Clinical trial NCT03230318
Conditions: Intrahepatic Cholangiocarcinoma Combined Hepatocellular and Cholangiocarcinoma
Keywords: iCCA intrahepatic cholangiocarcinoma FGFR2 gene fusion or FGFR2 gene mutation or amplification biliary cancer bile duct cancer FGFR2 gene rearrangement liver cancer targeted therapy combined hepatocellular and cholangiocarcinoma cHCC-CCA derazantinib
Sponsor: Basilea Pharmaceutica
Start date: 2017-09-28; Completion date: 2022-10-25
Enrollment: 148 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This Phase II, open-label, single-arm study evaluated the anti-cancer activity of derazantinib in subjects with inoperable or advanced intrahepatic cholangiocarcinoma (iCCA) who received at least one prior regimen of systemic therapy. Patients received an oral once-daily total dose of 300 mg derazantinib capsules.

Detailed description:
This was a multi-center, open-label, single arm study which evaluated the anti-cancer activity of derazantinib in adult patients with inoperable or advanced iCCA in the following study population:

Patients with inoperable or advanced iCCA and with fibroblast growth factor receptor 2 (FGFR2) fusions (Substudy 1) or FGFR2 mutations/amplifications (Substudy 2), treated with at least one prior regimen of systemic therapy.

Derazantinib was supplied as 100 mg capsules. A dose of 300 mg once-daily (three capsules of 100 mg each) of derazantinib was administered orally to patients, 1 hour before, or 2 hours after, a meal.

Arms: arm 1: Oral administration
Interventions: intervention 1: derazantinib
Intervention descriptions: intervention 1: Derazantinib was administered orally at 300 mg once daily

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
DZB-CS-301
Derazantinib
Study title:
A pivotal study of derazantinib in patients with inoperable or 
advanced intrahepatic cholangiocarcinoma and FGFR2 gene 
fusions or FGFR2 gene mutations or amplifications
Study number:
DZB-CS-301 (formerly ARQ 087-301)
Study phase:
2
Product name:
Derazantinib (formerly ARQ 087) 
IND number:
116397
EudraCT number:
2016-004448-12
Sponsor:
Basilea Pharmaceutica International Ltd. 
Grenzacherstrasse 487
CH-4058 Basel
Switzerland
Study Physician:
Version / Date:
Protocol Version 9.0 / 17 November 2020
Confidentiality statement
The information contained in this document is commercial confidential information which is the property 
of Basilea Pharmaceutica International Ltd, or is under its control. This information is provided to you in 
confidence as an investigator, potential investigator or consultant, for review by you, your staff and an 
applicable Independent Ethics Committee/Institutional Review Board, and may not be disclosed by the 
recipient to any other third party without prior written authorization from Basilea Pharmaceutica 
International Ltd, except to the extent necessary to obtain informed consent from potential participants in 
the clinical study to which the document refers. If it is determined that disclosure to potential participants 
or to another third party is required by applicable law or regulations or to obtain such informed consent 
from potential participants in such clinical study, the party to whom the information is disclosed must be 
informed that the information is confidential and that it may not be further disclosed without prior written 
authorization from Basilea Pharmaceutica International Ltd.
Note: This is an electronically controlled document (Document ID: Clinical-002427).


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SYNOPSIS
Study title:
A pivotal study of derazantinib in patients with inoperable or 
advanced intrahepatic cholangiocarcinoma and FGFR2 gene 
fusions or FGFR2 gene mutations or amplifications (FIDES-01)
IND number:
116397
EudraCT number:
2016-004448-12
Study number:
DZB-CS-301 
Study Phase:
Phase 2
Investigational 
product:
Derazantinib
Active ingredient:
(R)-6-(2-fluorophenyl)-N-(3-(2-((2-
methoxyethyl)amino)ethyl)phenyl) -5,6-
dihydrobenzo[h]quinazolin-2-amine dihydrochloride
Investigational 
device to screen for 
FGFR2 fusions
(Substudy 1):
The FGFR2 break-apart FISH Probe Kit test will be used to detect 
gene fusions, also referred to as rearrangements, involving the 
FGFR2 gene via fluorescence in situ hybridization (FISH) in 
formalin-fixed paraffin-embedded (FFPE) primary liver cancer 
specimens, including intrahepatic cholangiocarcinoma (iCCA) 
tissue samples to aid in identifying or confirming patients’ 
eligibility for treatment with derazantinib.
Tissue samples will be sent to ARUP laboratories, which is the 
Sponsor`s central laboratory, for FISH testing. Tumor samples 
may be analyzed at other laboratories identified by the Sponsor to 
further characterize the identified genetic aberrations (GAs) and 
molecular markers predictive of response.
Pre-screening results obtained from tests performed by the study 
sites (‘local testing’) detailed in Section 6.8 may enable treatment 
initiation prior to central confirmation of FGFR2 fusions.
Investigational 
device to screen for 
FGFR2 mutations or 
amplifications
(Substudy 2):
For Next-Generation Sequencing (NGS) testing to detect FGFR2
mutations/amplifications, no mandatory central laboratory will be 
established (see Section 6.8.2 for further details).  
NGS testing will be performed or commissioned by the respective 
study site using standard protocols approved by the local 
Institutional Review Board (IRB)
/ Independent
Ethics 
Committee 
(IEC), 
Clinical 
Laboratory 
Improvement 
Amendments (CLIA), or other similar agency, or, as applicable, 
US FDA-approved and/or fully CE-marked industrial-scale 
assays. For enrollment of patients in the EU, assays must be either 
fully CE-marked or CE-marked for analytical performance, 


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unless assays are exempt from this requirement by the In Vitro 
Diagnostics 
Directive
(IVDD; 
Directive 
98/79/EC),
i.e., manufactured 
and 
appropriately 
validated 
within 
health-institution laboratories for use in that environment and not 
subject to commercial transactions. The use of both tissue- and 
plasma-based NGS assays is allowed.
Tumor samples may be analyzed at other laboratories identified 
by the Sponsor to further characterize the identified GAs and 
molecular markers predictive of response.
Indication under 
investigation:
Substudy 1:
Inoperable* or advanced FGFR2 fusion positive iCCA.
Substudy 2:
Inoperable or advanced iCCA harboring FGFR2 mutations or 
amplifications (see Appendix 8).
Primary objective: 
Substudy 1:
To evaluate the anti-cancer activity by Objective Response Rate 
(ORR) by central radiology review as per Response Evaluation 
Criteria in Solid Tumors (RECIST) version 1.1 in patients with 
inoperable or advanced iCCA whose tumors harbor FGFR2
fusions (by FISH performed by a central laboratory) and who 
received at least one prior regimen of systemic therapy.
Substudy 2:
To evaluate the anti-tumor activity of derazantinib by 
progression-free survival at 3 months (PFS 3) based on survival 
status or central radiology review (RECIST 1.1) in patients with 
inoperable or advanced iCCA whose tumors harbor FGFR2
mutations or amplifications, and who received at least one prior 
regimen of systemic therapy.
Secondary 
objectives:
Substudy 1 and Substudy 2

To evaluate progression free survival (PFS) by central 
radiology review and overall survival (OS)

To evaluate duration of response (DoR) by central radiology 
review

To evaluate the safety profile (toxicities) of derazantinib in 
this patient population

To evaluate changes, and assess the minimally important 
difference, in health-related quality-of-life (HRQOL) and 
symptom response from baseline using the European 
Organization for Research and Treatment of Cancer (EORTC)
* Throughout this protocol, ‘inoperable’ means that surgery is not indicated due to disease extension, co-morbidities, 
or other technical reasons.


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QLQ-C30, QLQ-BIL21, Global- Self Evaluated Transition 
(G-SET) / Health Transition Index (HTI), and the EQ-5D 
visual analog scale (VAS).
Substudy 2

To evaluate the anti-cancer activity by ORR by central 
radiology review as per RECIST version 1.1 in patients with
inoperable or advanced iCCA whose tumors harbor FGFR2
mutations or amplifications, and who received at least 
one prior regimen of systemic therapy
Exploratory 
objectives:

To evaluate changes in pharmacodynamic (PD) biomarkers

To evaluate ORR, PFS, OS, and DoR by PD biomarkers

To evaluate the relationship between derazantinib exposure 
and effectiveness, toxicity and PD biomarkers

To explore the concordance of a liquid biopsy diagnostic test 
compared to baseline tumor biopsy

To evaluate population pharmacokinetics (PopPK)

To evaluate the urinary excretion of derazantinib, and 
possibly its metabolites, in a subset of patients

To compare time to progression (TTP) on the first and/or the 
last prior line of systemic therapy (reported) versus TTP on 
derazantinib by central radiology review (TTP will be 
calculated from the first date of receiving study drug or prior 
line of systemic therapy until radiographic disease 
progression)
Study design:
This is a multi-center, open-label, single arm study evaluating 
derazantinib in adult patients with inoperable or advanced iCCA 
and FGFR2 GAs. 

Substudy 1 enrolls patients with FGFR2 fusions.

Substudy 2 enrolls patients with FGFR2 mutations or 
amplifications (see Appendix 8).

A subset of up to 20 patients (PK subgroup) will be asked to 
participate in rich PK blood sampling and PK urine sampling 
to assess the renal excretion of derazantinib (and its 
metabolites) (see Section 6.6). 
Substudy 1 is considered pivotal, and will enroll approximately 
100 patients to determine the ORR (see Section 10.7).


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Substudy 2 will use
a Simon’s two-stage design,
with 
approximately 15 mITT-evaluable patients in Stage 1, and an 
additional 28 mITT-evaluable patients if the study proceeds to 
Stage 2.
Patient eligibility may be assessed in two steps: 
1) Molecular pre-screening to confirm FGFR2 GA status (FGFR2
fusions, or FGFR2 mutations/amplifications; see Table 1 and 
Table 2, and Appendix 8) using validated/approved genetic 
testing devices; and 
2) Clinical screening procedures to confirm study treatment 
eligibility once molecular eligibility is confirmed by the tumor’s 
FGFR2 GA status.  
Molecular pre-screening for FGFR2 fusions in Substudy 1 may 
be based on local or central testing. If pre-screening is performed 
based on a local test, then a central confirmation by the FGFR2
break-apart FISH Probe Kit test is required for Substudy 1 
(FGFR2 fusions). 
Molecular pre-screening for FGFR2 mutations/amplifications in 
Substudy 2 should be based on NGS testing (for details, see
Table 2 and Appendix 8) performed or commissioned by the 
respective study site.
Patients may be prescreened for the tumor’s FGFR2 GA status 
(prior to initiation of or during ongoing systemic therapy). If the 
patient is still receiving prior systemic therapy, clinical screening 
procedures will be delayed until radiographically confirmed 
disease progression or intolerance to the ongoing systemic 
therapy is documented. After the study treatment eligibility is 
confirmed, patients will be enrolled and treated with continuous 
300 mg once daily (QD) dosing of derazantinib capsules. 
A treatment cycle is defined as 28 days. 
During the treatment period, patients will be evaluated every 
2 weeks for the first cycle (Cycle 1 Days 1 and 15) and once 
every cycle thereafter (Day 1 of each cycle).  
Tumor measurements will be done at Screening (within 28 days 
prior to the first dose of derazantinib), once every 8 weeks 
(two cycles) from the day of the first dose for the first six cycles, 
and once every 12 weeks (three cycles) thereafter. For patients 
with partial response (PR) or complete response (CR), the 
Investigator should perform a confirmation tumor measurement 
4 to 5 weeks after the scan showing PR or CR. For patients with 
progressive disease (PD) per Investigator assessment, a central 


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radiology reviewer confirmation should be received prior to the 
patient’s discontinuation from the study treatment if progression 
is seen on the first or second on-treatment scan. Patients who 
discontinue study drug for a reason other than radiographic 
disease progression, withdrawal of consent, death, or loss to 
follow-up should continue tumor evaluation visits if possible 
every 8–12 weeks until they start another anti-cancer therapy, 
experience disease progression, withdraw consent, die, or are lost 
to follow-up.
Pharmacodynamic assessment will include evaluation of tumor 
markers (CA19.9, CA125, CEA), biomarkers (FGF19, FGF21, 
FGF23), and cell-free circulating tumor deoxyribonucleic acid 
(ctDNA). Blood samples for PD assessments will be collected 
only from patients enrolled after completion of the interim 
analysis, and subject to the granting of appropriate regulatory and 
IRB/IEC approval.
Archival tumor tissue samples will be obtained for all patients to 
enable additional molecular analyses with regard to the identified 
GAs and markers predictive of response at the laboratories 
selected by the Sponsor (see Section 6.8).
The PopPK parameters of derazantinib will be determined. 
Exploratory assessments of metabolites of derazantinib may also 
be investigated. All patients will be scheduled for sparse PK 
sampling. A subset of up to 20 patients (PK subgroup) will be 
asked to participate in rich PK sampling and/or urinary PK 
sampling (see Section 6.6).
HRQOL and symptom response will also be measured. 
Safety follow-up will be conducted at least 30 days after the 
administration of the last dose of study medication.  Safety 
follow-up will include collection of adverse events (AEs) and 
changes in concomitant medication.  
Central reading of all electrocardiogram (ECG) results will be 
performed (for details, see Section 6.4).
Survival follow-up will continue until the study has completed or 
other discontinuation criteria are met.
Study endpoints
Primary efficacy endpoint (Substudy 1)

ORR will be the proportion of patients with confirmed 
complete responses and partial responses by central radiology 
review as per RECIST version 1.1.


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Primary efficacy endpoint (Substudy 2)

PFS 3 will be the proportion of patients who have progression-
free survival at 3 months from the first date of receiving study 
drug as assessed by survival status and central radiology 
review as per RECIST version 1.1.
Secondary efficacy endpoints (Substudy 1 and Substudy 2)

DoR will be calculated from the first date of documented 
tumor response to disease progression by central radiology
review.

PFS will be calculated from the first date of receiving study 
drug until radiographic disease progression by central 
radiology review or death.

OS will be calculated from the first date of receiving study 
drug until death.

Changes in HRQOL and symptom response will be evaluated 
using the EORTC QLQ-C30, QLQ-BIL21, and EQ-5D VAS.
Secondary efficacy endpoint (Substudy 2)

ORR will be the proportion of patients with confirmed 
complete responses and partial responses by central radiology 
review as per RECIST version 1.1.
Exploratory efficacy endpoints

Changes in tumor markers and biomarkers from baseline to 
maximum change during the course of the treatment will be 
evaluated.

ORR, PFS, OS, and DoR will be evaluated by molecular 
profile, gene expression profile, biomarkers.

Describe the proportion of patients with concordant molecular 
assessment from a liquid biopsy sample measuring GAs in 
circulating-cell free DNA compared to the DNA obtained at 
from a tumor biopsy at baseline.

TTP will be calculated based on central radiology review from 
the first date of receiving study drug or prior line of systemic 
therapy until radiographic disease progression).
–
TTP will be evaluated for derazantinib overall and by line 
of prior systemic therapy. 
–
In addition, TTP will be assessed on the first and/or the 
last prior line of systemic therapy (reported) and will be 
compared to TTP on derazantinib


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
PopPK parameters of derazantinib will be evaluated (in 
addition, 
exploratory 
assessments 
of 
metabolites 
of 
derazantinib may also be investigated from the plasma PK 
samples).

The percentage of administered derazantinib (and possibly its 
metabolites) in urinary excretion over 24 h at steady-state may 
also be investigated.

The exposure-response relationship between derazantinib 
exposure and study measures of efficacy, toxicity and PD 
biomarkers will be analyzed.
Safety endpoint
Toxicities will be evaluated using NCI CTCAE version 4.03 
criteria.
Study duration:
Approximately 4 years
Sites and location:
Up to approximately 70 sites in the USA, Canada, Europe, Asia, 
and Latin America
Planned sample size: This is a single-arm, open-label study with group-sequential 
design. 
Substudy 1 (iCCA with FGFR2 fusions)
Approximately 100 patients who meet the study entry criteria will 
receive 300 mg QD orally of derazantinib capsules. In order to 
evaluate 100 patients for efficacy, it is anticipated that over 
1,000 patients will be tested for the presence of an FGFR2 fusion. 
Substudy 2 (iCCA with FGFR2 mutations or amplifications)
Up to approximately 43 mITT-evaluable patients who meet the 
study entry criteria will receive 300 mg QD orally of derazantinib 
capsules. 
A 
Simon’s 
two-stage 
design 
will 
be 
used, 
with 
15 mITT-evaluable patients in Stage 1, and an additional 
28 mITT-evaluable patients if the study proceeds to Stage 2.
In order to evaluate 43 patients for efficacy, it is anticipated that 
more than 800 patients will be tested for the presence of FGFR2
mutations or amplifications.
Study population:
The study population consists of patients with inoperable or 
advanced iCCA and with FGFR2 fusions (Substudy 1) or FGFR2
mutations/amplifications (Substudy 2), treated with at least one 
prior regimen of systemic therapy. 


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Patients’ eligibility may be assessed in two steps: 1) pre-screening 
to assess the FGFR2 GA status, which will be followed by 
2) clinical screening procedures.  
Tissue samples for genetic testing will be obtained from patients 
who meet the following pre-screening eligibility criteria:
1. Signed written informed consent to permit tissue analysis
2. 18 years of age or older
3. No medical history that is excluded per the study treatment 
eligibility criteria
4. Eastern Cooperative Oncology Group (ECOG) performance 
status ≤ 1 (Appendix 2)
5. Eligible for or receiving systemic therapy for inoperable or 
advanced iCCA
6. Not currently eligible for curative local or surgical therapy
To be enrolled in the study, once the FGFR2 GA status is 
determined, each prospective patient must meet all of the 
following inclusion criteria and none of the exclusion criteria.
Inclusion criteria 
1. Signed written informed consent granted prior to initiation of 
any study-specific procedures
2. 18 years of age or older
3. Histologically or cytologically confirmed locally advanced, 
inoperable (where surgery is not indicated due to disease 
extension, co-morbidities, or other technical reasons), or 
metastatic iCCA or mixed histology tumors (combined 
hepatocellular-cholangiocarcinoma [cHCC-CCA]) 
4. Substudy 1:
FGFR2 fusion status based on the following assessments:
a) If central laboratory designated by the Sponsor: 
Positive FISH test; and/or
b) If non-central laboratory:*
i)
Positive FISH or NGS test: patients may be enrolled 
and may start dosing, but central confirmation is 
required** (see Section 5.7.1)
* Using standard protocols and approved by local IRB/IEC, 
CLIA, or other similar agency. For enrollment of patients in the 
EU, assays must be fully CE-marked.
** The patient must not be enrolled if a negative FISH test is 
obtained from the central laboratory prior to commencing study 
treatment. Patients without central confirmation of an FGFR2
fusion by the central FISH test will be assessed on a 
case-by-case basis (see Section 5.7.1).


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ii) Negative FISH or NGS test: tissue may be submitted 
to the central laboratory designated by the Sponsor, 
and patients may only be enrolled if the central test is 
positive
Substudy 2:
FGFR2 mutations/amplifications without any concurrent 
FGFR2 translocations based on NGS testing performed or 
commissioned by the respective study site (see Section 6.8.2
for further details). .
Note 1: If the FGFR2 mutation/amplification status is derived from 
plasma-based NGS testing, a tumor block or slides prepared thereof 
should be submitted for subsequent correlative tissue-based NGS 
test at a laboratory identified by the Sponsor.
Note 2: If the NGS test used cannot identify FGFR2 translocations, 
a FISH test is mandatory to confirm that none are present.
5. Received at least one regimen of prior systemic therapy and 
then experienced documented radiographic progression (for 
Substudy 1), and have no satisfactory treatment alternatives
(for Substudy 2)
6. Measurable disease by RECIST version 1.1 criteria 
7. ECOG performance status ≤ 1 (Appendix 2)
8. Adequate organ functions as indicated by the following 
laboratory values (based on screening visit values from the 
central laboratory).

Hematological
–
Hemoglobin (Hgb) ≥ 9.0 g/dL 
–
Absolute neutrophil count (ANC) 1.5 × 109/L 
–
Platelet count ≥ 75 × 109/L 
–
International normalized ratio (INR) 0.8 to upper 
limit of normal (ULN) or 3 for patients receiving 
anticoagulant therapy such as warfarin or heparin

Hepatic
–
Total bilirubin ≤ 2 × ULN 
–
Aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) 3 ULN (5 × ULN for 
patients with liver metastases) 
–
Albumin 2.8 g/dL

Renal
–
Serum creatinine 1.5 × ULN, or
–
Creatinine clearance of ≥ 30 mL/min as estimated 
by the Cockcroft-Gault equation


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9. Female and male patients of child-producing potential must 
agree to avoid becoming pregnant or impregnating a partner, 
respectively, during the study*, and for at least 120 days after 
the last dose of derazantinib.
Male patients are considered not to be of child-producing 
potential if they have azoospermia (whether due to vasectomy 
or an underlying medical condition). Female patients are 
considered not to be of child-producing potential if they are:

postmenopausal†, or

have had a hysterectomy and/or bilateral oophorectomy, 
bilateral 
salpingectomy 
or 
bilateral 
tubal 
ligation/occlusion, at least 6 weeks prior to screening, or 

have a congenital or acquired condition that prevents 
childbearing.
Male or female patients of child-producing potential must 
agree to comply with one of the following until at least 
120 days after the last dose of derazantinib:
a) Abstinence from heterosexual activity‡
b) Using (or having their partner use) a highly effective 
method of contraception during heterosexual activity. 
Highly effective methods of contraception are§:

an intrauterine device (IUD)

vasectomy of a female patient’s male partner

a contraceptive rod implanted into the skin

combined (estrogen- and progestogen-containing) or 
progestogen-only hormonal contraception associated 
with inhibition of ovulation (oral contraceptive pill 
[estrogen/progestin pill or progestin-only pill]
contraceptive 
skin 
patch/implant, 
vaginal 
contraceptive ring, or subcutaneous contraceptive 
injection)
* From the day of first study medication, or for oral contraception from 14 days before first study medication. 
† Postmenopausal is defined as at least 12 months with no menses without an alternative medical cause; in women 
< 45 years of age a high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to 
confirm a post -menopausal state in women not using hormonal contraception or hormonal replacement therapy. In 
the absence of 12 months of amenorrhea, a single FSH measurement is not sufficient.
‡ Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is consistently 
employed as the subject’s preferred and usual lifestyle and if it is employed during the entire period of risk 
associated with the study treatment and if it is considered highly effective by local regulatory agencies and 
ERCs/IRBs. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and 
withdrawal are not highly effective methods of contraception.
§ If a contraceptive method listed above is restricted by local regulations/guidelines, then it does not qualify as a highly 
effecive method of contraception for subjects participating at sites in this country/region.


