment and discover potential mechanisms 
of resistance and sensitivity. 
18.0 
Records and Data Collection Procedures  
18.1 
Submission Timetable 
Data submission instructions for this study can be found in the Data Submission 
Schedule. 
18.2 
Survival Follow-up/Event Monitoring 
See Section 4.  
18.3 
CRF completion 
This study will use Medidata Rave® for remote data capture (rdc) of all study data. Data 
collection for this study will be done exclusively through the Medidata Rave® clinical 
data management system. Access to the trial in Rave is granted through the iMedidata 
application to all persons with the appropriate roles assigned in Regulatory Support 
System (RSS). To access Rave via iMedidata, the site user must have an active account 
and the appropriate Rave role (Rave CRA, Read-Only, Site Investigator) on the 
organization roster at the enrolling site. 
18.4 
Site responsibilities 
Each site will be responsible for ensuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.5 
Supporting documentation  
This study requires supporting documentation for evidence of response to study therapy 
and progression after study therapy. These documents should be submitted within 
14 days after the visit at which response or progression is determined. 
Results of genomic testing should be uploaded when they are available. 
Imaging reports for PET/CT or PET/MRI as well as for standard imaging should be 
uploaded within 14 days after the visit. 
18.6 
Labeling of materials 
Each site will be responsible for ensuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 

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18.7 
Overdue lists 
A list of overdue forms and outstanding queries will be available in Rave through the 
Rave Task Summary. In addition to this, the Overdue Materials report is available on the 
Cancer Center Systems homepage. 
19.0 
Budget 
19.1 
Costs charged to patient: routine clinical care 
Routine clinical care costs will be the responsibility of the patient and/or the patient’s 
insurance company, including pembrolizumab and its administration 
19.2 
Tests to be research funded: 
• 
Futibatinib (TAS-120) will be provided by Taiho Oncology 
• 
Correlative studies 
• 
Collection, processing and storage of blood for research. 
19.3 
Other budget concerns: 
Taiho Oncology will provide a grant through NCCN to Mayo Clinic to help with costs 
for the conduct of this study. 
Mayo Clinic Cancer Center will provide Development funding to cover additional costs 
associated with the conduct of this study. 
 
 
 

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20.0 
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Schulze K, Imbeaud S, Letouzé E, et al. Exome sequencing of hepatocellular carcinomas identifies 
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Lang L, Teng Y. Fibroblast Growth Factor Receptor 4 Targeting in Cancer: New Insights into 
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Miura S, Mitsuhashi N, Shimizu H, et al. Fibroblast growth factor 19 expression correlates with 
tumor progression and poorer prognosis of hepatocellular carcinoma. BMC Cancer. 2012;12. 
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Kang HJ, Haq F, Sung CO, et al. Characterization of hepatocellular carcinoma patients with 
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Kim RD, Sarker D, Meyer T, et al. First-in-human phase i study of fisogatinib (BLU-554) 
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tas-120, a highly selective, coalently bound FGFR inhibitor, in patients with advanced solid 
tumors. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018. ; 
2018. 
22.  
Peggs KS, Quezada SA, Korman AJ, Allison JP. Principles and use of anti-CTLA4 antibody in 
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Kassel R, Cruise MW, Iezzoni JC, Taylor NA, Pruett TL, Hahn YS. Chronically inflamed livers 
up-regulate expression of inhibitory B7 family members. Hepatology. 2009;50(5):1625-1637. 
doi:10.1002/hep.23173 
27.  
Ferrari C, Boni C, Rossi M, et al. T cell regulation in HBV-related chronic liver disease. J 
Hepatol. 2017;66(5):1096-1098. doi:10.1016/j.jhep.2016.10.002 
28.  
Budhu A, Forgues M, Ye QH, et al. Prediction of venous metastases, recurrence, and prognosis in 
hepatocellular carcinoma based on a unique immune response signature of the liver 
microenvironment. Cancer Cell. 2006;10(2):99-111. doi:10.1016/j.ccr.2006.06.016 
29.  
Li M, Sun R, Xu L, et al. Kupffer Cells Support Hepatitis B Virus–Mediated CD8 + T Cell 
Exhaustion via Hepatitis B Core Antigen–TLR2 Interactions in Mice. J Immunol. 
2015;195(7):3100-3109. doi:10.4049/jimmunol.1500839 
30.  
Xu D, Fu J, Jin L, et al. Circulating and Liver Resident CD4+CD25+ Regulatory T Cells Actively 
Influence the Antiviral Immune Response and Disease Progression in Patients with Hepatitis B. J 
Immunol. 2006;177(1):739-747. doi:10.4049/jimmunol.177.1.739 
31.  
Zhang HH, Mei MH, Fei R, et al. Regulatory T cells in chronic hepatitis B patients affect the 
immunopathogenesis of hepatocellular carcinoma by suppressing the anti-tumour immune 
responses. J Viral Hepat. 2010;17(SUPPL. 1):34-43. doi:10.1111/j.1365-2893.2010.01269.x 
32.  
Martinet J, Dufeu-Duchesne T, Bruder Costa J, et al. Altered functions of plasmacytoid dendritic 
cells and reduced cytolytic activity of natural killer cells in patients with chronic HBV infection. 
Gastroenterology. 2012;143(6):1586-1596.e8. doi:10.1053/j.gastro.2012.08.046 
33.  
Fisicaro P, Valdatta C, Massari M, et al. Antiviral Intrahepatic T-Cell Responses Can Be Restored 
by Blocking Programmed Death-1 Pathway in Chronic Hepatitis B. Gastroenterology. 
2010;138(2):682-693.e4. doi:10.1053/j.gastro.2009.09.052 
34.  
Bengsch B, Martin B, Thimme R. Restoration of HBV-specific CD8+ T cell function by PD-1 
blockade in inactive carrier patients is linked to T cell differentiation. J Hepatol. 2014;61(6):1212-