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Exclusion criteria
Prospective study participants who meet ANY of the following 
criteria will not be eligible for enrollment into this study.
1. Receipt of treatment before the first dose of study drug 
(Cycle 1 Day 1) within an interval shorter than the following, 
as applicable:

One chemotherapy or biological (e.g., antibody) cycle 
interval

Five half-lives of any small-molecule investigational or 
licensed medicinal product

2 weeks, for any investigational medicinal product with 
an unknown half-life

4 weeks of curative radiotherapy

7 days of palliative radiotherapy

28 days of radiotherapy
2. Major surgery or locoregional therapy within 4 weeks of the 
first dose of derazantinib
3. Previous treatment with any FGFR inhibitor (e.g., Balversa®
[erdafitinib], 
Pemazyre®
[pemigatinib], 
infigratinib, 
rogaratinib, futibatinib,
lenvatinib,
ponatinib, dovitinib, 
nintedanib, AZD4547, LY2784455)  
4. Unable or unwilling to swallow the complete daily dose of 
derazantinib capsules
5. Clinically unstable central nervous system (CNS) metastases 
(to be eligible, patients must have stable disease 3 months, 
confirmed by magnetic resonance imaging (MRI) or 
computed tomography (CT) scan, and/or have CNS 
metastases well controlled by low-dose steroids, anti-
epileptics, or other symptom-relieving medications)
6. Current evidence of clinically-significant corneal or retinal 
disorder likely to increase the risk of eye toxicity, including 
but 
not 
limited 
to 
bullous/band 
keratopathy, 
keratoconjunctivitis
(unless 
keratoconjunctivitis 
sicca),
corneal abrasion, inflammation/ulceration, confirmed by 
ophthalmologic examination
7. Concurrent uncontrolled or active hepatobiliary disorders, 
untreated or ongoing complications after laparoscopic 
procedures or stent placement, including but not limited to 
active cholangitis, biloma or abscess (to be eligible, the 
patients have to be treated and disorders/complications should 
be resolved within 2 weeks prior to the first dose of 
derazantinib)


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8. History of significant cardiac disorders: 

Myocardial infarction (MI) or congestive heart failure 
defined as Class II to IV per the New York Heart 
Association (NYHA) classification within 6 months of 
the first dose of derazantinib (MI that occurred 
> 6 months prior to the first dose of derazantinib are
permitted)

QTcF > 450 msec for men and QTcF > 460 msec for 
women
9. Serum electrolyte abnormalities defined as follows:

Hyperphosphatemia: serum phosphate > institutional 
upper limit of normal (ULN)

Hyperkalemia: serum potassium > institutional ULN

Hypokalemia: serum potassium < institutional lower 
limit of normal (LLN)

Hypercalcemia: corrected serum calcium > 3.1 mmol/L 
(> 12.5 mg/dL)

Hypocalcemia: corrected serum calcium < 1.75 mmol/L 
(< 7.0 mg/dL)

Hypomagnesemia: < 0.4 mmol/L (< 0.9 mg/dL)
10. Significant gastrointestinal disorder(s) that could, in the 
opinion of the Investigator, interfere with the absorption, 
metabolism, or excretion of derazantinib (e.g., Crohn’s 
disease, ulcerative colitis, extensive gastric resection)
11. History of additional malignancy that is progressing or 
requires active treatment. Exceptions include basal cell 
carcinoma of the skin, squamous cell carcinoma of the skin 
that has undergone potentially curative therapy, and in situ
cervical cancer. 
12. Concurrent uncontrolled illness not related to cancer, 
including but not limited to:

Psychiatric illness/substance abuse/social situation that 
would limit compliance with study requirements

Known uncontrolled human immunodeficiency virus 
(HIV) infection

Severe bacterial, fungal, viral, and/or parasitic infections 
under treatment with therapeutic oral or intravenous (IV) 
medication at the time of first dose of study drug 
administration


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13. Blood or albumin transfusion within 5 days of the blood draw 
being used to confirm eligibility
14. Pregnant or breast feeding
15. Known hypersensitivity to derazantinib, or to any of the study 
drug excipients (starch, lactose, crospovidone, magnesium 
stearate).
Test product, dose, 
mode of 
administration: 
Derazantinib will be supplied as 100 mg capsules.
A dose of 300 mg QD (three capsules of 100 mg each) of 
derazantinib will be administered by mouth 1 hour before, or 
2 hours after, a meal.
Duration of 
treatment: 
It is expected that most patients will receive between one and 
eight months of treatment with derazantinib capsules.
Patients will receive treatment with derazantinib capsules until 
death, radiographic disease progression, unacceptable toxicity, or 
until another of the specified criteria is met for stopping therapy. 
Radiographic progressive disease must be confirmed by central 
radiology review prior to treatment discontinuation if progression 
is seen on the first or second on-treatment scan. 
In Substudy 1, if the locally-documented FGFR2 fusion positive 
status was tested and not confirmed by FISH by the central 
laboratory designated by the Sponsor after the commencement of 
study treatment, these patients will be assessed on a case-by-case 
basis (see Section 5.7.1).
For patients who demonstrate continued benefit from receiving 
derazantinib at the time of study closure, the Sponsor aims to 
provide continued individual patient access to derazantinib, 
e.g., under a rollover study protocol, or in the context of 
compassionate use / named-patient access where applicable.
Pharmacokinetic 
and 
pharmacodynamic 
variables:
Blood samples for PD assessments of tumor markers (CA19.9, 
CA125, CEA), biomarkers (FGF19, FGF21, FGF23) and ctDNA 
will be collected and evaluated in batches either during, or at the 
end of, the study (see Section 6.7). 
Blood samples for PD assessments will be collected only from 
patients enrolled after completion of the interim analysis, and 
subject to the granting of appropriate regulatory and IRB/IEC
approval. These blood samples will be collected on Day 1 of 
Cycle 1, every 8 weeks (two cycles) for the first six cycles, once 
every 12 weeks (three cycles) thereafter, and at the End of 
Treatment visit. 


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Archival tumor tissue samples will be obtained for all patients to 
enable additional molecular analyses with regard to the identified 
GAs and markers predictive of response at the laboratories 
selected by the Sponsor (see Section 6.8).
Blood samples for sparse PK sampling will be collected on Day 1 
and Day 15 of Cycle 1, and Day 1 of Cycles 2, 3 and 4, to 
determine the PopPK parameters of derazantinib. Exploratory 
assessments of metabolites of derazantinib may also be 
investigated from the PK plasma samples (see Section 6.6). 
A subset of up to 20 patients (PK subgroup) will be asked to 
participate in rich PK blood sampling and PK urine sampling to 
assess the renal excretion of derazantinib (and its metabolites) 
(see Section 6.6). Patients will be asked for a additional consent 
to participate in the blood/urinary PK assessments. 
Exploratory 
assessments 
of 
derazantinib 
(and 
possibly 
metabolites) will be investigated from the PK urine samples.
Statistical methods:
Substudy 1
To prove the drug effect over placebo in ORR in this single-arm 
pivotal study, the hypothesis is specified as: 
H0: ORR = 0.10 and Ha: ORR=0.23.
The hypothesis test will be performed at a one-sided 2.5% 
significance level. A 10% response rate is chosen for the null 
hypothesis, which is much higher than the observed ORR of
7~8% 
in 
larger 
historical 
studies
and 
publications 
(Lamarca 2014). The 23% response rate for the alternative 
hypothesis is estimated.
Approximately 100 patients will be enrolled for this two-stage 
group sequential study with futility stopping.  An interim analysis 
for futility will be done when 40 patients who satisfied modified 
intent-to-treat (mITT) criteria had at least one post-baseline tumor 
evaluation. The study will be terminated for futility if four or 
fewer responses are observed among 40 evaluable patients.*  
If 5 or more objective responses are observed and confirmed 
based on central radiology review prior to enrollment of 
40 evaluable patients, the interim analysis may be performed 
based on fewer than 40 patients. 
* The interim analysis was conducted on 8 January 2019; futility was rejected (informative p-value 0.0275).


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If the treatment is ineffective, i.e., ORR=0.1, the probability of 
futility stopping is 63%. If the true response rate ORR=0.23, the 
probability of futility stopping is only 3%. The design will 
provide approximately 90% power to reject the null hypothesis at 
one-sided significance level 0.025 or equivalently to have the 
lower bound of confidence interval of ORR ≥10%.
All patients who receive at least one dose of derazantinib capsules 
will be considered evaluable for safety analyses.  
Substudy 2
A Simon’s two-stage design will be used in Substudy 2. The null 
hypothesis (H0) that the true 3-month rate of progression-free 
survival (PFS3) is p0 ≤ 0.45 will be tested against a one-sided 
alternative. In the first stage, 15 mITT-evaluable patients will be 
accrued. If there are 7 or fewer patients with PFS 3 in these 
15 patients, then Substudy 2 will be stopped. Otherwise, 
28 additional mITT-evaluable patients will be accrued for a total 
of 43. H0 will be rejected if a PFS 3 is observed in 25 or more of 
these 43 patients. The type I error rate is 0.0481, and power 
is approximately 0.8 when the true PFS3 rate for derazantinib is 
p1 = 0.65.
All patients who receive at least one dose of derazantinib capsules 
will be considered evaluable for safety analyses.  
Data Monitoring 
Committee:
The Data Monitoring Committee (DMC) will be established to 
ensure the safety of study patients and the validity of study results. 
The DMC composition and operation will be described in the 
DMC Charter. The DMC may recommend study termination or 
continuation based on periodic review of safety and/or efficacy 
data in this study. 


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TABLE OF CONTENTS
SYNOPSIS ..........................................................................................................................2
TABLE OF CONTENTS ..................................................................................................17
LIST OF TABLES ............................................................................................................21
LIST OF APPENDICES ...................................................................................................21
LIST OF ABBREVIATIONS ...........................................................................................22
INTRODUCTION .......................................................................................................26
1.1
Therapeutic rationale..........................................................................................27
1.2
Investigational product description....................................................................27
1.3
Proposed indication and dosage .........................................................................28
1.4
Nonclinical data..................................................................................................28
1.4.1
Nonclinical pharmacology overview.............................................................28
1.4.2
Nonclinical toxicology studies ......................................................................30
1.5
Clinical experience.............................................................................................33
1.5.1
ARQ 087-101 Part 1: Dose escalation/food-effect cohorts...........................33
1.5.2
Part 2: Expanded cohort/signal confirmation................................................34
1.5.3
Part 1/Part 2 safety analysis...........................................................................34
1.5.4
Phase 1 PK study (DZB-CS-102) in healthy subjects...................................35
1.5.5
ARQ 087-101 FGFR2-fusion positive iCCA patients ..................................35
1.5.6
ARQ 087-101 FGFR2-mutation/amplification positive iCCA patients........36
STUDY OBJECTIVES ...............................................................................................36
2.1
Primary objective ...............................................................................................36
2.2
Secondary objectives..........................................................................................36
2.3
Exploratory objectives........................................................................................37
INVESTIGATIONAL PLAN......................................................................................37
3.1
Overall study design and plan............................................................................37
3.2
Rationale for study design..................................................................................39
3.3
Study endpoints..................................................................................................39
3.3.1
Primary endpoints..........................................................................................39
3.3.2
Secondary efficacy endpoints........................................................................40
3.3.3
Exploratory efficacy endpoints......................................................................40
3.3.4
Safety endpoint..............................................................................................41
3.4
Study duration ....................................................................................................41
STUDY POPULATION SELECTION .......................................................................41
4.1
Study population ................................................................................................41
4.2
Inclusion criteria.................................................................................................42


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4.3
Exclusion criteria................................................................................................44
4.4
Number of patients.............................................................................................46
STUDY TREATMENTS.............................................................................................46
5.1
Informed consent................................................................................................47
5.2
Pre-screening visit..............................................................................................47
5.3
Screening evaluation ..........................................................................................48
5.4
Treatment visits..................................................................................................49
5.4.1
Cycle 1, Day 1 ...............................................................................................49
5.4.2
Cycle 1, Day 15 (± 3 days)............................................................................49
5.4.3
Cycle 2+, Day 1 (± 3 days)............................................................................50
5.4.4
End of Treatment visit...................................................................................51
5.5
30-day Safety Follow-up visit............................................................................51
5.6
Survival Follow-up (at least every 3 months ± 14 days)....................................52
5.7
Discontinuation from the treatment or study......................................................52
5.7.1
Patient discontinuation from treatment..........................................................52
5.7.2
Patient discontinuation from the study..........................................................53
5.8
Study discontinuation.........................................................................................53
STUDY PROCEDURES.............................................................................................54
6.1
Medical history and prior/concomitant medications..........................................54
6.2
Physical examination and ECOG performance status........................................54
6.3
Complete ophthalmological examination...........................................................54
6.4
12-lead electrocardiogram..................................................................................55
6.5
Clinical laboratory tests......................................................................................55
6.6
Pharmacokinetic assessments.............................................................................56
6.6.1
Sparse PK sampling (all patients)..................................................................56
6.6.2
Rich PK sampling (additional consent required)...........................................56
6.6.3
Urinary PK sampling (additional consent required)......................................56
6.7
Pharmacodynamic assessments..........................................................................57
6.8
Tumor tissue testing for confirmation of patient eligibility...............................57
6.8.1
FISH testing...................................................................................................57
6.8.2
NGS testing....................................................................................................58
6.9
Tumor imaging assessments...............................................................................60
6.10 Patient-reported outcomes..................................................................................61
6.11 Protocol deviations.............................................................................................62
TREATMENT .............................................................................................................63
7.1
Investigational product.......................................................................................63
7.1.1
Labeling and packaging.................................................................................63


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7.1.2
Drug accountability .......................................................................................63
7.1.3
Storage and handling .....................................................................................64
7.1.4
Derazantinib administration ..........................................................................64
7.2
Missed or vomited doses....................................................................................64
7.3
Dose modifications for drug-related toxicities...................................................64
7.3.1
General recommendations.............................................................................64
7.3.2
Hyperphosphatemia.......................................................................................65
7.3.3
Management of retinal adverse events ..........................................................66
7.3.4
Management of QTc prolongation or other significant ECG 
abnormalities .................................................................................................67
7.4
Treatment compliance........................................................................................67
7.5
Blinding..............................................................................................................68
7.6
Prior treatment....................................................................................................68
7.7
Concomitant treatments......................................................................................68
7.7.1
Permitted treatment........................................................................................68
7.7.2
Prohibited treatment / treatment to be avoided or used with caution............69
7.8
Potential risks and benefits for study participants..............................................69
SAFETY ASSESSMENTS .........................................................................................70
8.1
Definitions..........................................................................................................70
8.1.1
Adverse events...............................................................................................70
8.1.2
Serious adverse events...................................................................................70
8.1.3
Unexpected adverse event or serious adverse event......................................70
8.1.4
Suspected unexpected serious adverse reactions...........................................71
8.1.5
Inpatient hospitalization ................................................................................71
8.1.6
Study drug-related adverse event or serious adverse event...........................71
8.1.7
Further adverse event and serious adverse event definitions ........................71
8.2
Responsibilities and procedures.........................................................................71
8.3
Adverse event and serious adverse event assessment criteria............................72
8.4
Serious adverse event reporting .........................................................................72
8.5
Post-treatment safety follow-up .........................................................................73
8.6
Grading of severity.............................................................................................73
8.7
Assessment of causality .....................................................................................73
8.7.1
Related adverse events...................................................................................74
8.7.2
Not related adverse events.............................................................................74
8.8
Contraception and pregnancy.............................................................................74
8.8.1
Contraception.................................................................................................74
8.8.2
Pregnancy testing...........................................................................................74


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8.8.3
Pregnancy ......................................................................................................75
8.8.4
Nursing women..............................................................................................75
QUALITY CONTROL AND ASSURANCE .............................................................75
PLANNED STATISTICAL METHODS....................................................................75
10.1 Study populations...............................................................................................75
10.2 Demographics, medical history, baseline characteristics, and concomitant 
medications.........................................................................................................76
10.3 Safety analyses ...................................................................................................76
10.4 Pharmacokinetic analyses ..................................................................................77
10.5 Pharmacodynamic analyses................................................................................77
10.6 Efficacy analyses................................................................................................77
10.6.1 Primary efficacy parameter ...........................................................................78
10.6.2 Secondary efficacy parameters......................................................................78
10.6.3 Exploratory efficacy analyses........................................................................78
10.7 Determination of sample size, interim analysis, and adaptations ......................79
10.8 Data Monitoring Committee ..............................................................................79
COMPLIANCE WITH GOOD CLINICAL PRACTICE AND ETHICAL 
CONSIDERATIONS...................................................................................................80
11.1 Institutional Review Board or Independent Ethics Committee approval...........80
11.2 Compliance with Good Clinical Practice and ethical considerations ................80
11.3 Patient information and consent.........................................................................80
STUDY MANAGEMENT AND MATERIALS.........................................................81
12.1 Monitoring, verification of data, audit, and inspection......................................81
12.2 Data recording and retention of study data ........................................................81
12.3 Electronic case report forms...............................................................................82
12.4 Confidentiality, publication, and disclosure policy............................................82
STUDY ADMINISTRATIVE INFORMATION........................................................83
13.1 Sponsor...............................................................................................................83
13.2 Global Medical Monitor.....................................................................................83
13.3 Drug Safety ........................................................................................................83
DOCUMENT HISTORY ............................................................................................83
REFERENCE LIST.....................................................................................................84


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LIST OF TABLES
Table 1
Substudy 1: Overview of genetic testing for FGFR2 fusions...................58
Table 2
Substudy 2: Overview of genetic testing for FGFR2
mutations/amplifications ..........................................................................59
Table 3
Dose delays/reductions for drug-related toxicity not otherwise 
specified....................................................................................................65
Table 4
Derazantinib dose reduction scheme ........................................................65
Table 5
Dose delays/reductions for drug-related hyperphosphatemia...................66
Table 6
Dose delays/reductions for drug-related opthalmological toxicity 
(central serious retinopathy / retinal pigment epithelial detachment) ......66
LIST OF APPENDICES
Appendix 1 Schedule of Assessments..........................................................................88
Appendix 2 ECOG Performance Status .......................................................................91
Appendix 3 Pharmacokinetic and pharmacodynamic sampling schedules..................92
Appendix 4 Examples of in vivo substrates, inhibitors, and inducers for specific 
CYP enzymes ...........................................................................................94
Appendix 5 Examples of in vivo substrates, inhibitors, and inducers of 
P-glycoprotein...........................................................................................97
Appendix 6 Assessment of anti-tumor activity per RECIST v. 1.1 .............................98
Appendix 7 Patient-reported outcomes guidelines.......................................................106
Appendix 8 FGFR2 genetic aberrations eligible for enrollment in Substudy 2...........108
Appendix 9 Drugs with the potential to prolong QT and/or cause Torsades de 
Pointes ......................................................................................................109
Appendix 10 Sponsor’s signature...................................................................................113
Appendix 11 Investigator’s signature.............................................................................114


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LIST OF ABBREVIATIONS
AE
Adverse event
AIC
Akaike information criterion 
AKT
v-Akt murine thymoma viral oncogene homolog
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
ARID1A
AT-rich interactive domain-containing protein 1A
ASCO
American Society of Clinical Oncology
AST
Aspartate aminotransferase
ATP
Adenosine triphosphate
AUC
Area under the curve
BAP1
BRCA1-Associated Protein 1
BIC
Bayesian information criterion
BRAF
v-raf murine sarcoma viral oncogene homolog
BUN
Blood urea nitrogen
CBC
Complete blood count
CCA
Cholangiocarcinoma
CDISC
Clinical Data Interchange Standards Consortium
CEA
Carcinoembryonic antigen
CFR
Code of Federal Regulations
cHCC-CCA
Combined hepatocellular-cholangiocarcinoma
CI
Confidence interval
CLIA
Clinical Laboratory Improvement Amendments
Cmax
Maximum observed plasma concentration
CNS
Central nervous system
CR
Complete response
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse 
Events
ctDNA
Cell-free circulating tumor deoxyribonucleic acid
DLT
Dose limiting toxicity
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DoR
Duration of response
EC50
Half maximal effective concentration
eCCA
Extrahepatic cholangiocarcinoma
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group


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eCRF
Electronic case report form
EDC
Electronic data capture
EGFR
Epidermal growth factor receptor
ELISA
Enzyme-linked immunosorbent assay
EORTC
European Organization for Research and 
Treatment of Cancer
ERK
Extracellular signal-regulated kinase
ESA
Erythropoietin Stimulating Agents
FDA
Food and Drug Administration
FFPE
Formalin-fixed paraffin-embedded
FGFR
Fibroblast growth factor receptor
FISH
Fluorescence in situ hybridization
GA
Genetic aberration
GCP
Good Clinical Practice
G-SET
Global- Self Evaluated Transition
G-CSF
Granulocyte colony stimulating factors
GGT
Gamma-glutamyl transferase 
GI50
Concentration for 50% of maximal inhibition of 
cell proliferation
GLP
Good Laboratory Practice
H0
Null hypothesis
Ha
Alternative hypothesis
HEK
Human embryonic kidney
hERG
Human ether-a-go-go-related gene 
Hgb
Hemoglobin
HIPAA
Health Information Portability and Accountability 
Act
HIV
Human immunodeficiency virus
HRQOL
Health-related quality of life
HTI
Health Transition Index
IC50
Inhibitor concentrations required for 50% 
inhibition
iCCA
Intrahepatic cholangiocarcinoma
ICF
Informed consent form
ICH
International Council for Harmonisation
IDH
Isocitrate dehydrogenase 
IEC
Independent ethics committee
IHC
Immunohistochemistry
INR
International normalized ratio


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IRB
Institutional review board
IRT
Interactive Response Technology
IV
Intravenous
IVDD
In Vitro Diagnostics Directive
Ki
Inhibitory constant
KM
Kaplan-Meier
KRAS
Kirsten rat sarcoma viral oncogene homolog
LDH
Lactate dehydrogenase
LFT
Liver function tests
LLN
Lower limit of normal
MAPK
Mitogen-activated protein kinases 
MedDRA
Medical Dictionary for Regulatory Activities
MEK
Tyrosine/threonine kinase
MI
Myocardial infarction
mITT
Modified intent-to-treat
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
NA
Not applicable
NCI
National Cancer Institute
NE
Not evaluated
NGS
Next-Generation Sequencing
nM
Nanomolar
NOAEL
No-observed-adverse-effect level
NSTD
Non-severely toxic dose
NYHA
New York Heart Association
ORR
Objective response rate
OS
Overall survival
pCCA
Perihilar cholangiocarcinoma
PD
Progressive disease
PD
Pharmacodynamic(s)
PFS
Progression-free survival
PFS 3
Progression-free survival at 3 months
P-gp
P-glycoprotein
PI3K
Phosphatidylinositol 3-kinase
PK
Pharmacokinetic(s)
PKC
Protein kinase C 
PLCγ
Phospholipase Cγ 
PopPK
Population pharmacokinetics
PR
Partial response


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PT
Preferred term
PT
Prothrombin time
PTT
Partial prothrombin time
QD
Once daily
QOD
Once every other day
QOL
Quality of life
RBC
Red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
ROS1
ROS proto-oncogene 1
RP2D
Recommended Phase 2 dose
RTK
Receptor tyrosine kinase
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SD
stable disease
SEER
Surveillance, Epidemiology, and End Results
SOC
Standard of care
SOP
Standard Operating Procedure
SPF
Sun Protection Factor
STAT
Signal transducers and activator of transcription
STD
Severely toxic dose
SUSAR
Suspected Unexpected Serious Adverse Reaction
TACE
Transarterial chemoembolization
TEAE
Treatment-emergent adverse event
TGI
Tumor growth inhibition
Tmax
Time to maximum observed concentration
TP53
Tumor protein p53
TTP
Time to progression
ULN
Upper limit of normal
US
United States
VAS
Visual analog scale
VEGFR
Vascular endothelial growth factor receptor
WBC
White blood cell
WBMRI
Whole-body magnetic resonance imaging


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INTRODUCTION
Cholangiocarcinoma (CCA) is the most common malignant tumor of the biliary tract, 
affecting approximately 2,500 patients annually in the United States (US), with an average 
incidence of 1.67 patients per 100,000 people per year (NORD 2015). Emerging at any 
portion of the biliary tree, it includes tumor subtypes that differ in etiology, 
pathophysiology, clinical presentation, and management. Depending on the anatomic 
location, CCA is classified as intrahepatic (iCCA) and extrahepatic (eCCA), which are 
further classified into perihilar (pCCA) or distal tumors. iCCA originates from the 
intrahepatic biliary ductal system and accounts for 10-20% of primary hepatic 
malignancies (Blechacz 2008, NCCN 2016).
There are a number of known potential risk factors for iCCA, including primary sclerosing 
cholangitis, hepatolithiasis, and liver fluke. However, these factors are not universally 
identified in most patients diagnosed with iCCA. Due to anatomic location, iCCA is usually 
diagnosed at a later stage than eCCA and has very limited treatment options. The iCCA
tumor biology is not well-understood; however, genomic profiling with whole-exome and 
Next-Generation Sequencing (NGS) or fluorescence in situ hybridization (FISH) has 
identified multiple molecular aberrations that may contribute to its carcinogenesis 
(Chong 2016, Sia 2015, Graham 2014, Borad 2014). Recent whole genome sequencing 
efforts have identified known mutations in genes such as epidermal growth factor receptor 
(EGFR), kirsten rat sarcoma viral oncogene homolog (KRAS), v-raf murine sarcoma viral 
oncogene homolog (BRAF) and tumor protein p53 (TP53), novel mutations in isocitrate 
dehydrogenase (IDH), BRCA1-Associated Protein 1 (BAP1) and AT-rich interactive 
domain-containing protein 1A (ARID1A), and novel fusions such as fibroblast growth 
factor receptor 2 (FGFR2) and ROS proto-oncogene 1 (ROS1). Inhibitors of these 
pathways are currently in clinical development (Chong 2016).
Patients diagnosed at an early stage of iCCA are candidates for curative resection or liver 
transplantation. Liver transplantation remains the treatment of choice with the best 
outcome as it intends to cure the disease, but due to the scarcity of organs it is restricted to 
very few patients (ACS 2012). Unfortunately, as mentioned above, iCCA is asymptomatic 
in the early stages and by the time it is diagnosed, most patients present with an advanced 
stage of the disease. Advanced disease means most patients (approximately 90%) are not 
eligible for curative surgery, leading to an overall survival of approximately 6 months. 
Non-surgical treatment options for advanced iCCA include locoregional therapy such as 
transarterial chemoembolization (TACE) and chemotherapy with or without radiation 
therapy. The current non-surgical standard of care for unresectable iCCA is combination 
chemotherapy with gemcitabine plus cisplatin (Okusaka 2010, Khan 2012). Other systemic 
chemotherapy options include capecitabine, oxaliplatin, fluoropyrimidines,
or a 
combination of these agents. It should be noted that none of these drugs have been approved 
for the treatment of iCCA (ACS 2012, Eckel 2011, Kondo 2008, NCCN 2016).
Disappointingly, even combined multi-agent chemotherapy does not offer a durable 
response in patients with advanced iCCA, and only 5–10% of patients survive 5 years after 
diagnosis (Anderson 2004).




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1.3
Proposed indication and dosage
Derazantinib is indicated for the treatment of patients with FGFR2 fusion positive 
inoperable or advanced iCCA. A Phase 1/2 study (ARQ 087-101) in solid tumors with 
FGFR genetic aberrations (GAs), including iCCA with FGFR2 fusion has completed 
enrollment, with a total of 119 patients. Derazantinib capsules will be administered by 
mouth 1 hour before, or 2 hours after, a meal at a dose level of 300 mg once daily (QD).
1.4
Nonclinical data
Derazantinib is a multi-kinase inhibitor with potent FGFR1, 2, and 3 activity. Supporting 
in vitro and in vivo studies are summarized below. 
1.4.1
Nonclinical pharmacology overview
1.4.1.1
In vitro studies
1.4.1.1.1
Biochemistry: Inhibition of FGFR kinase activity of derazantinib
FGFR kinase biochemical assays were performed. Derazantinib selectivity against all four 
FGFR isoforms was assayed. Derazantinib inhibited wild-type FGFR1, FGFR2, and 
FGFR3 with biochemical inhibitor concentration required for 50% inhibition (IC50) values 
in the 1.8 to 4.5 nM range and FGFR4 with somewhat lower potency (IC50 value of 
34.3 nM) (TR-087-048). Enzymatic kinetic experiments for derazantinib with both FGFR1
and FGFR2 were performed. The inhibition constant (Ki) values were determined to be 
2.7 ± 0.2 nM and 0.68 ± 0.07 nM, respectively, demonstrating strong affinity of 
derazantinib for FGFR1 and FGFR2. Michaelis-Menten graphs were generated and four 
inhibition modes (competitive, uncompetitive, noncompetitive, and mixed) were evaluated 
in both Akaike information criterion (AIC) and Bayesian information criterion (BIC) to 
determine the best fitting model. After the analyses, the competitive model received the 
lowest AIC and BIC and the heaviest weight of AIC and BIC which indicates that 
derazantinib profiled as a competitive inhibitor for both FGFR1 and FGFR2 (data on file).
The data which indicate that derazantinib is a competitive inhibitor for both FGFR1 and 
FGFR2 are further strengthened by the fact that the values for the α-factor approached 
infinity in both cases (data on file). It was therefore concluded that derazantinib is an 
adenosine-triphosphate-(ATP)-competitive inhibitor for both FGFR1 and FGFR2.
Activation of FGFR kinases requires autophosphorylation on multiple tyrosine residues 
(Lew 2009, Furdui 2006). Inhibition of this autoactivation reaction by derazantinib was 
evaluated by titrating increasing concentrations of the inhibitor with unphosphorylated 
FGFR1 and FGFR2 kinases in an autophosphorylation assay. Derazantinib inhibited the 
autophosphorylation of FGFR1 and FGFR2 in a dose-dependent manner. This observation 
suggests that, in addition to inhibiting the active form of the kinase, derazantinib binds to 
its unphosphorylated or inactive form, thus delaying its activation.
To understand the selectivity of derazantinib across the kinome, the compound was tested 
against a panel of 298 kinases at a concentration of 0.1 µM. Among the 298 kinases 
assayed, approximately 50 (including FGFR1, FGFR2, FGFR3, and FGFR4) were 
inhibited by greater than 50% by derazantinib (TR-087-049). In this subset of kinases, 
examination of IC50 values revealed that 19 kinases (excluding FGFRs) exhibited 
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1.4.1.1.2
Anti-proliferative effect and FGFR pathway inhibition by derazantinib in 
human cancer cell lines
To determine whether derazantinib inhibits the phosphorylation of FGFR1, FGFR2, 
FGFR3, and FGFR4 in cells, full-length FGFR1, FGFR2, FGFR3, and FGFR4 was 
ectopically expressed in COS-1 cells and the effect of derazantinib on phosphorylation of 
FGFRs was examined. It was found that derazantinib inhibited the phosphorylation of 
FGFR1, FGFR2, and FGFR3 with half maximal effective concentration (EC50) values of 
< 0.123 μM, 0.185 μM, and 0.463 μM, respectively. Derazantinib did not inhibit the 
phosphorylation of FGFR4 in this overexpression system (EC50 > 10 µM). The 
anti-proliferative effect of derazantinib was also examined in a panel of Ba/F3 cell lines 
that had been engineered to be dependent on individually overexpressed tyrosine protein 
kinases for survival, including cell lines dependent on individual FGFR isoforms and 
FGFR fusions. The concentration for 50% of maximal inhibition of cell proliferation (GI50) 
values for Ba/F3-FGFR1, Ba/F3-FGFR2, Ba/F3-FGFR3, and Ba/F3-FGFR4 ranged 
between 232 nM and 1346 nM, with Ba/F3-FGFR2 the most sensitive cell line to 
derazantinib followed by Ba/F3-FGFR1 and Ba/F3-FGFR3. FGFR fusions were also 
examined in the Ba/F3 system, including TEL-FGFR2, FGFR2-AAF3, FGFR2-BICC1, 
FGFR2-CASP7, FGFR2-CCDC6, FGFR2-CCDC6, and FGFR3-BAIAP-2L1. The GI50
values were between 39.9 nM and 1121 nM, with FGFR3-BAIAP2L1 being the most 
sensitive cell line.
Anti-proliferative activity of derazantinib was evaluated on five cholangiocarcinoma
(CCA) cell lines (OZ, NOZ, HuCCT1, HCCC9810, and HuH28) and two adrenocortical 
cell lines (NCI-H295R and SW 13). The results showed that in all cell lines cell growth 
was potently inhibited by derazantinib with IC50 values ranging from 1.4 to 3.9 µM. These 
results suggest that CCA and adrenocortical carcinoma could be therapeutic indications for 
derazantinib (TR-087-107).
1.4.1.2
In vivo studies
1.4.1.2.1
Evaluation of derazantinib in human and murine xenografts of various 
histological types in athymic mice
The in vivo anti-tumor effect of derazantinib was assessed in athymic mice bearing 
Ba/F3-FGFR2, Ba/F3-INSR, SNU-16, and NCI-H716 cell line-derived tumors. The 
Ba/F3-FGFR2 and Ba/F3-INSR are transfected models. The SNU-16 cell line harbors 
amplified FGFR2 and contains a PDHX-FGFR2 fusion, while the NCI-H716, also 
amplified for FGFR2, contains an FGFR2-COL14A1 fusion. Derazantinib demonstrated 
potent tumor growth inhibition (TGI) in the Ba/F3-FGFR2 model, while failing to inhibit 
the growth of the Ba/F3-INSR model. Meaningful (> 50 TGI vs. control) tumor inhibition 
was observed in both cancer cell line derived xenograft models. In the SNU-16 xenograft 
study, treatment with 75 mg/kg and 50 mg/kg achieved 83% (p=0.002) and 69% (p=0.013) 
TGI, respectively. Partial and complete regressions were also observed in both dose groups. 
In the NCI-H716 human cecum model, 50 mg/kg and 75 mg/kg on a Q1Dx14 schedule 
demonstrated significant TGI of 68% (p = 0.0001) and 96% (p = 0.0001), respectively. 
Doses of 150 mg/kg of derazantinib were not well tolerated, resulting in unacceptable 
weight loss and general lethargy.


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1.4.1.3
In vivo pharmacodynamics
The in vivo pharmacodynamic effect of derazantinib was examined in NCI-H716, SNU-16, 
and MFM-223 tumor-bearing animals. A single dose of derazantinib led to a reduction in 
phospho-FGFR, phospho-FRS2α, phospho-ERK (extracellular signal-regulated kinase), 
phospho-AKT (v-Akt murine thymoma viral oncogene homolog), and phospho-S6 in all 
three models tested, while the total FGFR2 protein was unaffected by derazantinib
treatment. These results indicate that a single dose of derazantinib was sufficient to 
attenuate FGFR signaling in NCI-H716, SNU-16, and MFM-223 xenograft tumors
(TR-087-040, TR-087-079, TR-087-080).
Evidence of derazantinib target engagement can be detected by measuring the inhibition of 
phosphorylation of derazantinib target receptor tyrosine kinase (RTK) as well as key 
downstream signaling proteins. In nonclinical xenograft tumor models, inhibition of the 
phosphorylation of FGFR, FRS2α, and ERK was observed using immunohistochemistry 
(IHC) staining on SNU-16 tumors at the repeated, efficacious dose of 75 mg/kg
(TR-087-047). By Western blotting analysis, tyrosine/threonine kinase (MEK) and ERK 
phosphorylation levels were reduced by 68% and 82%, respectively. This dose resulted in 
plasma levels of derazantinib of 4.9 ± 2.3 µM.
1.4.1.4
Nonclinical pharmacokinetic studies
The pharmacokinetics and toxicokinetics of derazantinib were characterized in rats and 
dogs. The oral bioavailability of derazantinib in rats was 37%, and in dogs ranged from 
38 to 46% (solution or powder filled capsule), respectively. Overall, in 28-day repeat dose 
studies (in both species), derazantinib had a half-life in plasma which ranged from 4 to 
10 hours and time to maximum observed concentration (Tmax) which ranged from 5 to 
16 hours. Derazantinib was not consistently dose proportional and was found to accumulate 
after repeat dosing in these species.
1.4.2
Nonclinical toxicology studies
Derazantinib was well tolerated over the course of the 13 weeks in Good Laboratory 
Practice (GLP) toxicity studies, with no-observed-adverse-effect levels (NOAELs) of 
10 mg/kg/day for rats and dogs being determined. In the 28-day GLP toxicity studies, a 
NOAEL dose of 20 mg/kg/day (18 days) was determined in dogs, and a non-severely toxic 
dose (NSTD) of 15 mg/kg/day was determined in rats. A severely toxic dose (STD) in rats 
was determined to be 50 mg/kg/day. 
The toxicity profile of orally administered derazantinib in rats and dogs was characterized 
principally by decreases in body weight and/or body weight gain, an effect generally 
correlated to a decrease in food consumption. Trends in reversibility during the recovery 
phase were observed for decreases in body weight and/or body weight gain and decreased 
food consumption in dogs but not in rats. Target organ toxicities based on the results of the 
28-day rat and dog studies were associated with those involving gastrointestinal (rat, dog), 
hematological (rat, dog), liver (rat, dog), bone (rat) and lung (rat) function.
In the 28-day rat study, all control, low, and mid dose (0, 5, and 15 mg/kg) animals survived 
to the scheduled terminal necropsy. All high dose (50 mg/kg) animals, excluding those 
designated for recovery, were sacrificed and/or necropsied between Days 12 and 14 of the 
dosing phase. Derazantinib-related clinical observations were limited to animals given 


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50 mg/kg/day, which made necessary the suspension of further dosing and unscheduled 
terminal necropsy. These clinical observations, along with decreases in body weight/body 
weight gain and food consumption, included hunched appearance and swelling of the 
abdomen (noted in one female), thinness, nasal and oral discharge, fecal abnormalities 
(few and non-formed), squinting of the eyes, and pelage/skin abnormalities. Clinical 
observations associated with thinness, decreases in body weight/body weight gain did not 
resolve following the 2-week recovery phase for animals given 50 mg/kg/day.
Additionally, in the 28-day rat study, derazantinib administration was associated with 
several effects on clinical pathology test results. The most toxicologically important effects 
included reduced erythropoiesis at >15 mg/kg/day, suspected lymphoid tissue injury at 
50 mg/kg/day (females), and liver injury at >15 mg/kg/day. Specifically, reduced 
erythropoiesis was associated with decreased red cell mass and absolute reticulocyte counts 
as well as changes in erythrocytic indices. Decreased lymphocyte counts were observed in 
females given 50 mg/kg/day. Increased alanine aminotransferase (ALT) activity was first 
observed in males given 5 mg/kg/day, followed by increased ALT and alkaline phosphatase 
(ALP) activity in animals given 15 mg/kg/day. At dose levels of 50 mg/kg/day, increased 
ALT, aspartate aminotransferase (AST), ALP, and gamma-glutamyl transferase (GGT) 
activities were observed. A few less specific derazantinib-related effects, especially 
changes in electrolyte values, were observed during the recovery phase in animals given 
50 mg/kg/day. These changes may have been associated with mild dehydration. No 
macroscopic findings were attributed to derazantinib at the terminal or recovery necropsy.
In animals sacrificed in moribund condition or at the terminal sacrifice, 
derazantinib-related microscopic findings were observed in the femur and sternum bone 
marrow, alimentary canal (tongue, esophagus, nonglandular stomach, duodenum, ileum, 
and jejunum), spleen, and lung. Most findings were limited to the 50 mg/kg/day dose level.
Exceptions were the lung and spleen, where findings were also observed at 15 mg/kg/day.
All derazantinib related microscopic findings observed at the terminal necropsy and in 
animals sacrificed at an unscheduled interval were reversed at the recovery necropsy, 
excluding femur and sternum physeal hypertrophy, increased splenic extramedullary 
hematopoiesis, and lung vacuolated macrophage infiltrates. Tongue and esophageal ulcers 
observed at 50 mg/kg/day were considered severely toxic.
In the 28-day dog study, administration of derazantinib was tolerated as an oral capsule 
administration in dogs at 3 and 10 mg/kg/day for 29 days and at 20 mg/kg/day for 18 days; 
however, it was not tolerated at 30 mg/kg/day for 7 days. Animals given 30 mg/kg/day had 
vomitus, abnormal feces, body weight loss, and/or markedly reduced food consumption 
during the first week of dosing. One male given 30 mg/kg/day was sacrificed on Day 6 of 
the dosing phase in moribund condition that included clinical observations of vomitus, 
limited use of the hind quarters, ataxia, rigid stance, hypoactivity, dilated and minimally 
responsive pupils, excessive salivation, occasional tonic front limbs, and postictal and close 
to seizure threshold. The male had clinical pathology findings consistent with 
inflammation/stress, dehydration, and lower serum potassium and chloride that likely 
resulted from vomiting. Potentially adverse, derazantinib-related microscopic findings of 
acute inflammation and ulceration of the esophagus were also noted, and the moribund 
condition of the male is partially attributed to these microscopic findings.