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1219. doi:10.1016/j.jhep.2014.07.005 
35.  
Tzeng HT, Tsai HF, Liao HJ, et al. PD-1 blockage reverses immune dysfunction and hepatitis B 
viral persistence in a mouse animal model. PLoS One. 2012;7(6):1-9. 
doi:10.1371/journal.pone.0039179 
36.  
Owusu Sekyere S, Suneetha PV, Kraft ARM, et al. A heterogeneous hierarchy of co-regulatory 
receptors regulates exhaustion of HCV-specific CD8 T cells in patients with chronic hepatitis C. J 
Hepatol. 2015;62(1):31-40. doi:10.1016/j.jhep.2014.08.008 
37.  
Wu W, Shi Y, Li S, et al. Blockade of Tim-3 signaling restores the virus-specific CD8 + T-cell 
response in patients with chronic hepatitis B. Eur J Immunol. 2012;42(5):1180-1191. 
doi:10.1002/eji.201141852 
38.  
Sangro B, Gomez-Martin C, De La Mata M, et al. A clinical trial of CTLA-4 blockade with 
tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol. 
2013;59(1):81-88. doi:10.1016/j.jhep.2013.02.022 
39.  
El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular 
carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and 
expansion trial. Lancet. 2017;389(10088):2492-2502. doi:10.1016/S0140-6736(17)31046-2 
40.  
Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular 
carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label 
phase 2 trial. Lancet Oncol. 2018;19(7):940-952. doi:10.1016/S1470-2045(18)30351-6 
41.  
Yau T, Kang Y-K, Kim T-Y, et al. Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in 
patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate 040. J 
Clin Oncol. 2019;37(15_suppl). 
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microenvironment in urothelial bladder cancer. Cancer Immunol Res. 2016;4(7):563-568. 
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Palakurthi S, Kuraguchi M, Zacharek SJ, et al. The Combined Effect of FGFR Inhibition and PD-1 
Blockade Promotes Tumor-Intrinsic Induction of Antitumor Immunity. Cancer Immunol Res. 
2019;7(9):1457-1471. doi:10.1158/2326-6066.CIR-18-0595 
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Liu MC, Shields PG, Warren RD, et al. Circulating tumor cells: A useful predictor of treatment 
efficacy in metastatic breast cancer. J Clin Oncol. 2009;27(31):5153-5159. 
doi:10.1200/JCO.2008.20.6664 
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Liu MC. By the numbers: Does circulating tumor cell enumeration have a role in metastatic breast 
cancer? J Clin Oncol. 2014;32(31):3479-3483. doi:10.1200/JCO.2014.56.6851 
46.  
Campton DE, Ramirez AB, Nordberg JJ, et al. High-recovery visual identification and single-cell 
retrieval of circulating tumor cells for genomic analysis using a dual-technology platform 
integrated with automated immunofluorescence staining. BMC Cancer. 2015;15(1):1-13. 
doi:10.1186/s12885-015-1383-x 
47.  
Kim ST, Lee WS, Lanman RB, et al. Prospective blinded study of somatic mutation detection in 
cell-free DNA utilizing a targeted 54-gene next generation sequencing panel in metastatic solid 
tumor patients. Oncotarget. 2015;6(37):40360-40369. doi:10.18632/oncotarget.5465 
48.  
Diehl F, Li M, Dressman D, et al. Detection and quantification of mutations in the plasma of 
patients with colorectal tumors. Proc Natl Acad Sci U S A. 2005;102(45):16368-16373. 
doi:10.1073/pnas.0507904102 
49.  
Diehl F, Schmidt K, Choti MA, et al. Circulating mutant DNA to assess tumor dynamics. Nat 
Med. 2008;14(9):985-990. doi:10.1038/nm.1789 
50.  
Dawson SJ, Tsui DWY, Murtaza M, et al. Analysis of circulating tumor DNA to monitor 
metastatic breast cancer. N Engl J Med. 2013;368(13):1199-1209. doi:10.1056/NEJMoa1213261 