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All other animals survived to their scheduled sacrifices. Due to adverse findings observed 
at 30 mg/kg/day, dosing was suspended on Day 8 and resumed on Day 12 of the dosing 
phase at 20 mg/kg/day. Abnormal feces observed for most animals given 20 mg/kg/day 
was not considered to be an adverse reaction because it did not impact the health of the 
animals. Animals given 30/20 mg/kg/day had white discolored haircoat of the entire head 
during the dosing and recovery phases; however, this observation was not adverse, and no 
corresponding microscopic finding was present. No derazantinib-related changes in 
electrocardiogram (ECG) parameters or ophthalmic examinations were observed.
No derazantinib-related clinical pathology effects were observed at 3 or 10 mg/kg/day.
A few potentially derazantinib-related findings in animals given 30/20 mg/kg/day were 
minor and not considered adverse or toxicologically important. Potentially adverse, 
derazantinib-related microscopic findings of acute inflammation and ulceration of the 
esophagus occurred in one male given 30/20 mg/kg/day. Derazantinib related microscopic 
findings noted during the dosing phase were not present in recovery animals.
In rats and dogs in 28-day/4-week studies, no apparent derazantinib-related effect was 
noted following the dosing phase examination. However, of note, two male rats 
(Animal Nos. B84426 and B84424) given 5 mg/kg/day, one male given 15 mg/kg/day 
(Animal No. B84442), and a female (Animal No. B84516) given 15 mg/kg/day, were seen 
to have corneal dystrophy on Day 26 of the dosing phase. This finding is not considered 
derazantinib-related due to its low incidence and lack of microscopic correlation.
In 28-day rat studies, minimal to slight physeal hypertrophy was an increase in the 
thickness of the physis mostly due to enlargement and mild disorganization of the zone of 
hypertrophy. Minimal physis hypertrophy persisted in the femur of two recovery males and 
one female given 50 mg/kg/day and in the sternum of one recovery female given 
50 mg/kg/day.
Transient effects on clinical chemistry such as increased glucose levels and phosphorous 
levels were observed in rats and/or dogs in shorter duration 7-day repeat dose toxicity 
studies and may be characteristic of FGFR kinase inhibitors (Cuevas-Ramos 2009,
Kharitonenkov 2011, Brown 2005).
In 13-week toxicity studies, 1, 3, or 10 mg/kg/day doses of derazantinib were well tolerated 
when administered daily via oral gavage to Sprague Dawley rats for 13 weeks. 
Derazantinib-related findings included minimal differences in red blood cell indices; 
minimally lower total white blood cell count, due to lower absolute lymphocyte and 
monocyte counts (females); and minimally lower albumin concentration in animals 
administered 10 mg/kg/day. Findings for animals administered ≥ 3 mg/kg/day included 
minimally higher cholesterol concentration (female) and vacuolated macrophage infiltrates 
in the alveoli of the lung; at the recovery sacrifice, these persisted in the lung of males 
administered 10 mg/kg/day and were partially reversed in females administered 
10 mg/kg/day. As none of these observations were considered adverse, the NOAEL is 
10 mg/kg/day via oral gavage. At the end of the dosing phase, the NOAEL of 10 mg/kg/day 
corresponded to combined male and female average peak concentration (Cmax) and area 
under the concentration-time curve from 0 to 24 hours post dose (AUC0-24) values of 
293 ng/mL and 5660 ng·hr/mL, respectively.


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In 13-week toxicity studies, 1, 3, or 10 mg/kg/day doses of derazantinib were well tolerated 
when administered daily via capsule to beagle dogs for 13 weeks. Derazantinib-related 
findings included increased lymphocytes in the left and/or right nictitating membranes of 
animals administered ≥ 3 mg/kg/day, which were mostly reversed by the end of the 
recovery phase, and minimally decreased red cell mass (males and females), absolute 
reticulocyte count (females), and minimally increased AST and ALT activities (females), 
without histological correlates, in animals administered 10 mg/kg/day. The NOAEL is 10 
mg/kg/day via capsule. At the end of the dosing phase, the NOAEL of 10 mg/kg/day 
corresponded to combined male and female Cmax and AUC0-24 values of 444 ng/mL and 
6680 ng·hr/mL, respectively, for males and females combined.
Derazantinib was evaluated for effects on the human ether-a-go-go-related gene (hERG) 
potassium channel using human embryonic kidney (HEK)293 cells transfected with hERG. 
Conflicting in vitro hERG results were obtained between two laboratories. In one study, 
the hERG IC50 for derazantinib was greater than 3 µM, whereas in the second study it was 
0.06 µM. Consequently, a dog telemetry study was conducted to further examine any 
cardio effects of derazantinib. There were no notable effects of derazantinib on pulse 
pressure, PR interval, QRS duration, QTcVDW interval, or arrhythmogenesis. No effect 
on QT was observed in dogs in the cardiovascular study (60 mg/kg) or in the ECG in the 
28-day and 13-week toxicity studies (up to 30/20 mg/kg).
Derazantinib was found to have phototoxic potential in the 3T3 Neutral Red Uptake 
Phototoxicity Test.
In genotoxicity assays, derazantinib was negative for mutagenicity in an AMES study, but 
positive via a predominantly aneugenic mode of action in an in vitro micronucleus assay. 
In a subsequent in vivo micronucleus assay in rats, evaluating both clastogenicity and 
aneugenicity, derazantinib was demonstrated to not be genotoxic.
1.5
Clinical experience
ARQ 087-101, entitled ‘A Phase 1/2 Study of ARQ 087 in Adult Subjects with Advanced 
Solid Tumors with FGFR Genetic Alterations, Including Intrahepatic Cholangiocarcinoma 
with FGFR2 Gene Fusion’, was an open-label, two-part Phase 1/2, dose escalation, and 
signal finding study of derazantinib capsules administered to patients with advanced solid 
tumors. The study was designed to explore the safety, tolerability, pharmacokinetics (PK), 
pharmacodynamics (PD), and preliminary efficacy of derazantinib, and to define a 
recommended Phase 2 dose (RP2D).
Further PK analyses were performed in study DZB-CS-102, entitled ‘A Phase 1, two-part, 
open-label, single-oral-dose study to investigate the absolute bioavailability and 
absorption, 
pharmacokinetics, 
distribution, 
metabolism, 
and 
excretion 
of 
[14C]-derazantinib in healthy male subjects’ (see Section 1.5.4).
1.5.1
ARQ 087-101 Part 1: Dose escalation/food-effect cohorts
Part 1 was the first-in-human part of the open-label clinical study with derazantinib
capsules. Adult patients with advanced solid tumors whose cancer had progressed 
following standard therapy, or who had been unable to tolerate standard therapy, and/or for 


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whom no standard treatment was available, were enrolled. The study was conducted to 
evaluate the safety, tolerability, PD, and PK of derazantinib in patients with advanced solid 
tumors. Treatment was initiated at a dose level of 25 mg every other day (QOD) under 
fasted conditions (1 hour prior to, or 2 hours after, the meal).
Dose escalation was done according to the standard 3+3 dose escalation schema. The 
maximum tolerated dose (MTD) was defined as the dose level at which no more than 
one patient with a dose limiting toxicity (DLT) was observed among six patients. 
Assessment of tumor response was performed according to Response Evaluation Criteria 
in Solid Tumors (RECIST) version 1.1 at baseline and every two cycles (a cycle was 
defined as a 28-day period). Safety assessments included physical examination, vital signs, 
Eastern 
Cooperative 
Oncology 
Group 
(ECOG) 
performance 
status, 
and 
hematology/biochemistry. Treatment-emergent adverse events (TEAEs) were graded 
according to the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03.
The study was initiated with a derazantinib dose of 25 mg QOD. Based on the drug safety 
profile and no significant difference in derazantinib PK exposure compared to higher dose 
levels (up to 425 mg QD), including the Food-effect Cohort PK data, 300 mg QD under 
fasted conditions (1 hour prior to, or 2 hours after, the meal) was defined as the RP2D and 
recommended for further evaluation in Part 2 (Expanded Cohort) of the study. 
In total, 80 patients were enrolled and treated in Part 1 at four sites in the US. All patients 
received at least one dose of derazantinib.
1.5.2
Part 2: Expanded cohort/signal confirmation
Once the RP2D was determined, patients with advanced solid tumors with FGFR GAs, 
including iCCA with FGFR2 fusions, were enrolled in Part 2. All patients in Part 2 received 
at least one dose of derazantinib capsules at the RP2D level of 300 mg QD (1 hour prior to 
or 2 hours after the meal).
As of 26 October 2018, study ARQ 087-101 had completed a total enrollment of 
119 patients, none of whom were ongoing. Enrollment into the study (Part 1 and Part 2) is 
completed, and the clinical study report for the entire study is being prepared.
1.5.3
Part 1/Part 2 safety analysis
As of 26 October 2018, enrollment in study ARQ 087-101 had been completed, with a total 
of 119 patients enrolled and evaluated for the safety and tolerability of derazantinib. 
61 patients were enrolled in Dose Escalation / Food Effect cohorts: three were dosed at 
25 mg QOD, six at 25 mg QD, six at 50 mg QD, four at 100 mg QD, five at 150 mg QD, 
five at 200 mg QD, seven at 250 mg QD, six at 325 mg QD, seven at 425 mg QD, five at 
400 mg QD, and an additional seven patients were dosed at 400 mg QD under fed 
conditions. The RP2D was defined as 300 mg QD. 
Due to dose-dependent increases in the overall number of drug-related AEs and 
no significant difference in derazantinib PK exposure compared to higher dose levels (up 
to 425 mg QD), the dose of 300 mg QD was defined as the RP2D. There were three events 
of CTCAE Grade 3 AST increased that were defined to be a DLT. All these events resolved 


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after dose reduction (one patient) or treatment discontinuation (two patients). The first 
event was observed at a dose level of 250 mg QD (dose was reduced to 200 mg QD) and 
the two other events were observed at 425 mg QD. No DLTs were reported in the 12 
patients treated at the dose level of 400 mg QD with or without food. However, there was 
an increase in the number of drug-related AEs at high dose levels (400–425 mg QD) 
compared to medium dose levels (250–325 mg QD), thus the dose of 300 mg QD was 
defined as RP2D. Additionally, at near steady state conditions (Day 22), derazantinib 
concentrations are dose proportional in the dose range of 100 to 300 mg QD dosing which 
supports a manageable and predictable dose reduction plan from 300 to 200 mg QD and 
from 200 to 100 mg QD. 
A total of 58 patients were enrolled and treated at the RP2D level. The enrollment of 
patients with advanced solid tumors with FGFR GAs was completed in January 2017. All 
patients had discontinued treatment as of 26 October 2018. The most common reasons for 
discontinuing treatment were radiological disease progression (per RECIST) 
69/119 (58.0%) and clinical disease progression 24/119 (20.2%).
At least one drug-related AE was reported in 102 of 119 patients (85.7%), with most being 
mild or moderate in severity. The five most common derazantinib-related AEs were nausea 
(42.9%), fatigue (41.2%), AST increased (26.1%), vomiting (21.8%), and diarrhea 
(21.0%). Derazantinib-related severe (≥ CTCAE grade 3) AEs were reported in 
23/119 patients (19.3%). 
Serious adverse events (SAEs) were reported in 34/119 (28.6%) patients. Four patients 
(4/119, 3.4%) experienced drug-related SAEs, including stomatitis, upper gastrointestinal 
hemorrhage, electrocardiogram QT prolongation, and abnormal ECG (each in one patient).
Eleven events (all assessed as unrelated) were reported with fatal outcome; in six cases, the
events were reported as disease progression, two were reported as general physical health 
deterioration, and three events were reported as cardiomyopathy, cachexia, and pneumonia.
Overall, at 300 mg QD dose level, derazantinib demonstrated a manageable safety profile,
with most derazantinib-related AEs being of CTCAE Grade 1–2, and provided adequate 
exposure to ensure patient response, along with predictable exposure in the event a dose 
reduction is necessary.
1.5.4
Phase 1 PK study (DZB-CS-102) in healthy subjects
Following a single oral 300 mg dose of radiolabeled [14C]-derazantinib in the Phase 1 
human absorption, distribution, metabolism, and excretion study DZB-CS-102, 76.5% of 
the dose was recovered in feces and 6.62% in urine, indicating that fecal excretion was the 
main route of elimination. As renal excretion was the minor route of elimination in healthy 
subjects, it is expected that renal excretion would also be the minor elimination route for 
subjects with renal impairment following oral dosing. The metabolite profiling in feces is 
ongoing. 
1.5.5
ARQ 087-101 FGFR2-fusion positive iCCA patients
As of 26 October 2018, a total of 29 patients with FGFR2-fusion positive iCCA had been
enrolled and treated with derazantinib capsules in study ARQ 087-101. FGFR2 GA status
was based on locally performed NGS or fluorescent in-situ hybridization (FISH). In the 


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29 patients with FGFR2-fusion positive status, six patients had a partial response (21%), 
the disease control rate (partial response or stable disease as best objective response) was 
83%, and the median progression-free survival was 5.7 months (Mazzaferro 2018). 
1.5.6
ARQ 087-101 FGFR2-mutation/amplification positive iCCA patients
As of 26 October 2018, a total of six patients with FGFR2-mutation/amplification positive 
iCCA had been enrolled and treated with derazantinib capsules in study ARQ 087-101. 
FGFR2 GA status was based on locally performed NGS. In the six patients with
FGFR2-mutation/amplification positive status, no patients had a partial response, four 
patients had some degree of tumor shrinkage per RECIST 1.1, the disease control rate 
(partial response or stable disease as best objective response) was 67%, and the median 
progression-free survival was 6.7 months (Droz dit Busset 2020).
Detailed nonclinical and clinical data can be found in the derazantinib Investigator’s
Brochure.
STUDY OBJECTIVES
2.1
Primary objective
Substudy 1
To evaluate the anti-cancer activity by Objective Response Rate (ORR) by central 
radiology review as per RECIST version 1.1 in patients with inoperable or advanced iCCA 
whose tumors harbor FGFR2 fusions (by FISH performed by the central laboratory) and 
who received at least one prior regimen of systemic therapy. 
Substudy 2
To evaluate the anti-tumor activity of derazantinib by progression-free survival at 3 months 
(PFS 3) based on survival status or central radiology review (RECIST version 1.1) in 
patients with inoperable or advanced iCCA whose tumors harbor FGFR2 mutations or 
amplifications, and who received at least one prior regimen of systemic therapy.
2.2
Secondary objectives
Substudy 1 and Substudy 2

To evaluate progression free survival (PFS) by central radiology review and overall
survival (OS)

To evaluate duration of response (DoR) by central radiology review

To evaluate the safety profile (toxicities) of derazantinib in this patient population

To evaluate changes, and assess the minimally important difference, in health-related 
quality-of-life (HRQOL) and symptom response from baseline using the EORTC 
QLQ-C30, QLQ-BIL21, Global Self Evaluated Transition (G-SET) / Health Transition 
Index (HTI), and the EQ-5D visual analog scale (VAS)
Substudy 2

To evaluate the anti-cancer activity by ORR by central radiology review as per RECIST 
version 1.1 in patients with inoperable or advanced iCCA whose tumors harbor FGFR2
mutations or amplifications, and who received at least one prior regimen of systemic 
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2.3
Exploratory objectives
The exploratory objectives of this study are:

To evaluate changes in pharmacodynamic (PD) biomarkers

To evaluate ORR, PFS, OS, and DoR by PD biomarkers

To evaluate the relationship between derazantinib exposure and effectiveness, toxicity 
and PD biomarkers

To explore the concordance of a liquid biopsy diagnostic test compared to baseline 
tumor biopsy

To evaluate population pharmacokinetics (PopPK)

To evaluate the urinary excretion of derazantinib, and possibly its metabolites, in a 
subset of patients

To compare TTP on the first and/or the last prior line of systemic therapy (reported) 
versus TTP on derazantinib by central radiology review (TTP will be calculated from 
the first date of receiving study drug or prior line of systemic therapy until radiographic 
disease progression)
INVESTIGATIONAL PLAN
3.1
Overall study design and plan
This is a multi-center, open label, single arm study evaluating derazantinib in adult 
patients with inoperable or advanced iCCA and FGFR2 GAs. 
Substudy 1 enrolls patients with FGFR2 fusions.
Substudy 2 enrolls patients with FGFR2 mutations/amplifications (see Appendix 8).
A subset of up to 20 patients (PK/biomarker subgroups) will be asked to participate in
a rich PK blood sampling and PK urine sampling to assess the renal excretion of 
derazantinib (see Section 6.6).
Substudy 1 is considered pivotal and will enroll approximately 100 patients to determine 
the ORR (see Section 10.7).
Substudy 2 will use a Simon’s two-stage design, with approximately 15 mITT-evaluable 
patients in Stage 1, and an additional 28 mITT-evaluable patients if the study proceeds to 
Stage 2.
Patient eligibility may be assessed in two steps: 1) molecular pre-screening to confirm 
FGFR2 GA status (see Section 5.2); clinical screening procedures to confirm study 
treatment eligibility (see Section 5.3). 
Molecular pre-screening for FGFR2 fusions in Substudy 1 may be based on local or central 
testing (see Section 6.8.1, Table 1). If pre-screening is performed based on a local test, then 
a central confirmation by the FGFR2 break-apart FISH Probe Kit test is required for 
Substudy 1 (FGFR2 fusions) (see Section 6.8.1 for further details).


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Molecular pre-screening for FGFR2 mutations/amplifications in Substudy 2 should be 
based on NGS testing (for details see Table 2 and Appendix 8) performed or commissioned 
by the respective study site.
If an eligible FGFR2 GA status is either known or has been established (see Appendix 8), 
the patient may undergo clinical screening procedures. If the patient is still receiving prior 
systemic therapy, clinical screening procedures will be delayed until radiographically 
confirmed disease progression or intolerance to the ongoing systemic therapy is 
documented. After the study treatment eligibility is confirmed, patients will be enrolled 
and treated with continuous 300 mg QD of derazantinib capsules. A treatment cycle is 
defined as 28 days. Patients will receive treatment with derazantinib capsules until death, 
radiographic disease progression, unacceptable toxicity, or until another of the specified 
criteria is met for stopping therapy.  
It is expected that most patients will receive between 1 and 8 months of treatment 
with derazantinib capsules. Dose delays and/or reductions will be allowed when 
derazantinib-related toxicity is observed (see Section 7.3 Dose Modifications). A related 
toxicity is defined as any toxicity considered related to derazantinib, i.e., definitively, 
probably, or possibly related, or when the relationship is unknown.
During the treatment period, patients will be evaluated every 2 weeks for the first cycle 
(Cycle 1 Days 1 and 15), and once every cycle thereafter (Day 1 of each cycle).  
Tumor measurements will be done at Screening (within 28 days prior to the first dose of 
derazantinib), once every 8 weeks (two cycles) from the day of the first dose for the first 
six cycles and once every 12 weeks (three cycles) thereafter. For patients with PR or CR, 
the Investigator should perform a confirmation tumor measurement 4 to 5 weeks after the 
scan showing PR or CR. For patients with PD per Investigator assessment, a central 
radiology reviewer confirmation should be received prior to the patient’s discontinuation 
from the study treatment if progression is seen on the first or second on-treatment scan. 
Patients who discontinue study drug for a reason other than radiographic disease 
progression, withdrawal of consent, death, or loss to follow-up should continue tumor 
evaluation visits if possible every 8–12 weeks until they start another anti-cancer therapy, 
experience disease progression, withdraw consent, die, or are lost to follow-up.
Pharmacodynamic assessments will include evaluation of tumor markers (CA19.9, CA125,
CEA), biomarkers (FGF19, FGF21, FGF23), and cell-free circulating tumor 
deoxyribonucleic acid (ctDNA). Blood samples for tumor markers will be collected for all 
enrolled patients. Blood samples for biomarkers and ctDNA will be collected only from 
patients enrolled after completion of the interim analysis, and subject to the granting of 
appropriate regulatory and IRB/IEC approval. These blood samples will be collected on 
Day 1 of the first cycle, every 8 weeks (two cycles) for the first six cycles, once every 
12 weeks (three cycles) thereafter, and at the End of Treatment visit. All collected samples 
will be evaluated in batches either during or at the end of the study. 


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Archival tumor samples will be obtained for all patients to enable additional molecular 
analyses with regard to the identified GAs and markers predictive of response at the 
laboratories selected by the Sponsor (see Section 6.8). In addition, further information on 
the molecular status of the tumor, including available full NGS reports may be collected.
To determine the PopPK parameters of derazantinib, blood samples will be collected on 
Day 1 and Day 15 of Cycle 1, and on Day 1 of Cycles 2, 3, and 4. Exploratory assessments 
of metabolites of derazantinib may also be investigated from these PK plasma samples.
All patients will be scheduled for sparse PK sampling. A subset of up to 20 patients 
(PK/biomarker subgroups) in each substudy will be asked to participate in rich PK 
sampling and/or urinary PK sampling (see Section 6.6). 
HRQOL and symptom response will be measured using the QLQ-C30, QLQ-BIL21, and 
the EQ-5D. The G-SET/HTI is a single item, and will be used as an external anchor to 
determine the minimal important difference of the EQ-5D VAS, EORTC QLQ-C30, and 
QLQ-BIL21 scales (see Section 6.10 and Appendix 7).
Safety follow-up will be conducted at least 30 days after the administration of the last dose 
of study medication. Safety follow-up will include collection of AEs and changes in 
concomitant medication. Survival follow-up will start the day of the last dose of 
derazantinib; it will continue until the study has completed or other discontinuation criteria 
are met.
3.2
Rationale for study design
Intrahepatic cholangiocarcinoma is a rare malignancy and according to the Surveillance, 
Epidemiology, and End Results (SEER) data, between 1973 and 2012, the estimated 
incidence of iCCA increased from 0.44 to 1.18 cases per 100,000 person-years.
Molecular analysis of iCCA has identified FGFR2 fusions and mutations as a potential 
drug target for FGFR inhibitors. FGFR mutations and fusions have been observed in 13.6% 
to 45% of iCCA. The documented fusions to date include: FRGR2-TACC3, 
FGFR2-BICC1, FGFR2-AHCYL1, FGFR2-PPHLN1, and FGFR2-MGEA5 (Arai 2014,
Borad 2014, Borad 2015, Graham 2014, Ross 2014, Sia 2015, Wu 2013).
Derazantinib, a potent pan-FGFR inhibitor, has shown anti-tumor effects in nonclinical 
studies on human tumors driven by oncogenic FGFR with an acceptable therapeutic 
window. In the Phase 1/2 clinical study, ARQ 087-101, derazantinib demonstrated early 
signs of clinical activity against malignancies with FGFR GAs, including iCCA harboring
FGFR2 fusions, mutations, or amplifications. 
3.3
Study endpoints
3.3.1
Primary endpoints
Substudy 1
ORR was selected as the primary endpoint of this study. This endpoint is an acceptable 
surrogate endpoint of clinical benefit in this disease. ORR will be the proportion of patients 
with confirmed complete responses and partial responses by central radiology review as 
per RECIST version 1.1.