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51.  
Jiao D, Li Y, Yang F, Han D, Wu J, Shi S, Tian F, Guo Z, Xi W, Li G, Zhao A, Yang AG, Qin W, 
Wang H WW. Expression of Prostate-Specific Membrane Antigen in Tumor-Associated 
Vasculature Predicts Poor Prognosis in Hepatocellular Carcinoma. Clin Transl Gastroenterol. 
2019. doi:10.14309/ctg.0000000000000041 
52.  
Hofman MS, Hicks RJ, Maurer T EM. Prostate-specific Membrane Antigen PET: Clinical Utility 
in Prostate Cancer, Normal Patterns, Pearls, and Pitfalls. Radiographics. 2018;38(1):200-217. 
doi:10.1148/rg.2018170108 
60.  
Matti A, Lima GM, Pettinato C, Pietrobon F, Martinelli F FS. How Do the More Recent 
Reconstruction Algorithms Affect the Interpretation Criteria of PET/CT Images? Nucl Med Mol 
Imaging. 2019;53(3):216-222. doi:10.1007/s13139-019-00594-x 
61.  
Otani T, Hosono M, Kanagaki M, Onishi Y, Matsubara N, Kawabata K KH. Evaluation and 
Optimization of a New PET Reconstruction Algorithm, Bayesian Penalized Likelihood 
Reconstruction, for Lung Cancer Assessment According to Lesion Size. AJR Am J Roentgenol. 
2019;213(2):W50-W56. doi:10.2214/AJR.18.20478 
62.  
Teoh EJ, McGowan DR, Schuster DM, Tsakok MT, Gleeson FV BK. Bayesian penalised 
likelihood reconstruction (Q.Clear) of (18)F-fluciclovine PET for imaging of recurrent prostate 
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doi:10.1259/bjr.20170727 
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Tragardh E, Minarik D, Almquist H, Bitzen U, Garpered S, Hvittfelt E, Olsson B OJ. Impact of 
acquisition time and penalizing factor in a block-sequential regularized expectation maximization 
reconstruction algorithm on a Si-photomultiplier-based PET-CT system for (18)F-FDG. EJNMMI 
Res. 2019;9(1):64. doi:10.1186/s13550-019-0535-4 
64.  
Broski SM, Goenka AH, Kemp BJ JG. Clinical PET/MRI: 2018 Update. AJR Am J Roentgenol. 
2018;211(2):295-313. doi:10.2214/AJR.18.20001 
65.  
Hope TA, Pampaloni MH NE. Simultaneous 68Ga-DOTA-TOC PET/MRI with gadoxetate 
disodium in patients with neuroendocrine tumor. Abdom Imaging. 2015;40(1432). 
66.  
Yeh R, Dercle L, Garg I, Wang ZJ, Hough DM GA. The Role of 18F-FDG PET/CT and PET/MRI 
in Pancreatic Ductal Adenocarcinoma. Abdom Radiol (New York). 2018;43(2):415-434. 
doi:10.1007/s00261-017-1374-2 
67.  
Vlachogiannis G, Hedayat S, Vatsiou A, et al. gastrointestinal cancers. 2018;926(February):920-
926. 
68.  
Zhu AX, Kang YK, Yen CJ, et al. Ramucirumab after sorafenib in patients with advanced 
hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, 
double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(2):282-296. 
doi:10.1016/S1470-2045(18)30937-9 
69.  
Lencioni R. New data supporting modified RECIST (mRECIST) for hepatocellular carcinoma. 
Clin Cancer Res. 2013;19(6):1312-1314. doi:10.1158/1078-0432.CCR-12-3796 
 

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Appendix I 
ECOG Performance Status 
 