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Substudy 2
PFS 3 will be the proportion of patients who have progression-free survival at 3 months 
from the first date of receiving study drug as assessed by survival status and central 
radiology review as per RECIST version 1.1.
3.3.2
Secondary efficacy endpoints
Substudy 1 and Substudy 2

DoR will be calculated from the first date of documented tumor response to disease 
progression by central radiology review.

PFS will be calculated from the first date of receiving study drug until radiographic 
disease progression by central radiology review or death

OS will be calculated from the first date of receiving study drug until death.

Changes in HRQOL and symptom response will be evaluated using the EORTC QLQ-
C30, QLQ-BIL21, and EQ-5D VAS.
Substudy 2

ORR will be the proportion of patients with confirmed complete responses and partial 
responses by central radiology review as per RECIST version 1.1.
3.3.3
Exploratory efficacy endpoints

Changes in PD biomarkers from baseline to maximum change during the course of the 
treatment will be evaluated.

ORR, PFS, OS, and DoR will be evaluated by PD biomarkers.

Describe the proportion of patients with concordant molecular assessment from a liquid 
biopsy sample measuring GAs in circulating-cell free DNA compared to the DNA 
obtained from a tumor biopsy at baseline.

TTP will be calculated based on central radiology review from the first date of
receiving study drug or prior line of systemic therapy until radiographic disease 
progression)
–
TTP will be evaluated for derazantinib overall and by line of prior systemic 
therapy. 
–
In addition, TTP will be assessed on the first and/or the last prior line of systemic 
therapy (reported) and will be compared to TTP on derazantinib

The exposure-response relationship between derazantinib exposure and study measures 
of efficacy, toxicity and PD biomarkers will be analyzed.

PopPK parameters of derazantinib will be evaluated (in addition, exploratory 
assessments of metabolites of derazantinib may also be investigated from the plasma 
PK samples)

The percentage of administered derazantinib (and possibly its metabolites) over 24 h at 
steady-state may also be investigated.


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3.3.4
Safety endpoint
Toxicities will be evaluated using NCI CTCAE version 4.03 criteria.
3.4
Study duration
The study is estimated to take approximately 4 years from First Patient First Visit to Last 
Patient Last Follow-up Visit. It is expected that most patients will receive between 1 and 
8 months of treatment with derazantinib capsules.
Patients will receive treatment with derazantinib capsules until death, radiographic disease 
progression, unacceptable toxicity, or until another of the specified criteria is met for 
stopping therapy (see Section 5.7). Radiographic progressive disease must be confirmed 
by central radiology review prior to treatment discontinuation if progression is seen on the 
first or second on-treatment scan. 
In Substudy 1, if the locally-documented (e.g., by NGS) FGFR2 fusion positive status was 
tested and not confirmed by FISH by the central laboratory designated by the Sponsor after 
the commencement of study treatment, these patients will be assessed on a case-by-case 
basis (see Section 5.7.1).
Once a patient is discontinued from the study treatment, he/she and/or their family will be 
contacted for the long-term survival at least once every 3 months (± 2 weeks) until the 
study has completed or other discontinuation criteria are met (e.g., death, lost to follow-up, 
or withdrawal of consent for long-term [survival] follow-up).
For patients who demonstrate continued benefit (in Substudy 1 or Substudy 2) from 
receiving derazantinib at the time of study closure, the Sponsor aims to provide continued 
individual access to derazantinib, e.g., under a rollover study protocol, or in the context of 
compassionate use / named-patient access where applicable.
STUDY POPULATION SELECTION
4.1
Study population
This is a multi-center, open label, single arm study evaluating derazantinib in adult patients 
with inoperable or advanced iCCA and FGFR2 fusions or FGFR2 mutations or 
amplifications treated with at least one prior regimen of systemic therapy.
Patients’ eligibility may be assessed in two steps: 1) pre-screening to assess the FGFR2
GA status that will be followed by 2) clinical screening procedures.
Tissue samples for genetic testing will be obtained from patients who meet the following 
pre-screening eligibility criteria:
1. Signed written informed consent to permit tissue analysis.
2. 18 years of age or older.
3. No medical history that is excluded per the study treatment eligibility criteria (see 
Section 4.3).
4. ECOG performance status ≤ 1 (Appendix 2).
5. Eligible for or receiving systemic therapy for inoperable or advanced iCCA.
6. Not currently eligible for curative local or surgical therapy.


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To be enrolled in the study, once the FGFR2 GA status is determined, each prospective 
participant must meet all of the following inclusion criteria and none of the exclusion 
criteria.
4.2
Inclusion criteria
Each prospective study participant must meet ALL of the following inclusion criteria in 
order to be eligible for this study:
1. Signed written informed consent granted prior to initiation of any study-specific 
procedures.
2. 18 years of age or older.
3. Histologically or cytologically confirmed locally advanced, inoperable (where 
surgery is not indicated due to disease extension, co-morbidities, or other technical 
reasons), or metastatic iCCA or mixed histology tumors (combined hepatocellular-
cholangiocarcinoma [cHCC-CCA]).
4. Substudy 1
FGFR2 fusion status based on the following assessments (see Section 6.8.1, Table 1):
a) If central laboratory designated by the Sponsor: 
Positive FISH test; and/or
b) If non-central laboratory:*
i)
Positive FISH or NGS test: patients may be enrolled and may start dosing, but 
central confirmation is required† (see Section 5.7.1).
ii) Negative FISH or NGS test: tissue may be submitted to the central laboratory 
designated by the Sponsor, and patients may only be enrolled if the central test 
is positive.
Substudy 2
FGFR2 mutation/amplification status (Appendix 8) based on NGS testing performed 
or commissioned by the respective study site (see Section 6.8.2, Table 2).
Note 1: If the FGFR2 mutation/amplification status is derived from plasma-based NGS testing, 
a tumor block or slides prepared thereof should be submitted for subsequent correlative
tissue-based NGS testing at a laboratory identified by the Sponsor.
Note 2: If the NGS test used cannot identify FGFR2 translocations, a FISH test is mandatory
to confirm that none are present.
5. Received at least one regimen of prior systemic therapy and then experienced 
documented radiographic progression (for Substudy 1), and have no satisfactory 
treatment alternatives (for Substudy 2).
6. Measurable disease by RECIST version 1.1 criteria.
* Using standard protocols and approved by local IRB/IEC, Clinical Laboratory Improvement Amendments (CLIA), or 
other similar agency. For enrollment of patients in the EU, assays must be fully CE-marked.
† The patient must not be enrolled if a negative FISH test is obtained from the central laboratory prior to 
commencing study treatment. Patients without central confirmation of an FGFR2 fusion by the central 
FISH test will be assessed on a case-by-case basis (see Section 5.7.1).


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7. ECOG performance status ≤ 1 (Appendix 2).
8. Adequate organ functions as indicated by the following laboratory values (based on 
screening visit values from the central laboratory).

Hematological
–
Hemoglobin (Hgb) ≥ 9.0 g/dL 
–
Absolute neutrophil count (ANC) 1.5 × 109/L 
–
Platelet count ≥ 75 × 109/L 
–
International normalized ratio (INR) 0.8 to upper limit of normal (ULN) or 
3 for patients receiving anticoagulant therapy such as warfarin or heparin

Hepatic
–
Total bilirubin ≤ 2 × ULN 
–
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
3 ULN (5 × ULN for patients with liver metastases) 
–
Albumin 2.8 g/dL

Renal
–
Serum creatinine 1.5 × ULN, or
–
Creatinine clearance of ≥ 30 mL/min as estimated by the Cockcroft-Gault 
equation
9. Female and male patients of child-producing potential must agree to avoid becoming 
pregnant or impregnating a partner, respectively, during the study*, and until at least 
120 days after the last dose of derazantinib.
Male patients are considered not to be of child-producing potential if they have
azoospermia (whether due to vasectomy or an underlying medical condition). Female 
patients are considered not to be of child-producing potential if they are:

postmenopausal†, or

have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy 
or bilateral tubal ligation/occlusion, at least 6 weeks prior to screening, or 

have a congenital or acquired condition that prevents childbearing.
Male or female patients of child-producing potential must agree to comply with one 
of the following until at least 120 days after the last dose of derazantinib:
a) Abstinence from heterosexual activity‡
* From the day of first study medication, or for oral contraception from 14 days before first study medication. 
† Postmenopausal is defined as at least 12 months with no menses without an alternative medical cause; in women < 
45 years of age a high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm 
a post -menopausal state in women not using hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is  not sufficient.
‡ Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is consistently 
employed as the subject’s preferred and usual lifestyle and if it is employed during the entire period of risk 
associated with the study treatment and if it is considered highly effective by local regulatory agencies and 
ERCs/IRBs. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and 
withdrawal are not highly effective methods of contraception.


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b) Using (or having their partner use) a highly effective method of contraception 
during heterosexual activity. Highly effective methods of contraception are*:

an intrauterine device (IUD)

vasectomy of a female patient’s male partner

a contraceptive rod implanted into the skin

combined (estrogen- and progestogen-containing) or progestogen-only 
hormonal contraception associated with inhibition of ovulation (oral 
contraceptive pill [estrogen/progestin pill or progestin-only pill]contraceptive 
skin patch/implant, vaginal contraceptive ring, or subcutaneous contraceptive 
injection)
4.3
Exclusion criteria
Prospective study participants who meet ANY of the following criteria will not be eligible 
for enrollment into this study.
1. Receipt of treatment before the first dose of study drug (Cycle 1 Day 1) within an 
interval shorter than the following, as applicable:

One chemotherapy or biological (e.g., antibody) cycle interval

Five half-lives of any small-molecule investigational or licensed medicinal product

Two weeks, for any investigational medicinal product with an unknown half-life

Four weeks of curative radiotherapy

Seven days of palliative radiotherapy

28 days of radiotherapy
2. Major surgery or locoregional therapy within 4 weeks of the first dose of 
derazantinib.
3.
Previous treatment with any FGFR inhibitor (e.g., Balversa® [erdafitinib], Pemazyre®
[pemigatinib], infigratinib, rogaratinib, futibatinib, lenvatinib, ponatinib, dovitinib, 
nintedanib, AZD4547, LY2784455).
4. Unable or unwilling to swallow the complete daily dose of derazantinib capsules
5. Clinically unstable central nervous system (CNS) metastases (to be eligible, patients 
must have stable disease 3 months, confirmed by magnetic resonance imaging 
(MRI) or computed tomography (CT) scan, and/or have CNS metastases well 
controlled by low-dose steroids, anti-epileptics, or other symptom-relieving 
medications)
6. Current evidence of clinically-significant corneal or retinal disorder likely to increase 
the risk of eye toxicity, including but not limited to bullous/band keratopathy, 
keratoconjunctivitis (unless keratoconjunctivitis sicca), corneal abrasion, 
inflammation/ulceration, confirmed by ophthalmologic examination
* If a contraceptive method listed above is restricted by local regulations/guidelines, then it does not qualify as a highly 
effecive method of contraception for subjects participating at sites in this country/region.


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7. Concurrent uncontrolled or active hepatobiliary disorders, untreated or ongoing 
complications after laparoscopic procedures or stent placement, including but not 
limited to active cholangitis, biloma or abscess (to be eligible, the patients have to be 
treated and disorders/complications should be resolved within 2 weeks prior to the 
first dose of derazantinib)
8. History of significant cardiac disorders: 

Myocardial infarction (MI) or congestive heart failure defined as Class II to IV per 
the New York Heart Association (NYHA) classification within 6 months of the first 
dose of derazantinib (MI that occurred > 6 months prior to the first dose of 
derazantinib are permitted)

QTcF > 450 msec for men and QTcF > 460 msec for women
9. Serum electrolyte abnormalities defined as follows:

Hyperphosphatemia: serum phosphate > institutional ULN 

Hyperkalemia: serum potassium > institutional ULN

Hypokalemia: serum potassium < institutional LLN

Hypercalcemia: corrected serum calcium > 3.1 mmol/L (> 12.5 mg/dL)

Hypocalcemia: corrected serum calcium < 1.75 mmol/L (< 7.0 mg/dL)

Hypomagnesemia: < 0.4 mmol/L (< 0.9 mg/dL)
10. Significant gastrointestinal disorder(s) that could, in the opinion of the Investigator, 
interfere with the absorption, metabolism, or excretion of derazantinib (e.g., Crohn’s 
disease, ulcerative colitis, extensive gastric resection)
11. History of additional malignancy that is progressing or requires active treatment. 
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin that has undergone potentially curative therapy, and in situ cervical cancer. 
12. Concurrent uncontrolled illness not related to cancer, including but not limited to:

Psychiatric illness/substance abuse/social situation that would limit compliance 
with study requirements

Known uncontrolled human immunodeficiency virus (HIV) infection

Severe bacterial, fungal, viral and/or parasitic infections under treatment with
therapeutic oral or IV medication at the time of first dose of study drug 
administration
13. Blood or albumin transfusion within 5 days of the blood draw being used to confirm 
eligibility
14. Pregnant or breast feeding
15. Known hypersensitivity to derazantinib, or to any of the study drug excipients (starch, 
lactose, crospovidone, magnesium stearate).


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4.4
Number of patients
In Substudy 1, approximately 100 patients who meet all eligibility criteria will be enrolled 
and treated with 300 mg QD orally of derazantinib capsules. In order to evaluate 
100 patients for efficacy, it is anticipated that over 1,000 patients will be tested for the 
presence of FGFR2 fusions.
In Substudy 2, up to approximately 43 mITT-evaluable patients (approximately 15 patients 
in Stage 1, and an additional 28 patients if the study proceeds to Stage 2) with iCCA and 
an FGFR2 mutation or amplification who meet the study entry criteria will receive oral 
derazantinib capsules 300 mg QD. To evaluate 43 patients for efficacy, it is anticipated that 
more than 800 patients will be tested for the presence of an FGFR2 mutation or 
amplification.
STUDY TREATMENTS
Before the start of any study required procedures, including forwarding any tissue sample 
for analysis, the Investigator or designee must obtain a signed written informed consent 
form (ICF) for the study from each prospective study participant or his/her legal 
representative. The Investigator or designee must confirm that the patient has documented 
iCCA.
In Substudy 1, the patient must test positive for FGFR2 fusion by the central laboratory 
designated by the Sponsor, or have documented FGFR2 fusion based on testing conducted 
at a local or central laboratory approved by local IRB/IEC, by CLIA or other similar 
agency. For enrollment of patients in the EU, commercially-used assays must be either 
fully CE-marked or CE-marked for analytical performance; tests manufactured by 
health institutions and used only on their own patients are exempt from the Medical 
Devices Regulation requirements, and do not have to be CE-marked.
If a patient has documentation from the central laboratory indicating that they test negative 
for FGFR2 fusion, that patient may not be enrolled in the study. If FGFR2 fusion is 
identified by a laboratory other than the Sponsor’s central laboratory, then archival and/or 
recent tissue biopsy samples must be collected for further confirmatory testing by FISH by
the Sponsor’s central laboratory. Tissue from patients with a negative test based on local 
testing may be submitted to central confirmatory FISH testing. If central FISH testing is 
positive, then the patient may be enrolled in the study.
In Substudy 2, the patient must test positive for FGFR2 mutations/amplifications and 
negative for any concurrent FGFR2 translocations (see Appendix 8) by NGS testing using 
standard protocols (see Section 6.8.2, Table 2).
Study visits will consist of a Pre-screening visit, if FGFR2
fusion and 
mutation/amplification status is unknown, and/or a Screening visit, during which the 
patient’s eligibility for the study and baseline disease status will be evaluated. Following 
the first dose of derazantinib capsules, patients will be evaluated every 2 weeks for the first 
cycle (Cycle 1 Days 1 and 15), and once every 4 weeks (Day 1 of each subsequent cycle) 
thereafter. A cycle is defined as 28 days/4 weeks. 


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Additionally, an End of Treatment visit, 30-day Safety Follow-up visit, and Survival 
Follow-up(s) will be performed (see Appendix 1 for the Schedule of Assessments). 
Following the Screening evaluation, and a determination by the Investigator and the 
Sponsor’s Medical Monitor that the patient meets all eligibility criteria, the patient will be 
enrolled. 
5.1
Informed consent
Sample ICFs with core information will be provided to each study site. Prior to study 
initiation at a given study site, each site/Investigator must obtain a written 
approval/favorable opinion from its respective IRB/IEC for the ICF and any other written 
information to be provided to patients. All ICFs must be compliant with International 
Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines and local 
regulations, and must be approved by the Sponsor prior to submission to the IRB/IEC. The 
written approval of the IRB/IEC, together with the approved patient information/ICF, must 
be maintained in the study master files.
Written informed consent must be obtained from a prospective study participant before any 
study-specific procedures are performed on that individual, including forwarding 
any tissue sample for analysis. Patients who agree to participate in the study will sign the 
most recently approved ICF and will be provided with a copy of the fully executed 
document. The ICF can be signed greater than 28 days prior to dosing, and does not need 
to be re-signed prior to dosing unless specific reasons apply (e.g., a new approved consent 
version has been issued). The original, fully executed ICF will be maintained in the 
respective patient’s clinical study file.
5.2
Pre-screening visit
After written informed consent is obtained, patients will be pre-screened prior to 
enrollment in the study. The objective of the pre-screening is to assess the patient’s FGFR2
fusion and mutation/amplification status. 

Pre-screening for FGFR2 fusions in Substudy 1 may be based on local or central 
testing. If pre-screening is performed based on a local test, then a central confirmation 
by the FGFR2 break-apart FISH Probe Kit test is required for Substudy 1 (see Section
6.8.1 for further details). 

Pre-screening for FGFR2 gene mutations or amplifications in Substudy 2 will be 
performed based on NGS testing of tissue or plasma samples (see Section 6.8.2 for 
further details).

Patients with known eligible FGFR2 GA status and no requirement for central 
confirmation (Substudy 1 only) may undergo clinical screening procedures after after
written informed consent is obtained.


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For genetic testing, blood samples or tumor tissue from either a fresh biopsy or an archival 
tumor block should be subjected to molecular testing only from patients who meet the 
following pre-screening eligibility criteria:
1. Signed, written informed consent to permit tissue analysis
2. 18 years of age or older
3. No medical history that is excluded per the study treatment eligibility criteria (see 
Section 4.3)
4. ECOG performance status ≤ 1 (see Appendix 2)
5. Eligible for or receiving systemic therapy for inoperable or advanced iCCA
6. Not currently eligible for curative local or surgical therapy
5.3
Screening evaluation
After an eligible FGFR2 fusion or FGFR2 mutation/amplification status is confirmed, the
patient’s further eligibility for the study and baseline disease status will be assessed. The 
following will be evaluated and documented within 28 days prior to the first dose of 
derazantinib:

Medical history (see Section 6.1).

Record prior and concomitant medications (medications used within 30 days prior to 
the first dose of derazantinib).

Tumor imaging assessments, according to RECIST 1.1 (see Section 6.9 and 
Appendix 6). Note: imaging assessments can be used as a Baseline assessment if they 
were performed within 28 days prior to the first dose of derazantinib. 

Physical examination (see Section 6.2).

Vital signs (height, weight, temperature, blood pressure, respiration rate, and pulse).

ECOG performance status (see Appendix 2).

Complete opthalmological examination (see Section 6.3).

Clinical blood tests (see Section 6.5).

Serum pregnancy test, if applicable, within 72 hours prior to dosing (see Inclusion 
criterion 9, Section 6.5, and Section 8.8.2).

12-lead ECG (see Section 6.4).
Patients who satisfy all of the inclusion criteria and none of the exclusion criteria may be 
enrolled in the study.
Also, in order to better understand the disease, for all patients with confirmed FGFR2 
fusion status or gene mutation/amplification, detailed records of prior systemic treatments 
and responses will be collected in the electronic data capture (EDC) system. In addition, 
all eligible (enrolled and dosed) patients will be asked to permit their CT/MRI scans 
performed during prior therapy(ies) to be submitted to the central imaging laboratory.


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5.4
Treatment visits
Enrolled patients will be evaluated on Day 1 and Day 15 of Cycle 1 and on Day 1 of every 
cycle thereafter. All visits are based on the date of the first dose at Cycle 1 Day 1 regardless 
of drug holds. If a patient visit deviates from the protocol permitted window, the next visit 
must be done at the correct time based on the date of Cycle 1 Day 1.
5.4.1
Cycle 1, Day 1
The following assessments will be made during this visit (all assessments except for AE
assessment, 12-lead ECG, and post-dose PK blood collection must be performed prior to 
the first dose):

EORTC QLQ-C30 and QLQ-BIL21, and EQ-5D, questionnaires (should be completed 
by the patient prior to being evaluated by the physician) (see Section 6.10 and 
Appendix 7)

Physical examination (see Section 6.2)

Vital signs (weight, temperature, blood pressure, respiration rate, and pulse)

ECOG performance status (see Appendix 2)

Clinical blood tests (see Section 6.5)

Serum or urine pregnancy test, if applicable (see Section 6.5, and Section 8.8.2)

Blood samples for PK (see Section 6.6 and Appendix 3)

Blood samples for tumor markers (see Section 6.7 and Appendix 3)

Blood samples for biomarkers and ctDNA will be collected only from patients enrolled 
after completion of the interim analysis, and subject to the granting of appropriate 
regulatory and IRB/IEC approval (see Section 6.7 and Appendix 3)

12-lead ECGs (performed pre-dose and 6–8 hours after the first dose) (see Section 6.4)

Record concomitant medications

Dispense and administer derazantinib capsules

Assess AEs after derazantinib administration
5.4.2
Cycle 1, Day 15 (± 3 days)
The following assessments will be made during this visit:

Physical examination (see Section 6.2)

Vital signs (weight, temperature, blood pressure, respiration rate, and pulse)

ECOG performance status (see Appendix 2)

Clinical blood tests (see Section 6.5) 

Blood samples for PK (see Section 6.6 and Appendix 3) 

12-lead ECGs (performed pre-dose and 6–8 hours after the daily dose) (see Section 6.4)

Assess AEs, including any potential eye toxicity*

Record concomitant medications
* Patients who develop ocular symptoms or changes in visual acuity while on the study should be referred to an 
ophthalmologist for a complete eye examination.


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5.4.3
Cycle 2+, Day 1 (± 3 days)
The following assessments will be made during this visit:

EORTC QLQ-C30 and QLQ-BIL21, and EQ-5D, questionnaires (should be completed 
by the patient prior to being evaluated by the physician) every 8 weeks (two cycles) for 
the first six cycles (on C3D1, C5D1, C7D1) and once every 12 weeks (three cycles) 
thereafter (on C10D1, C13D1, etc.) The G-SET/HTI should be additionally completed 
by the patient after 8 weeks (at Cycle 3 Day 1) and 16 weeks (at Cycle 5 Day 1)  
(see Section 6.10 and Appendix 7).

Physical examination (see Section 6.2)

Complete opthalmological examination at C2D1, C3D1, C4D1, and C5D1 only, and if 
clinically indicated thereafter; see Section 6.3)

Vital signs (weight, temperature, blood pressure, respiration rate, and pulse)

ECOG performance status (see Appendix 2)

Clinical blood tests (see Section 6.5)

Serum or urine pregnancy test, if applicable (see Section 6.5, and Section 8.8.2)

Blood samples for tumor markers, biomarkers, and ctDNA every 8 weeks (two cycles)
for the first 6 cycles (on C3D1, C5D1, C7D1) and once every 12 weeks (three cycles)
thereafter (on C10D1, C13D1, etc.) (see Section 6.7 and Appendix 3). Note: Blood 
samples for biomarkers and ctDNA will be collected only from patients enrolled after 
completion of the interim analysis, and subject to the granting of appropriate regulatory 
and IRB/IEC approval (see Section 6.7 and Appendix 3)

Blood samples for PK (Day 1 of Cycles 2, 3, and 4) (see Section 6.6 and Appendix 3)

Urine sample for PK (Day 1 of Cycle 2 only), starting on an empty bladder before daily 
dose administration and until 24 h after dosing (immediately prior to the next dose) (see 
Appendix 3)

CT/MRI (chest, abdomen, and pelvis) tumor measurement and staging every 8 weeks 
(two cycles) for the first six cycles (on C3D1, C5D1, C7D1) and once every 12 weeks 
(three cycles) thereafter (on C10D1, C13D1, etc.) (see Section 6.9 and Appendix 6)

12-lead ECG. Additional ECG(s) may be conducted if clinically indicated
(see Section 6.4)

Assess AEs, including any potential eye toxicity*

Record concomitant medications

Dispense derazantinib capsules and perform drug accountability of returned drug. Note: 
To avoid unnecessary waste of study drug, in cases where treatment was interrupted 
and/or dose was reduced, the patient can continue dosing from the previously dispensed 
bottle until the next drug dispensing visit where re-supply is needed to maintain the 
protocol dosing regimen.
* Patients who develop ocular symptoms or changes in visual acuity while on the study should be referred to an 
ophthalmologist for a complete eye examination.


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5.4.4
End of Treatment visit 
The following assessments will be made during the End of Treatment visit (+ 7 days from 
the date of the last dose administration or after the decision to permanently discontinue 
dosing was made):

EORTC QLQ-C30 and QLQ-BIL21, and EQ-5D, questionnaires (should be completed 
by the patient prior to being evaluated by the physician) (see Section 6.10 and 
Appendix 7)

Physical examination (see Section 6.2)

Complete opthalmological examination (see Section 6.3)

Vital signs (weight, temperature, blood pressure, respiration rate, and pulse)

ECOG performance status (see Appendix 2)

Clinical blood tests (see Section 6.5)

Serum pregnancy test, if applicable (see Section 6.5, and Section 8.8.2)

12-lead ECG (see Section 6.4)

Blood samples for tumor markers (see Section 6.7 and Appendix 3)

Blood samples for biomarkers and ctDNA will be collected only from patients enrolled 
after completion of the interim analysis, and subject to the granting of appropriate 
regulatory and IRB/IEC approval

CT/MRI (chest, abdomen, and pelvis) tumor measurement and staging if the prior scan 
was not done within four weeks (28 days) prior to this visit or if the prior scan did not 
show radiographic disease progression (see Section 6.9 and Appendix 6)

Assess AEs, including any potential eye toxicity*

Record concomitant medications

Perform drug accountability of returned drug
5.5
30-day Safety Follow-up visit
All patients will be followed for a minimum of 30 days after the last dose of derazantinib.
During the 30-day safety follow-up period, AEs and changes in concomitant medication 
should be reported. 
Patients with unresolved study drug-related AEs (occurred during the study treatment 
period or the 30-day safety follow-up period) will be followed until, in the opinion of the 
Investigator, study drug related toxicities have resolved to baseline, CTCAE Grade 1, 
stabilized, or are deemed to be irreversible. A study drug-related AE is defined as an AE 
that is definitely, probably, or possibly related to the treatment with derazantinib, or when 
the relationship is unknown. If a patient receives other anti-cancer therapy within the 
30-day safety follow-up period, the follow-up for AEs will cease, beginning the first day 
of the new therapy.
* Patients who develop ocular symptoms or changes in visual acuity while on the study should be referred to an 
ophthalmologist for a complete eye examination.


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In addition, at the 30-day Safety Follow-up visit, the following assessments will be made:

EORTC QLQ-C30 and QLQ-BIL21, and EQ-5D, questionnaires (should be completed 
by the patient prior to being evaluated by the physician) (see Section 6.10 and 
Appendix 7)

Physical examination (see Section 6.2)

Complete opthalmological examination (see Section 6.3)

Vital signs (weight, temperature, blood pressure, respiration rate, and pulse)

ECOG performance status (see Appendix 2)

Clinical blood tests (see Section 6.5)

Serum- or urine pregnancy testing (to be performed monthly until 120 days after the 
last administration of study drug) (see Section 8.8.2)
5.6
Survival Follow-up (at least every 3 months ± 14 days)
Patients will be followed for survival from the day of the last dose of derazantinib. 
All patients and/or family will be contacted at 3-month intervals (± 14 days) and record the 
patient status as Alive (date); Dead (date); Alive, but withdrew consent for further 
follow-up; Lost to Follow Up. Survival updates may be made more often than every 
3 months if the patient is seen at the investigational site for other reasons and for study 
level survival sweep(s). Survival follow-up will continue until the study has completed or 
other discontinuation criteria are met.
Note: Survival follow-up can be done either as an office visit, over the telephone, or by 
collection of public records in accordance with local laws.
5.7
Discontinuation from the treatment or study
5.7.1
Patient discontinuation from treatment
Patients will be removed from the study treatment at any time if they meet any of the 
following criteria:

Documented radiographic progression of disease
–
Radiographic progression must be confirmed by central radiology prior to 
treatment discontinuation if progression is seen on the first or second post-
treatment scan
–
Patients may remain on study treatment if, in the opinion of the Investigator and 
with the agreement of the Medical Monitor, they continue to derive benefit from 
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
Central negative or unconfirmed FISH test result for an FGFR2 fusion in patients 
enrolled based on a locally-documented FGFR2 fusion positive
–
If the central FISH test could not be performed for technical reasons and the 
patient did not experience radiographic progression, the patient may be allowed to 
continue the study treatment
–
If the central FISH test result is negative for an FGFR2 fusion, the patient should 
be discontinued from the study treatment, other than in exceptional cases when,
based on ethical considerations and an individual benefit-risk assessment,
discontinuation of the patient from the study treatment is considered unacceptable

Documented clinical progression of disease

Clinical unacceptable toxicities despite optimal treatment or dose reduction

Pregnancy (see Section 8.8.2).

Patient decision to discontinue treatment and study visits

Withdrawal of consent from treatment and study follow up calls

Non-compliance with any part of the study, as assessed by the Investigator or Medical 
Monitor

Investigator’s decision after discussion with the Medical Monitor or designee

Death
5.7.2
Patient discontinuation from the study
Patients who discontinue from study treatment will still be followed for survival either 
through direct contact or collection of public records (e.g., death certificate) in accordance 
with local laws, unless they meet any of the following criteria:

Withdrawal of consent for long-term (survival) follow-up

Lost to follow-up

Death
5.8
Study discontinuation
The Sponsor reserves the right to temporarily or permanently discontinue the study at any 
site or at any time. Reasons for study discontinuation may include, but are not limited to, 
the following:

Safety concerns

Poor enrollment

Non-compliance with the protocol, GCP guidelines, or other regulatory requirements 
by the Investigator(s)

Request to discontinue the study by a regulatory or health authority

Discontinuation of product development

Manufacturing difficulties/concerns
The Sponsor and/or designee will promptly inform all Investigators and the appropriate 
regulatory authorities if the study is suspended or terminated for safety reasons. In the event
of such a study termination, the Investigator must notify the IRB or IEC, as appropriate.


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STUDY PROCEDURES
6.1
Medical history and prior/concomitant medications
Medical history will include but not be limited to the following:

Demography: year of birth, gender, race (unless local regulations do not permit), 
ethnicity (US patients)

Clinically significant prior diagnoses, surgeries, and current medications
–
Medications used within 30 days prior to the first dose of derazantinib and 
throughout the treatment period should be reported

Prior cancer history, current cancer diagnosis, tumor stage at the time of diagnosis and 
screening, previous anti-cancer therapy including dates, duration and outcome of 
treatment, previous radiation therapy including anatomic site, dose and dates of 
treatment, previous cancer-related surgical procedures, including type of the procedure 
and dates. 
–
For all patients with confirmed FGFR2 GAs eligible for the study (i.e., either 
FGFR2 fusions, or mutations/amplifications listed in Appendix 8), detailed 
records of prior systemic treatments and responses will be collected in the EDC 
system; 
–
All eligible (enrolled and dosed) patients will be asked to forward CT/MRI scans 
performed during prior therapy(ies) to the central imaging laboratory.
6.2
Physical examination and ECOG performance status
Complete physical examination of the major body systems (Screening visit, Cycle 1 Days 1 
and 15, Day 1 of all subsequent cycles, End of Treatment visit, and 30-day Safety 
Follow-up visit), height (Screening visit only), weight, vital signs (temperature [oral, 
axillary, or tympanic], blood pressurte, respiration rate, and pulse), and ECOG 
Performance Status (Appendix 2). ECOG performance status will also be evaluated during 
the Pre-Screening visit.
6.3
Complete ophthalmological examination
A complete opthalmological examination should be administered by an ophthalmologist at 
the Screening visit, for the first four cycles (i.e., Day 1 of Cycles 2–5), at the End of 
Treatment visit, at the 30-day Safety Follow-up visit, and if clinically indicated. The 
complete eye examination may include the following:

visual acuity

tonometry

anterior segment evaluation

retinal evaluation, which may include tests such as fluorescein angiography and optical 
coherence tomography
For the individual patient, the same methods of assessment should be used throughout the 
study. 
During the study, per Investigator’s discretion, a routine opthalmological examination may 
be performed.


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Patients who develop ocular symptoms or changes in visual acuity while on the study 
should be referred to the ophthalmologist for a complete opthalmological examination.
6.4
12-lead electrocardiogram
A standard, triplicate, 12-lead ECG must be performed using the pre-programmed device 
provided by the Sponsor:

at the Screening visit 

on Day 1 and Day 15 of Cycle 1 (pre-dose, and approximately 6–8 hours after the 
dosing)

on Day 1 of Cycle 2 (pre-dose)

on Day 1 of Cycle 3 (pre-dose, and approximately 6–8 hours after the dosing)

on Day 1 of Cycle 4 and all subsequent cycles (pre-dose); and 

at the End of Treatment visit
Measurements should be separated by ~1 min and be taken within a 5 min time window. 
The on-treatment ECGs should be performed as close as possible to the corresponding PK 
blood collection time point during those visits; if possible, ECG should be measured first,
and then blood collected for PK within 5–10 minutes. Additional ECGs may be conducted 
if clinically indicated.
ECGs must always be recorded after at least 5 min rest and while the patient is in a supine 
or semi-supine position. ECGs must be assessed, and the printouts signed and dated, by the 
Investigator or his/her designee.
All ECGs are to be transmitted to a central ECG laboratory for evaluation, including QTc 
assessment.
6.5
Clinical laboratory tests
Safety laboratory determinations will include hematology, blood chemistry, liver function 
tests, and coagulation tests at the Screening visit (within 1 week prior to dosing), Cycle 1 
Days 1 and 15, Day 1 of all subsequent cycles, the End of Treatment visit, and the 30-day 
Safety Follow-up visit. If clinically indicated, some or all of these tests may be repeated on 
other study days. All laboratory tests will be performed at a central laboratory designated 
by the Sponsor.

Hematology: complete blood count (CBC) including hemoglobin, hematocrit, white 
blood cell count (WBC) with 5-part differential, red blood cell (RBC) count, and 
platelet count

Blood chemistry: albumin, bicarbonate, blood urea nitrogen (BUN), calcium, chloride, 
creatinine, glucose, magnesium, phosphate, potassium, total protein, sodium, and uric 
acid
–
Creatinine clearance as calculated by the Cockcroft-Gault equation (at the 
Screening visit only)
–
25-hydroxy vitamin D and 1,25-dihydroxy vitamin D (at C1D1, C3D1, C5D1, and 
the End of Treatment visit only), 


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
Liver function tests (LFT): ALT, AST, ALP, total and direct bilirubin, lactate 
dehydrogenase (LDH)

Coagulation tests: prothrombin time (PT), INR, and partial prothrombin time (PTT) 
(at the Screening and End of Treatment visits and if clinically indicated)

Serum pregnancy test: for women of child-producing potential at the Screening visit 
(within 72 hours prior to dosing), and End of Treatment visit. In addition, serum- or 
urine pregnancy testing will be performed monthly (on Day 1 of each treatment cycle) 
while the patient receives study treatment, at the 30-day Safety Follow-up visit, and 
monthly until 120 days after the last administration of study drug. Pregnancy testing 
after the End of Treatment may be performed at the patient’s local gynecologist to 
reduce the burden related to study visits at the site, but must be communicated to the 
study investigator.
6.6
Pharmacokinetic assessments
Blood samples will be taken to determine the PopPK parameters of derazantinib.
Exploratory assessments of metabolites of derazantinib may also be investigated from the 
same samples.
Time windows are allowed for sample collection as detailed in Appendix 3.
6.6.1
Sparse PK sampling (all patients)
On Cycle 1 Day 1 and Day 15, and on Cycle 3 Day 1, PK plasma samples will be collected 
pre-dose and between 6 and 8 hours after the daily dose of derazantinib. On Day 1 of Cycles 
2 and 4, PK plasma samples will be collected at pre-dose (see Appendix 3). The blood 
sampling date and time and the time of derazantinib administration on the day of the PK 
blood draw and on the day prior to the PK blood draw should be recorded on the electronic 
case report form (eCRF). 
6.6.2
Rich PK sampling (additional consent required)
In the PK/biomarker subgroup (up to 20 patients), on Day 1 of Cycle 1 and Cycle 2, serial 
PK plasma samples will be collected pre-dose, and 1, 2, 4, 6, 8, 10, 12, and 24 h after the 
daily dose of derazantinib (immediately prior to the next dose); the 10 and 12 h time-points 
are optional. On Day 15 of Cycle 1 and Day 1 of Cycle 3, PK plasma samples will be 
collected pre-dose and between 6 and 8 hours after the daily dose of derazantinib. On Day 1 
of Cycle 4, PK plasma samples will be collected at pre-dose (see Appendix 3). Patients will 
be asked for an additional consent to participate in these assessments.
6.6.3
Urinary PK sampling (additional consent required)
Patients who undergo urinary PK sampling should also undergo rich blood PK sampling.
In the PK/biomarker subgroup (up to 20 patients), urine will be collected over a 24 h 
interval on Day 1 of Cycle 2 to determine renal excretion of derazantinib. Exploratory 
assessments of metabolites of derazantinib may also be investigated from the PK urine 
samples (see Appendix 3). Patients will be asked for an additional consent to participate in 
these assessments.


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6.7
Pharmacodynamic assessments
The goal of PD assessments is to identify additional markers to allow a better prediction of 
response to derazantinib or other cancer treatments, and to evaluate the tumoral and serum-
or plasma-based PD response in patients treated with derazantinib.
Blood samples for PD assessments will be collected for serum tumor markers (CA19.9, 
CA125, CEA), biomarkers (FGF19, FGF21, FGF23), and ctDNA prior to the first dose on 
Day 1 of Cycle 1, and on Day 1 of every 8 weeks (every two cycles) for the first six cycles 
(C3D1, C5D1, C7D1), once every 12 weeks (three cycles) thereafter (C10D1, C13D1, 
etc.), and at the End of Treatment visit. Blood samples for serum tumor markers will 
be collected for all enrolled patients. Blood samples for biomarkers and ctDNA will be 
collected only from patients enrolled after completion of the interim analysis.
Archival tumor samples will be obtained for all patients to enable additional molecular 
analyses with regard to the identified GAs and markers predictive of response at the 
laboratories selected by the Sponsor (see Section 6.8). 
The planned analyses include, but are not limited to, biomarkers identifying additional 
markers to allow a better prediction of response to derazantinib or other cancer treatments,
biomarkers representing further MAPK (RAS/RAF/MEK/ERK), PI3K/AKT, and 
JAK/STAT pathways, biomarkers indicating PI3K, PTEN, EGFR, MET and ERB3 
signaling, and biomarkers demonstrating phosphorylation status of phospho-S6,
phosphor-STAT, phospho-AKT, phospho-MEK, phospho-ERK, and RNA-expression of 
proteins activated by the MAPK-pathway, such as SPRY2 and DUSP6.
All collected samples will be evaluated in batches either during or after the end of the study.
All testing will be performed at a laboratory designated by the Sponsor. Samples remaining 
from PD analyses may be used to supplement diagnostic analysis batches, and vice versa.
6.8
Tumor tissue testing for confirmation of patient eligibility
To be eligible for enrollment, the patient must either test positive for FGFR2 fusion
(Substudy 1), or test positive for FGFR2 mutation/amplification (Substudy 2).
6.8.1
FISH testing
FISH testing will be the primary method to confirm FGFR2 fusions in Substudy 1.
If the FGFR2 fusion is identified by a laboratory other than the Sponsor’s central 
laboratory, then archival and/or recent tissue biopsy samples or a tissue block suitable for 
biomarker analysis must be available for confirmatory testing using the break-apart FISH 
test by the Sponsor’s central laboratory (ARUP laboratories; Salt Lake City, USA). 
These samples should be sent to the central laboratory as early as possible, and no later 
than 4 weeks after the patient received the first dose of derazantinib. 


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Table 1 describes the testing approach depending on FGFR2 GA status and available 
results from local molecular pre-screening. Central laboratory FISH testing using the 
break-apart FISH test should be performed on all tissue samples from potentially eligible 
patients with iCCA for whom:

No local pre-screening results (by FISH or NGS) are available, or

Where pre-screening results (by FISH or NGS) have identified an FGFR2 fusion and 
the patient is planned for study inclusion or has already been included in the study
Tissue from Substudy 1 patients with a negative result from a test other than the central 
laboratory FISH test designated by the Sponsor may also be submitted to central 
confirmatory FISH testing. If the central FISH testing is positive, the patient may be
enrolled in the study.  
Table 1
Substudy 1: Overview of genetic testing for FGFR2 fusions
Local pre-screening result
Confirmatory testing approach
Main testing purpose/comment
No local testing performed
Central FISH (mandatory)
Detect eligible FGFR2 fusion status
Local FISH test positive for 
FGFR2 fusion
Central FISH (mandatory)
Confirm or exclude FGFR2 fusion
NGS (optional)
Characterize FGFR2 fusion
Local NGS test positive for 
FGFR2 fusion
Central FISH (mandatory)
Confirm FGFR2 fusion
Local NGS test negative for 
FGFR2 fusion
Central FISH (optional, depending 
on tissue availability)
Detect eligible FGFR2 fusion status
Tumor tissue requirements: 
Central FISH:
≥ 6 consecutive, unstained, 5 ± 1 µm thick sections placed on positively charged slides.
NGS testing:
≥ 10 consecutive, unstained, 5 ± 1 µm thick sections placed on positively charged slides, 
and one H&E slide.
Central FISH testing will be performed on formalin-fixed paraffin-embedded (FFPE) 
primary liver cancer specimens, including iCCA tissue samples. A minimum of 
6 consecutive, unstained, 5 ± 1 µm thick sections placed on positively charged slides are 
required. Archived tissue specimens may be submitted if they meet the requirements 
outlined in the Laboratory Manual.
Archival tumor samples will be obtained for all patients to enable additional molecular 
analyses with regard to the identified GAs and markers predictive of response at the 
laboratories selected by the Sponsor.
6.8.2
NGS testing
NGS testing will be the primary method to establish a tumor’s FGFR2 mutation/
amplification status in Substudy 2; any level of FGFR2 gene amplification will be eligible. 
Patients with an eligible FGFR2 mutation/amplification will not be eligible for clinical 
screening if the tumor concurrently harbors any FGFR2 translocation. Table 2 describes 
the testing approach depending on FGFR2 GA status and available results from local 
molecular pre-screening.