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, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair. 
5 
Dead 
*As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-
655, 1982. 
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the 
scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
From 
 
 
 

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Appendix II 
Child Pugh Scores 
The score employs five clinical measures of liver disease. Each measure is scored 1-3, with 3 
indicating most severe derangement.[1] 
Measure 
1 point 
2 points 
3 points 
Total bilirubin, μmol/L 
(mg/dL) 
<34 
(<2) 
34-50 (2-3) 
>50 (>3) 
Serum albumin, g/dL 
>3.5 
2.8-3.5 
<2.8 
Prothrombin time (PT), 
INR 
<1.7 
1.71-2.30 
>2.30 
Ascites 
None 
Mild (or suppressed with 
medication) 
Moderate to Severe (or 
refractory) 
Hepatic encephalopathy 
None 
Grade I-II 
Grade III-IV 
 
Chronic liver disease is classified into Child-Pugh class A to C, employing the added score from 
above.[1] 
Points Class One year survival Two year survival 
5-6 
A 
100% 
85% 
7-9 
B 
81% 
57% 
10-15 C 
45% 
35% 
 
References 
1. 
Cholongitas, E; Papatheodoridis, GV; Vangeli, M; Terreni, N; Patch, D; Burroughs, AK (Dec 
2005). "Systematic review: The model for end-stage liver disease--should it replace Child-Pugh's classification 
for assessing prognosis in cirrhosis?". Alimentary pharmacology & therapeutics. 22 (11-12): 1079–
89. doi:10.1111/j.1365-2036.2005.02691.x. PMID 16305721. 
2. 
Child CG, Turcotte JG (1964). "Surgery and portal hypertension". In Child CG. The liver and portal 
hypertension. Philadelphia: Saunders. pp. 50–64. 
3. 
Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R (1973). "Transection of the oesophagus for 
bleeding oesophageal varices". The British journal of surgery.60 (8): 646–
9. doi:10.1002/bjs.1800600817. PMID 4541913. 
 

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Appendix III Barcelona Clinic Liver Cancer (BCLC) Staging Classification & Treatment 
Schedule32 
 
PST=performance status test. N=nodules. M=metastases. PEI=percutaneous ethanol injection. *Cadaveric liver 
transplantation or living donor liver transplantation. Modified from33 34 with permission from The American 
Association for the Study of Liver Disease. 
 
 
 
32 Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003,362:1907–1917. 
33 Llovet JM Bru C Bruix J Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver 
Dis. 1999; 19: 329-338 
34 Bruix J Llovet JM Prognostic prediction and treatment strategy in hepatocellular carcinoma.Hepatology. 2002; 35: 
519-524 

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Appendix IV Guidelines for Contraception 
Your study doctor will discuss prohibited and acceptable birth control methods for use during your 
participation in this study and for 120 days after the last dose of study drug. These guidelines apply to 
all persons capable of becoming pregnant or persons capable of fathering a child and their partners of 
child-bearing potential. 
You should notify your study doctor if birth control methods other than those specified below are 
started during the course of this study or if you start any prescription drug or other medication 
(including herbal and over-the-counter medications) not prescribed by the study doctor.  
One of the two forms of birth control must be highly effective and the second method may also be 
highly effective or selected from the list of other contraceptive methods.  
Highly 
Effective 
Methods of 
Contraception 
Progestogen only hormonal contraception associated with inhibition of 
ovulation (oral, injectable, or implantable) 
Hormonal methods of contraception including 
• 
combined oral contraceptive pills (that is, those that contain 
both estrogen and progestogen) 
• 
intravaginal (e.g. vaginal ring) 
• 
transdermal, injectables, implants and intrauterine devices 
(IUDs) 
Sometimes, hormonal levels of birth control can be affected by the 
study drug. Your doctor will tell you whether hormonal forms of birth 
control are allowed for this study. 
Non-hormonal IUDs 
Bilateral tubal occlusion 
Vasectomized partner 
Complete abstinence 
Less than 
Highly 
Effective 
Methods of 
Contraception 
Diaphragm with spermicide 
Cervical cap with spermicide 
Vaginal sponge with spermicide 
Progestin only pills 
Male condoms with or without 
spermicide* 
*A male and a female condom 
must not be used together 
Female Condoms* 
Unacceptable 
Methods of 
Contraception 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
Withdrawal (coitus interruptus) 
Spermicide only 
Lactation/amenorrhea method (LAM) 
If you choose abstinence as a method of contraception, your doctor will discuss other methods of 
contraception with you in the case you choose not to continue abstinence. Pregnancy testing remains 
mandatory even if you do choose abstinence as your method of contraception. If pregnancy occurs in 
you or your partner, you must report the pregnancy to the study investigator and agree to be followed 
for the entire course of pregnancy and birth. 
 