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NGS testing may also be used to detect and characterize FGFR2 fusions in Substudy 1, 
provided tumor tissue is submitted for the mandatory confirmatory FISH test (see Section 
6.8.1).
Usually, NGS testing results will already be available for patients based on prior testing in 
the context of standard of care for the patient, or will be performed at the study site or 
commissioned at facilities of commercial providers.
If required to comprehensively determine the eligible FGFR2 GA status, NGS testing may 
be complemented by validated/approved other molecular tests. Tumor samples may be 
analyzed at other laboratories identified by the Sponsor to further characterize the 
identified GAs and molecular markers predictive of response.
Table 2
Substudy 2: Overview of genetic testing for FGFR2
mutations/amplifications
Local pre-screening 
result
Confirmatory testing approach
Main testing purpose/comment
No local testing performed Mandatory: Validated/approved NGS test* 
(FFPE tissue samples).
Additional FISH testing is ONLY 
mandatory if FGFR2 translocations cannot 
be detected by the applied NGS test.
Detect eligible FGFR2
mutation/amplification status.
Exclude any concurrent FGFR2
translocations.
Local tissue- or plasma-
based NGS test* positive 
for FGFR2
mutation/amplification
Additional FISH testing is ONLY 
mandatory if FGFR2 translocations cannot 
be detected by the applied NGS test.
Exclude any concurrent FGFR2
translocations.
Local tissue-based NGS 
test* negative for FGFR2
mutation
Optional: Use different validated/ approved
NGS assay.*
Additional FISH testing is ONLY 
mandatory if FGFR2 translocations cannot 
be detected by the applied NGS test.
Confirm presence of FGFR2
mutation/amplification.
Exclude any concurrent FGFR2
translocations.
Tumor tissue for additional correlative analyses should be submitted from all patients enrolled in the 
study; tumor tissue requirements: 
NGS testing:
≥ 10 consecutive, unstained, 5 ± 1 µm thick sections placed on positively charged slides, 
and one H&E slide.
Central FISH:
≥ 6 consecutive, unstained, 5 ± 1 µm thick sections placed on positively charged slides.
* For enrollment of patients in the EU, assays must be either fully CE-marked or CE-marked for analytical 
performance, unless such assays are exempt from this requirement by the IVDD (Directive 98/79/EC), 
i.e., manufactured and appropriately validated within health-institution laboratories for use in that 
environment and not subject to commercial transactions. 
For enrollment of patients outside of the EU, assays must use standard protocols approved by the local 
IRB/IEC, CLIA, or other similar agency, or, where applicable, US FDA-approved fully CE-marked 
industrial scale assays.
The Sponsor will review and confirm the appropriateness of the NGS testing approach for each study 
site, and will reimburse costs for NGS testing as appropriate, unless the NGS testing is already available 
for a patient in the context of prior standard of care testing.


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For Substudy 2, available liquid biopsy findings from NGS testing from contemporary 
liquid biopsies may be used to determine the patient’s FGFR2 molecular status (Table 2); 
however, a tumor block or slides prepared thereof should be submitted for correlative
tissue-based NGS testing at a laboratory identified by the Sponsor. De novo NGS testing 
should be performed on tumor tissue samples from potentially eligible patients with iCCA 
for whom no local molecular pre-screening results are available (Table 2).If possible, NGS 
testing should be performed on formalin-fixed paraffin-embedded (FFPE) primary liver 
cancer specimens; alternatively, tissue samples of different organ origin may be used if in 
accordance with the assay’s specifications. Archived tissue specimens may be submitted 
(for minimum tissue requirements, see Table 2) if they meet the requirements outlined in 
the Laboratory Manual. Detailed instructions for collection, shipment, and testing of blood 
and tissue samples for PK and PD assessments will be provided in the Laboratory Manual.
NOTE: Samples for PK, and PD assessments will be labeled by personnel from the 
institution with the patients’ study ID; patients’ identity will not be made known to 
employees from the Sponsor, additional collaborators, or other investigators. Samples will 
only be used for the purposes of the protocol and will only be used by the Sponsor’s
personnel or by an external laboratory chosen by the Sponsor to outsource the analyses 
according to internal guidelines. Samples will be kept until all protocol-related analyses 
are completed, for a period not exceeding 10 years or as required by local law.
6.9
Tumor imaging assessments
Baseline tumor imaging assessments must be done at the time of the Screening visit. 
However, if an assessment has been performed for routine clinical management prior to 
obtaining informed consent after administration of the last dose of any prior anti-tumor 
treatment, and within 28 days of first dose of study treatment on C1D1, then this may be 
used for Screening purposes; in such situations it is not necessary to repeat tests if the 
assessments are of sufficient diagnostic quality. 
Tumor assessments (CT or MRI scan) of the chest, abdomen, and pelvis will be done once 
every 8 weeks (every two cycles) from the day of the first dose for the first six cycles 
(C3D1, C5D1, C7D1), and once every 12 weeks (every three cycles) thereafter (C10D1, 
C13D1, etc.). The End of Treatment scan will be done if the previous scan was not done 
within four weeks (28 days) prior to the End of Treatment visit or if the previous scan did 
not show radiographic disease progression. The same imaging modality (CT or MRI) must 
be used throughout the study unless the patient develops a contraindication to the modality 
used for the Screening scan.
A bone scan (BS), or alternatively a whole-body MRI (WBMRI), should be performed at 
Screening only in patients with new symptoms (e.g., new persistently-elevated ALP) to 
assess bone metastasis; screening of asymptomatic patients for clinically unapparent bone 
metastases is not supported by applicable guidelines (Chen 2020, Vogel 2018, 
Benson 2017) but may be done at the Investigator’s discretion if local routine practice. 
Patients with positive BS/WBMRI at baseline will undergo further radiological
assessments of bone lesions performed at protocol-scheduled time points for tumor 
assessments (see Appendix 1) and as per institutional practice. Lytic/mixed lesions with 


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soft-tissue component may be included in the evaluation of disease burden if they meet
measurability criteria, while blastic lesions are considered non-measurable, in accordance 
with RECIST 1.1.
For patients with PR or CR, the Investigator should make every attempt to perform the 
confirmation scan 4 to 5 weeks after the last scan was performed. Radiographic PD must 
be confirmed by central radiology prior to treatment discontinuation if progression is seen 
on the first or second post-treatment scan.
Patients who discontinue study drug should have a tumor evaluation visit as soon as 
possible after the event (e.g., clinical deterioration; ± 28 days window). If a previous scan 
was obtained within 28 days prior to the date of discontinuation, then a scan at treatment 
discontinuation is not mandatory but recommended if the clinical situation indicates an 
altered disease status. For patients who discontinue study treatment due to documented PD, 
this is the final required tumor imaging. 
Patients who discontinue study drug for a reason other than radiographic disease 
progression, withdrawal of consent, death, or loss to follow-up should continue tumor 
evaluation visits if possible every 12 weeks until they start another anti-cancer therapy, 
experience disease progression, withdraw consent, die, or are lost to follow-up.
Standard imaging studies should be performed according to the imaging manual provided 
by the central imaging laboratory designated by the Sponsor. Tumor response will be 
evaluated per RECIST version 1.1 (see Appendix 6).
6.10
Patient-reported outcomes
HRQOL and symptom response will be measured using the EORTC QLQ-C30
QLQ-BIL21, the EQ-5D, and the G-SET/HTI. Guidelines for completion of these 
instruments are provided in Appendix 7.
The EORTC QLQ-C30 measures five functional dimensions (physical, role, emotional, 
cognitive, and social), three symptom scales (fatigue, pain, and nausea and vomiting), 
six single symptom items (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, 
and financial impact), and global health and quality-of-life.
It will be administered in conjunction with a disease-specific quality of life questionnaire 
QLQ-BIL21, which is the only scale focusing specifically on the HRQoL of patients with 
cholangiocarcinoma. The EORTC QLQ-BIL21 comprises five multi-item measures of 
cholangiocarcinoma and gallbladder cancer-associated symptoms (eating symptoms, 
jaundice, tiredness, pain symptoms, anxiety), and three single items on treatment side 
effects, difficulties with drainage bags/tubes, and concerns regarding weight loss 
(Kaupp-Roberts 2016).
The EQ-5D is a standardized instrument measuring health outcomes, with five health state 
dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. 
The EQ-5D also includes a graded vertical visual analog scale (VAS) on which the patients 
rate their general state of health at the time of the assessment. 


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The G-SET/HTI is a single item, and will be used as an external anchor to determine the 
minimal important difference of the EQ-5D VAS, EORTC QLQ-C30, and QLQ-BIL21 
scales. It will be administered twice during the study, consistent with the protocol by the 
EORTC Quality of Life Group (Musoro 2018) for evaluating the minimal important 
difference. The G-SET/HTI will be provided after 8 weeks (at Cycle 3 Day 1) and 16 weeks 
(at Cycle 5 Day 1). The G-SET/HTI is a patient-rated change in health between two time 
periods using a five-point ordinal scale (1=much better now than 8
weeks 
ago; 2=somewhat better now than 8 weeks ago; 3=about the same as 8 weeks ago; 
4=somewhat worse now than 8 weeks ago; 5=much worse now than 8 weeks ago) (adapted 
from Ware 2002, Lloyd 2014). 
The QLQ-C30, QLQ-BIL21, and EQ-5D questionnaires will be provided to the patients to 
complete before the first dose on Day 1 of the first cycle, every 8 weeks (two cycles) for 
the first six cycles (C3D1, C5D1, C7D1), once every 12 weeks (three cycles) thereafter 
(C10D1, C13D1, etc.), at the End of Treatment visit, and at the 30-day Safety Follow-up 
visit. The G-SET/HTI will be provided after 8 weeks (at Cycle 3 Day 1) and 16 weeks (at 
Cycle 5 Day 1). The questionnaires should be completed by the patient without assistance 
during the scheduled visit, before the patient sees the physician (i.e., at the start of the visit), 
with the EQ-5D to be completed first.
6.11
Protocol deviations
The Investigator should conduct the study in compliance with the protocol which was given 
approval/favorable opinion by the IRB/IEC and where applicable by the regulatory 
authorities except where necessary to eliminate immediate hazards to the patient.
A deviation to any protocol procedure, or waiver to any stated criteria will not be allowed 
in this study. The Sponsor must be notified of all intended or unintended deviations to the 
protocol (e.g., inclusion/exclusion criteria, dosing, missed study visits) on an expedited 
basis.
The Investigator or designee should document all protocol deviations and explain 
(if possible) any deviation from the approved protocol.
Any data recorded on the study eCRF will be collected and included in the database 
according to Clinical Data Interchange Standards Consortium (CDISC) standards and 
subjected to the same procedures as other data. If a patient was ineligible or received an 
incorrect dose or investigational treatment and had at least one administration of 
investigational product, data should be collected for safety purposes.
The Investigator should notify the IRB/IEC of deviations from the protocol in accordance 
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TREATMENT
7.1
Investigational product
Derazantinib is an investigational oral drug supplied as 100 mg capsules.
The Investigator must ensure that derazantinib capsules will be used only in accordance 
with the protocol.
7.1.1
Labeling and packaging
Derazantinib is supplied as capsules in bottles and labeled in the local languages as 
investigational agent, according to relevant guidelines. The Sponsor will provide 
derazantinib capsules required for completion of this study. It will be shipped to the 
pharmacist/study personnel at the clinical sites during the study through the Interactive 
Response Technology (IRT) system.
7.1.2
Drug accountability
When a drug shipment is received, the Investigator or designee will check the amount and 
condition of the drug, check for appropriate local language in the label, drug expiration 
date, and acknowledge receipt in the IRT system. A Packing Slip will be included with the 
shipment and must be completed upon receipt and returned as instructed on the form. In 
addition, the Investigator or designee shall contact the Sponsor as soon as possible if there 
is a problem with the shipment.
A Drug Accountability Log will be provided for derazantinib capsules. The log must be 
kept current and should contain the protocol number, the name and clinical site of the 
Investigator, dates and quantities of drug received, patient’s identification number to whom 
derazantinib capsules were dispensed, the date and quantity dispensed, and balance 
remaining, if from individual patient drug units, as well as the lot number, dose, and the 
initials of the dispenser. Drug accountability is performed to the capsule level.
To avoid unnecessary waste of derazantinib capsules, in cases where treatment was 
interrupted and/or dose was reduced, the patient can continue dosing from the previously 
dispensed bottle until the next drug dispensing visit where re-supply is needed to maintain 
the protocol dosing regimen.
At the end of the study or as directed, all study drug, including unused, partially used, or 
empty containers, will be returned to the designee as instructed by the Sponsor.
Derazantinib capsules will be returned only after the study monitor has completed a final 
inventory to verify the quantity to be returned. The return of derazantinib capsules must be 
documented and the documentation must be included in the shipment. Unused drug 
supplies may be destroyed by the Investigator when approved in writing by the Sponsor 
and the Sponsor has received copies of the site’s drug handling and disposition Standard 
Operation Procedures (SOPs) or equivalent.
All derazantinib capsules inventory forms must be made available for inspection by a 
Sponsor authorized representative or designee and regulatory agency inspectors. The 
Investigator is responsible for the accountability of all used and unused study supplies at 
the site.


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7.1.3
Storage and handling
Drug supplies must be stored in a secure, limited access storage area. Derazantinib capsules 
are stable when stored at controlled room temperature per storage instructions provided in 
the label.
If storage conditions deviate from the above storage requirements, the Investigator will 
document the deviation and inform the study monitor within 24 hours of discovery of the 
deviation. The supplies should be held and not dispensed until the deviation has been 
reviewed by the Sponsor’s Quality Assurance or designee. If it is determined that the 
product is no longer suitable for use, the bottles must be reported as damaged in the IRT 
and a resupply shipment will be made.
7.1.4
Derazantinib administration
Derazantinib capsules will be administered once a day, by mouth. All patients will dose at 
300 mg once daily (QD) unless a dose reduction is required. Derazantinib capsules must 
be administered 1 hour before, or at least 2 hours after, a meal, except in the rich PK patient 
subset, who will be fasted on Day 1 of Cycle 1 (first dose), when derazantinib will be 
administered after at least 10 h from the last meal, and no food will be taken during the 4 h 
following derazantinib administration.
In the event of nausea or vomiting which is assessed as at least CTCAE Grade ≥2, a light 
meal before subsequent derazantinib administration is allowed, to minimize the severity of 
the event.
For administrative reasons, the treatment period is defined by 4-week cycles (28 days).
For an individual patient, treatment will continue until death, disease progression (clinical 
or radiological), unacceptable toxicity, or another discontinuation criterion is met. It 
isexpected that most patients will receive derazantinib capsules for 1 to 8 months.
7.2
Missed or vomited doses
A missed or vomited dose should not be replaced. The patient should be instructed to take 
the next scheduled dose at the regularly scheduled time. If the patient vomited the first dose 
of derazantinib, the patient may be re-challenged at the Investigator’s discretion.
Only if a derazantinib dose is vomited within 2 hours of administration, this should be 
considered as a missed dose and reported in eCRF.
7.3
Dose modifications for drug-related toxicities
7.3.1
General recommendations
In general, once the dose of derazantinib has been modified for a patient, all subsequent 
cycles should be administered to that patient at the modified dose. The modified dose will 
be considered the maximum dose for all subsequent cycles for that patient.
When a drug-related toxicity is observed, dose delays and/or reductions in derazantinib
administration are allowed. A drug-related toxicity is defined as any toxicity considered 
definitely, probably, or possibly related to derazantinib, or when the relationship is 


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unknown. If dose reduction is indicated, a patient should be assigned to the lower dose. 
Dose re-escalation is not permitted. In the event of a dose modification, the dose change(s) 
must be captured in the EDC system. If questions or considerations regarding dose 
modification arise or a specific dose modification is needed, the Sponsor’s Medical 
Monitor or designee should be consulted.
In the event of nausea or vomiting (both assessed as potential risks for derazantinib), which 
is assessed as at least CTCAE Grade ≥2, a light meal before subsequent derazantinib 
administration is allowed, to minimize the severity of the event; immediate dose 
modifications upon CTCAE Grade ≥ 2 nausea or vomiting are not recommended, subject
to the Investigator’s discretion and medical judgement.
Table 3
Dose delays/reductions for drug-related toxicity not otherwise specified
Event grade
Action
Grade 1 or 2
Continue current dose level, unless dose interruption/modification may be clinically 
indicated (as assessed by the Investigator and agreed upon by Medical Monitor or 
designee) 
Grade 3
Withhold derazantinib until recovery to Grade 1 or baseline. Administer 
derazantinib at the next lower dose for subsequent dosing, unless further dose 
reduction is required
Grade 4
Permanently discontinue derazantinib if the event is at least possibly related to
derazantinib.
Table 4
Derazantinib dose reduction scheme
Current dose
Dose after reduction
3 capsules QD (300 mg daily)
2 capsules QD (200 mg daily)
2 capsules QD (200 mg daily)
1 capsule QD (100 mg daily)
1 capsule QD (100 mg daily)
1 capsule QOD (100 mg every other day)
7.3.2
Hyperphosphatemia
Because hyperphosphatemia is not defined by CTCAE v. 4.03, for the purpose of this 
protocol hyperphosphatemia is defined as:
Grade 1:
> ULN to < 7.0 mg/dL (< 2.26 mmol/L)
Grade 2:
Non-invasive intervention required (e.g., withhold drug or modify dose) 
orbetween 7.0 – 9.0 mg/dL (2.26 – 2.90 mmol/L)
Grade 3:
Severe or medically significant, but not immediately life threatening,
or > 9.0 – 10.0 mg/dL (˃ 2.90 – 3.23 mmol/L)
Grade 4:
Life-threatening consequences, urgent intervention indicated e.g., dialysis
or > 10.0 mg/dL (> 3.23 mmol/L)
Table 5 guides interventions for the management of hyperphosphatemia considered at least 
possibly related to derazantinib. For all patients, it is recommended to restrict phosphate 
intake to 600–800 mg daily.


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Table 5
Dose delays/reductions for drug-related hyperphosphatemia
Serum phosphate level
Action
(For serum phosphate ≥7.0 mg/dL, consider adding an oral
phosphate binding/reducing agent until serum phosphate level
returns to < 5.6 mg/dL)
< 7.0 mg/dL (< 2.26 mmol/L)
Continue derazantinib at current dose.
7.0 – 9.0 mg/dL (2.26 – 2.90 mmol/L)
Withhold derazantinib with weekly reassessments until the level
returns to < 5.6 mg/dL; the patient may restart derazantinib at
the dose prior to hyperphosphatemia. If hyperphosphatemia
lasts > 2 weeks, consider restarting at the next lower dose.
˃ 9.0 – 10.0 mg/dL (˃ 2.90 – 3.23
mmol/L)
Withhold derazantinib with weekly reassessments until the level
returns to < 5.6 mg/dL; the patient may restart at the next lower
dose level.
> 10.0 mg/dL (> 3.23 mmol/L) or
significant alteration from baseline
renal function; or
Grade 3 hypercalcemia
Withhold derazantinib with weekly reassessments until the level
returns to < 5.6 mg/dL; the patient may restart at two dose
levels lower, or permanently discontinue derazantinib (e.g., if 
considered life threatening event).
7.3.3
Management of retinal adverse events
A complete ophthalmological examination (see Section 6.3) should be performed by an 
ophthalmologist at the Screening visit, for the first four cycles (i.e., Day 1 of Cycles 2–5), 
and at the End of Treatment visit. Further complete ophthalmological examinations only 
need to be performed if clinically indicated. Table 6 provides specific guidance for the 
management of dose delays/reductions in the case of retinal adverse events possibly related 
to derazantinib.
Table 6
Dose delays/reductions for drug-related opthalmological toxicity (central 
serious retinopathy / retinal pigment epithelial detachment)
Grade
Action
Asymptomatic clinical or diagnostic
observations only (Grade 1)
Withhold derazantinib until resolution. If the event resolves
within 4 weeks, restart at the next lower dose level. If stable 
but not resolved for two consecutive opthalmological 
examinations, restart at the next lower dose level.
Visual acuity 20/40 or better or
≤3 lines of decreased vision from baseline
(Grade 2)
Withhold derazantinib until resolution. If the event resolves
within 4 weeks, the patient may restart at the next lower
dose level.
Visual acuity worse than 20/40 or
> 3 lines of decreased vision from baseline
(Grade 3)
Withhold derazantinib until resolution. If the event resolves
within 4 weeks, the patient may restart at two dose levels
lower. If the event recurs, consider permanent
discontinuation of derazantinib.
Visual acuity 20/200 or worse in affected
eye (Grade 4)
Permanently discontinue derazantinib.