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Appendix V 
Patient Medication Diary 
Patient Medication Diary is provided as a standalone document per Mayo Clinic IRB requirements. 

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Appendix VI Classification of Substrates, Inhibitors, & Inducers of CYP Enzymes & 
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. 
  
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 PK 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.  
Example of CYP3A Inhibitors  
Cytochrome P450 (CYP) 
Enzymes  
Strong Inhibitorsa ≥ 5-fold 
increase in AUC  
Moderate inhibitorsb ≥2 but <5-
fold increase in AUC  
CYP3A  
boceprevir, clarithromycin, 
cobicistat, conivaptan, danoprevir 
and ritonavir, diltiazem, 
elvitegravir and ritonavir, 
grapefruit juice,c indinavir and 
ritonavir, idelalisib, itraconazole, 
ketoconazole, lopinavir and 
ritonavir, 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  
a Strong inhibitors are drugs that increase the area under the concentration-time curve (AUC) of sensitive index substrates of 
a given metabolic pathway ≥5-fold.  
b Moderate inhibitors are drugs that increase the AUC of sensitive index substrates of a given metabolic pathway ≥2 to <5-
fold.  
c The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation dependent. 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).  
 
Example of CYP3A Inducers  
Cytochrome P450 (CYP) 
Enzymes  
Strong Inducers ≥ 80% 
decrease in AUC  
Moderate Inducers 50-80% 
decrease in AUC  
CYP3A  
carbamazepine, enzalutamide, 
mitotane, phenytoin, rifampin, St. 
John’s worta  
bosentan, efavirenz, etravirine, 
modafinil  
a The effect of St. John’s wort varies widely and is preparation-dependent.  
 
 
 

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Example of CYP3A Substrates  
Cytochrome P450 (CYP) 
Enzymes  
Sensitive substratesa  
Moderate sensitive substrateb 
CYP3Ac  
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  
a Sensitive substrates are drugs that demonstrate an increase in AUC of ≥5-fold with strong index inhibitors of a given 
metabolic pathway in clinical drug-drug interaction studies.  
b Moderate sensitive substrates are drugs that demonstrate an increase in AUC of ≥2 to <5-fold with strong index inhibitors 
of a given metabolic pathway in clinical drug-drug interaction studies.  
c Because a number of CYP3A substrates (eg, darunavir, maraviroc) are also substrates of MDR1 (P-gp), the observed 
increase in exposure could be due to inhibition of both CYP3A and MDR1 (P-gp).  
 
Example of Inhibitors for P-gp and BCRP  
Transporters  
Gene  
Inhibitor  
P-gpa  
ABCB1  
Amiodarone, carvedilol, 
clarithromycin, dronedarone, 
itraconazole, lapatinib, lopinavir 
and ritonavir, propafenone, 
quinidine, ranolazine, ritonavir, 
saquinavir and ritonavir, telaprevir, 
tipranavir and ritonavir, verapamil  
BCRPb  
ABCG2  
Curcumin, cyclosporine A, 
eltrombopag  
a P-gp: (1) AUC fold-increase of digoxin ≥2 with co-administration and (2) in vitro inhibitor.  
b 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.  
 
Example of Substrates for P-gp and BCRP  
Transporters  
Gene  
Substrate  
P-gpa  
ABCB1  
Dabigatran, digoxin, fexofenadine  
BCRPb  
ABCG2  
Rosuvastatin, sulfasalazine  
a 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.  
b BCRP: (1) AUC fold-increase ≥2 with pharmacogenetic alteration of ABCG2 (421C>A) and (2) in vitro transport by BCRP 
expression systems.  
 

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Appendix VII Patient Questionnaire Booklet
Patient Information Sheet
Patient Completed Booklet
________________________________________________________________________
You have been given a booklet to complete for this study. The booklet contains some 
questions about your health as a patient receiving treatment for cancer. You answers will 
help us to better understand how the treatment you are receiving is affecting the way you 
feel.
1. This booklet contains oneset of questions:
•
EORTC-QLQ-C30 Questionnaire (30 questions)
2. Please select one answer for each question.
3. Please complete the booklet during your scheduled clinical visit and return it to your 
nurse or your physician.
Thank you for taking the time to help us.

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EORTC-QLQ-C30 
 

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