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7.3.4
Management of QTc prolongation or other significant ECG abnormalities
If significant QTc prolongation and/or significant ventricular arrythmia is observed, i.e., a 
prolonged QTc interval ≥501 msec on at least two separate ECGs (consistent with a 
CTCAE v4.03 Grade 3 event), derazantinib must be withheld, and the patient must be 
monitored by the investigator and hourly (triplicate) 12-lead ECG obtained until the QTc 
has returned to ≤ 470 msec. The clinical context and possible factors contributing to QTc 
prolongations such as electrolyte abnormalities (potassium, calcium or magnesium), 
concomitant medications, or other clinical factors such as cardiac ischemia must be 
carefully assessed, and any findings documented in the eCRF. The decision to continue 
treatment with derazantinib should be reviewed and supported by a cardiologist.
Once QTc prolongation has resolved, and if a decision was made to continue treatment 
with derazantinib, patients may continue treatment at a lower dose with an ECG monitoring
schedule defined by the cardiologist. 
Patients who experience a QTc interval ≥501 msec on at least two separate ECGs after 
dose reduction will be discontinued from study.
All significant QTc prolongations or other relevant ECG abnormalities, will also be 
evaluated centrally.
7.4
Treatment compliance
All doses given during the patient’s visits with the Investigator will be administered under 
the supervision of clinical study personnel. The patients will be instructed to return all 
unused study drug at the next visit. Compliance to the study drug regimen will be evaluated 
by counting unused capsules.
During the treatment period, if compliance is not between 80% and 120%, inclusive, the 
patient will be counseled about the importance of adherence to the mandated regimen.
If the patient continues to be noncompliant in terms of dosing, the patient may have to be 
discontinued from the study treatment.
Administration of derazantinib capsules will be recorded in the Drug Accountability Log 
and eCRF. Patients must return empty bottles and remaining capsules. Returned capsules 
must be recorded in the Drug Accountability Log which is supplied to the site.
At each visit after the study treatment is initiated, the Investigator or designee must record 
the date, interval between visits, quantity and strengths, and any dose changes/interruptions 
of study drug dispensed/administered. To avoid unnecessary waste of derazantinib
capsules, in cases where treatment was interrupted and/or dose was reduced, the patient
can continue dosing from the previously dispensed bottle until the next drug dispensing 
visit where re-supply is needed to maintain the protocol dosing regimen.
% compliance =
# of capsules dispensed – # of capsules returned
# of capsules prescribed/daya × # of daysb in the dosing interval × 100
a
Number of capsules prescribed (i.e., 3 or as determined per the dose reduction guidelines for toxicity 
considered related to derazantinib and specified in the eCRF
b
Number of days during that interval that the patient should have dosed (i.e., excluding any days that the patient
was instructed to hold dosing due to an AE)


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7.5
Blinding
This is an open-label study. Neither the patient, the Investigator/site staff, nor the Sponsor 
will be blinded to the treatment administered.
7.6
Prior treatment
Reasonable efforts will be made to determine all relevant prior treatments received by the 
patient within 30 days prior to the first derazantinib dose, including accurate start and stop 
dates of the regimens. All relevant information must be recorded in the appropriate 
patient’s eCRF. All surgical procedure history, prior chemotherapy, and radiation therapy 
must be recorded on the appropriate eCRF.
7.7
Concomitant treatments
All information regarding concomitant treatments (medications or procedures) must be 
recorded on the patient’s eCRF (including the name of the medication or procedure and 
duration of treatment). Complete information of analgesics and acid-reducing agents’ 
consumption should be obtained and recorded.
7.7.1
Permitted treatment
Palliative and supportive care for disease-related symptoms will be offered to all patients.
In addition, the following treatments are allowed:

Standard therapies for concurrent medical conditions

Erythropoietin Stimulating Agents (ESA): Please follow the American Society of 
Clinical Oncology (ASCO), the American Society of Hematology, MEDICARE 
guidelines for the use of epoetin in patients with cancer and Food and Drug 
Administration (FDA) alerts dated 09 March 2007, 08 November 2007, 12 March 2008, 
31 July 2008, and 02 December 2008.

Hematopoietic growth factors, including filgrastim (Neupogen®), or other granulocyte 
colony stimulating factors (G-CSF). Please follow ASCO guidelines for the use of 
white blood cell growth factors (http://jco.ascopubs.org/content/24/19/3187.full).

Prophylactic antiemetics may be administered according to standard practice 

Megestrol acetate (Megace®)

Use of topical corticosteroids, topical and systemic antibiotics according to standard of 
care (SOC) or institutional guidelines

Treatment with non-conventional therapies (i.e., herbs or acupuncture) and 
vitamin/mineral supplements are acceptable, provided that they do not interfere with 
the study endpoints, in the opinion of the Investigator

Bisphosphonates and denosumab for bone metastases or hypercalcemia of malignancy

Palliative radiotherapy for non-hepatic local pain control provided that, in the opinion 
of the Investigator, the patient does not meet the criteria for treatment discontinuation 
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7.7.2
Prohibited treatment / treatment to be avoided or used with caution
The following treatments are not allowed during the study:

Any concurrent anti-cancer therapy including chemotherapy, radiotherapy, hormonal, 
targeted therapy, or immunotherapy
–
Palliative radiotherapy for non-hepatic local pain-control may be allowed, 
provided the patient does not meet criteria of progressive disease and treated 
lesions will not be included in the target/non-target lesion assessment 

Other investigational agents

Immunosuppressive therapies, including systemic corticosteroids (except up to a 
25 mg/day prednisone-equivalent dose or when used intermittently in an antiemetic 
regimen, for CNS metastases management or as premedication for imaging studies) 
The following treatments should be avoided, if possible, or used with caution during the 
study:

Derazantinib may inhibit CYP2C8, CYP1A2, or CYP2D6 metabolism, hence co-
administration of derazantinib with drugs known to be substrates of CYP2C8, 
CYP1A2, or CYP2D6 should be avoided or used with caution (see Appendix 4)

Derazantinib may be a substrate and inhibitor of human P-glycoprotein (P-gp), 
therefore co-administration of derazantinib with drugs known to be P-gp substrates with 
narrow therapeutic index should be avoided or used with caution (see Appendix 5)

Drugs with known liver toxicity, e.g., clotrimazole, should be avoided or used with 
caution; if such drugs need to be administered, LFT should be done every 4–5 days 
during the drugs’ co-administration

Drugs with the potential to prolong QT interval (see Appendix 9)
7.8
Potential risks and benefits for study participants
Derazantinib, a multi-kinase inhibitor with activity against FGFR1, FGFR2, mutant 
FGFR2, FGFR3, and mutant FGFR3 kinases, has demonstrated efficacy and an acceptable 
safety profile in nonclinical studies. In clinical trials in iCCA (Mazzaferro 2018, 
Papadopoulos 2017, Droz dit Busset 2020), derazantinib has been shown to be active with 
a manageable safety profile. It is therefore expected that patients may derive a benefit from 
derazantinib monotherapy in the current study.
Hyperphosphatemia, fatigue, ocular disorders, gastrointestinal disorders (constipation, 
diarrhea, nausea, vomiting, stomatitis, and dry mouth), transaminase elevation, 
hypertension, creatinine increased / renal disorders, hyponatremia, nail toxicities and 
alopecia are the most frequently reported adverse drug reactions (ADRs) with FGFR 
inhibitor treatments (Chae 2017, Katoh 2019, Balversa® USPI, Pemazyre® USPI), and are 
considered to be FGFR inhibitor class effects. Of these, hyperphosphatemia, fatigue, ocular 
disorders, blood creatinine increased/renal disorders, hyponatremia, and nail toxicities are 
assessed as important potential risks for derazantinib, and increased transaminases is 
assessed as an important identified risk for derazantinib. The following events are assessed 
as potential risks for derazantinib: QT prolongation, gastrointestinal disorders, 
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and are mostly manageable, and the event alopecia has no significant impact on the 
condition of the patients. Non-clinical and clinical data on QT prolongation rule out a large 
(i.e., mean effect > 20 ms) effect of derazantinib on QTcF. There have been no serious 
events / arrhythmias reported as being consequent to QT prolongation, and the risk is 
mostly preventable with the implemented routine risk minimization measures. As the 
safety data are accumulating and remain subject to final evaluation for ongoing studies 
with derazantinib, the Sponsor will continue to evaluate safety data to characterize further 
potential risks and assess identified risks.
SAFETY ASSESSMENTS
8.1
Definitions
8.1.1
Adverse events
An AE is defined as any untoward medical occurrence in a patient or clinical 
investigational subject administered a pharmaceutical product, and that does not 
necessarily have a causal relationship with study-drug treatment. An AE can therefore be 
any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product.
8.1.2
Serious adverse events
An SAE is any adverse experience occurring at any dose that results in any of the following 
outcomes:

Death

Life-threatening

Requires new inpatient hospitalization defined as a hospital admission lasting 
> 24 hours (not including emergency room visit without hospital admission), or 
prolongation of existing hospitalization

Persistent or significant disability/incapacity

Congenital anomaly/birth defect

Other important medical event that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed above. An important medical event may be 
considered an SAE based upon appropriate medical judgment.
8.1.3
Unexpected adverse event or serious adverse event
An unexpected AE or SAE is one for which the nature or severity of the event is not 
consistent with the applicable product information, as summarized in the Investigator’s 
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8.1.4
Suspected unexpected serious adverse reactions
All AEs that are determined by the Investigator or by the Sponsor as having a reasonable 
suspected causal relationship to a study drug and that are both unexpected and serious 
are considered to be suspected unexpected serious adverse reactions (SUSARs), and are 
subject to expedited regulatory reporting.
8.1.5
Inpatient hospitalization
An inpatient hospitalization is a hospital admission that lasts more than 24 hours.
8.1.6
Study drug-related adverse event or serious adverse event
A study drug-related AE or SAE is defined as an AE or SAE that is definitely, probably, 
or possibly related to the treatment with derazantinib, or when the relationship is unknown.
8.1.7
Further adverse event and serious adverse event definitions
Wherever possible, a specific disease or syndrome rather than individual associated signs 
and symptoms should be identified. However, if an observed or reported sign or symptom 
is not considered a component of a specific disease or syndrome by the Investigator, it 
should be recorded as a separate AE.
Laboratory data are to be collected as stipulated in Section 6.5. Clinical syndromes 
associated with laboratory abnormalities are to be recorded as appropriate (e.g., diabetes 
mellitus instead of hyperglycemia).
Scheduled hospitalizations or elective surgical for a pre-existing condition that is unrelated 
to the disease under study and has not worsened are not considered SAEs.  
Prolongation of a scheduled hospitalization is considered an SAE.
Complications associated with scheduled procedures are considered AEs or SAEs.
Progression of disease is considered an efficacy outcome parameter and should not be 
captured as an AE or SAE unless its outcome is death.
Adverse events, that occur following the execution of the ICF but prior to dosing must be 
recorded in the medical history page of the eCRF; if serious, these must be reported as 
SAEs as described in Section 8.4. Adverse events, including SAEs, that occur after patients 
receive any anti-cancer therapy in the follow-up period, other than the study-defined 
treatments, will not be recorded as AEs or SAEs.
8.2
Responsibilities and procedures
The responsibility for the safety of an individual patient lies in all cases with the 
Investigator. This includes the timely review of all safety data obtained during the course 
of the study.
An Investigator must instruct his/her patients to report any AE and SAE they experience.
Investigators capture, evaluate, and document all AEs and SAEs occurring during a 
patient’s enrollment in the study, commencing with the first day of treatment and including 
the protocol-defined 30-day post-treatment follow-up period, as source documents and on 
designated eCRF pages. SAEs related to study-specific procedures (e.g., tissue biopsy) will 
be reported from the date of signing the informed consent.




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All SAEs will be evaluated by the Sponsor’s Medical Monitor or designee. In the case of 
a SUSAR, the Sponsor or designee will report the event to all pertinent regulatory 
authorities having jurisdiction over ongoing derazantinib trials in an expedited manner 
(within 7 days or 15 days of knowledge) and to all Investigators involved in derazantinib
clinical trials.
The Investigators must in turn notify their governing IRB/IEC.
8.5
Post-treatment safety follow-up
In this study, the post-treatment safety follow-up period is defined as at least 30 days after 
the last dose of assigned treatment. 
All patients will be followed for a minimum of 30 days after discontinuation of the study 
drug. However, if a patient receives other anticancer therapy within the 30-day follow-up 
period, the follow-up for AEs will cease, beginning on the first day of the new therapy. 
Note: Survival follow-up will continue.
Unresolved study-drug-related AEs and SAEs at the end of the 30-day safety follow-up 
period will be followed until they have, in the opinion of the Investigator, resolved to 
baseline or CTCAE Grade 1, stabilized, or are deemed to be irreversible. 
After the follow-up period, only study-drug-related SAEs must be collected and reported; 
these must also be followed until they have, in the opinion of the Investigator, resolved to 
baseline or CTCAE Grade 1, stabilized, or are deemed to be irreversible.
8.6
Grading of severity
Each AE or SAE will be graded for severity according to NCI CTCAE (version 4.03). The 
criteria can be found at http://ctep.cancer.gov/reporting/ctc.html. 
For AEs not listed in the NCI CTCAE version 4.03, a similar grading system should be 
used as follows:

Grade 1: Mild AE

Grade 2: Moderate AE

Grade 3: Severe AE

Grade 4: Life-threatening or disabling AE

Grade 5: Death
For AEs that can be described by the NCI CTCAE guidelines, the NCI CTCAE Grade 4 
(life-threatening or disabling AE) is assessed based on unique clinical descriptions of 
severity for each AE, and these criteria may be different from those used for the assessment 
of AE seriousness. An AE assessed as Grade 4 based on the NCI CTCAE grades may or 
may not be assessed as serious based on the seriousness criteria.
8.7
Assessment of causality
The relationship between an AE and derazantinib will be determined by the Investigator 
on the basis of his/her clinical judgment and following definitions:


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8.7.1
Related adverse events

The AE follows a reasonable temporal sequence from study drug administration and 
cannot be reasonably explained by the patient’s clinical state or other factors 
(e.g., disease under study, concomitant diseases, concomitant medications)

The AE follows a reasonable temporal sequence from study drug administration, and is 
a known reaction to the drug under study or its chemical group, or is predicted by known 
pharmacology, a known reaction to agent, or chemical group

A related AE is any AE considered related to derazantinib, i.e., definitely, possibly, or 
probably related to derazantinib.
8.7.2
Not related adverse events

The AE does not follow a reasonable temporal sequence from study product 
administration, or can be reasonably explained by the patient’s clinical state or other 
factors (e.g., disease under study, concurrent diseases, and concomitant medications).
8.8
Contraception and pregnancy
Derazantinib may have adverse effects on a fetus in utero, and may have transient adverse 
effects on the composition of sperm. 
8.8.1
Contraception 
Participants in this study must be informed that taking the study medication may involve 
unknown risks to the fetus if pregnancy were to occur during the study. In order to be 
enrolled in the study, both male and female patients of child-producing potential must agree 
to the contraception requirements in Inclusion criterion 9, and must comply with these 
requirements from the day of first study medication, or for oral contraception from 14 days 
prior to the first study medication, throughout the study period, and until at least 120 days 
after administration of the last dose of study medication. 
If there is any doubt that a patient of child-producing potential will reliably comply with 
the requirements for contraception, the patient should not be enrolled in the study.
8.8.2
Pregnancy testing
Serum pregnancy testing will be performed for women of child-producing potential at 
the Screening visit (within 72 hours prior to dosing), and the End of Treatment visit 
(see also Section 6.5). In addition, serum- or urine pregnancy testing will be performed 
monthly (on Day 1 of each treatment cycle) while the patient receives study treatment, at 
the 30-day Safety Follow-up visit, and until 120 days after the last administration of study 
drug. Pregnancy testing after the End of Treatment may be performed at the patient’s local 
gynecologist to reduce the burden related to study visits at the site, but must be 
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8.8.3
Pregnancy
If a female patient inadvertently becomes pregnant while on study drug treatment, the 
patient must be immediately discontinued from the study. 
The Investigator must contact the patient at least monthly and document the patient’s status 
until the pregnancy has been completed or terminated. The outcome of the pregnancy must 
be reported to the Sponsor without delay, and within 24 hours if the outcome is a serious 
adverse experience (e.g., death, abortion, congenital anomaly, or other disabling or life-
threatening complication to the mother or newborn). The Investigator must make every 
effort to obtain permission to follow the outcome of the pregnancy and report the condition 
of the fetus or newborn to the Sponsor. If possible, the newborn should be followed up for 
8 weeks after delivery.
If a male patient impregnates his female partner, the Investigator must be informed 
immediately, and the pregnancy reported to the Sponsor and followed up as described 
above.
8.8.4
Nursing women
As it is unknown whether derazantinib is excreted in human milk, because of the potential 
for serious adverse reactions in the nursing infant, patients who are breast-feeding are not 
eligible for enrollment in this study under Exclusion criterion 14.
QUALITY CONTROL AND ASSURANCE
The study will be conducted under the Sponsorship of Basilea. Derazantinib capsules, 
clinical supplies, and eCRFs will be supplied by the Sponsor or its representative.
Representatives of the Sponsor will monitor the study to verify study data, medical records, 
and eCRFs in accordance with current ICH GCP and other applicable regulations and 
guidelines.
PLANNED STATISTICAL METHODS
Details of the statistical analyses presented below will be provided in the study’s statistical 
analysis plan (SAP). A change to the data analysis methods described in the protocol will 
require a protocol amendment only if it alters a principal feature of the protocol. The SAP 
will be finalized prior to database lock. Any changes to the methods described in the plan 
will be described and justified in the final clinical study report.
10.1
Study populations
Four analysis populations will be defined as follows:

Safety/ITT Population: All patients who receive any amount of study drug.

Modified intent-to-treat (mITT) Population: All patients who receive any amount of 
study drug and have at least one post-baseline disease assessment.


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
Per Protocol Population: All patients in the mITT Population who have no major
protocol violations during the study, receive at least one cycle (28 doses) of ARQ 087, 
have at least one post-baseline efficacy measurement, and test positive for FGFR2
fusion by the central laboratory.

PK population: All patients who receive at least 1 dose of study drug and have at least 
one PK sample.
–
Rich PK population (with PK parameter determination): All patients enrolled in the 
subset who receive at least 1 dose of study drug and have at least one PK sample.
–
Urine excretion population: All patients who provide a full 24 h interval urine 
collection on Day 1 of Cycle 2.
10.2
Demographics, 
medical 
history, 
baseline 
characteristics, 
and 
concomitant medications
Demographics, baseline characteristics, and medical history information will be 
summarized for the Safety population using descriptive statistics. No formal statistical 
comparisons will be performed.
Demographic, baseline characteristics, and medical history data for each patient will be 
provided in data listings.
10.3
Safety analyses
The following key safety parameters will be evaluated:

Incidence of TEAEs 

Changes in clinical laboratory parameters, CTCAE graded laboratory toxicities, vital 
signs, ECOG performance status, ECG parameters, physical examinations, and usage 
of concomitant medications
All AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
coding system and displayed in tables and data listings using system organ class (SOC) 
and preferred term (PT). Analyses of AEs will be performed for those events that are 
considered treatment-emergent, where treatment-emergent is defined per protocol as any 
AE or SAE with onset beginning on the day of administration of the first dose of study 
drug, throughout the treatment period until 30 days after cessation of study treatment 
(or until the start of alternate anticancer therapy, whichever occurs earlier), or any event 
that was present at baseline but worsened in intensity or was subsequently considered drug-
related by the Investigator through the end of the study.
The number and percentage of patients with any TEAE, with any TEAE assessed by the 
Investigator as related to treatment (definite, probable, or possible relationship to 
derazantinib, or the relationship is unknown), and with any SAE will be summarized for 
all enrolled patients. In these tabulations, each patient will contribute only once to each of 
the incidence rates in the descriptive analysis, regardless of the number of episodes. 
No formal hypothesis-testing analysis of AE incidence rates will be performed.


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All AEs occurring on-study will be listed in patient data listings. By-patient listings also 
will be provided for the following: patient deaths, SAEs, and AEs leading to withdrawal.
Abnormal findings from physical exams and lab tests will be analyzed using descriptive 
analyses.
10.4
Pharmacokinetic analyses
All patients enrolled in the rich PK subset who receive at least 1 dose of study drug and 
have at least one PK sample will be included for the determination of PK parameters by 
non-compartmental analysis. The following parameters will be determined: Cmax, tmax, 
AUC0-24, AUClast. Of these patients, those that provide 24 h interval urine samples on Cycle 
2 will be included for the determination of urinary excretion parameters: Ae, Ae%, CLR.
Plasma concentrations and PK parameters will be summarized with descriptive statistics, 
including mean, standard deviation, coefficient of variation, median, geometric mean, 
coefficient of variation of geometric mean, minimum and maximum. 
In all other patients who receive at least one dose of study drug and have at least one PK 
sample, plasma concentrations will be summarized separately with descriptive statistics , 
including mean, standard deviation, coefficient of variation, median, geometric mean, 
coefficient of variation of geometric mean, minimum and maximum.
A PopPK analysis will be performed with the possibility of pooling PK data from other 
clinical studies. A separate PopPK analysis report will be provided.
10.5
Pharmacodynamic analyses
Summary statistics including mean, standard deviation, median, coefficient of variation, 
minimum and maximum for baseline, each post-baseline measurement, and change from 
baseline will be performed on serum tumor markers and biomarkers (e.g., CA19.9, CEA, 
CA125, FGF19, FGF21, FGF23) utilizing standard blood chemistry methodologies and 
enzyme-linked immunosorbent assay (ELISA)-based assays. 
To explore the association of blood concentration with clinical outcome, the above 
descriptive statistics of tumor markers and biomarkers will also be presented separately for 
each response category (CR, PR, and stable disease [SD] combined vs. PD). Logistic 
regression will also be utilized if appropriate.
10.6
Efficacy analyses
All efficacy endpoints will be summarized on the data from patients. All analyses will 
include summary statistics, including number of patients (n) and percentage (%) for 
categorical variables and number of patients, mean, standard deviation, median, minimum, 
and maximum for continuous variables. Two-sided exact 95% confidence intervals (CIs) 
based on the large sample assumption will be provided where appropriate. Time-to-event 
analyses will be performed using Kaplan-Meier (KM) methods.


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10.6.1
Primary efficacy parameter
Substudy 1
The primary efficacy endpoint will be ORR, defined as the achievement of confirmed CR 
or PR using RECIST v1.1, as assessed by the central radiology reviewers. Point estimates 
and 2-sided 95% CIs will be provided. Hypothesis testing will be performed for 
H0: ORR=0.1 versus Ha: ORR=0.23 at the interim and final analyses as specified:
The decision rules are specified as: 

If the interim one-sided p-value, p1 > 0.5 (i.e., the observed ORR is less than 10%), the 
trial will stop due to futility; otherwise, the trial will continue to the second stage. At 
the final stage, if the p-value is ≤ to 2.5% (one-sided), or equivalently the lower limit 
of the CI is ≥ 10%, the null hypothesis will be rejected.
In the final analysis, the ITT population will be the primary analysis population.
Substudy 2
The primary efficacy endpoint will be progression-free survival at 3 months (PFS 3) based 
on survival status or central radiology review RECIST 1.1. For Substudy 2, a Simon’s two-
stage design will be used, with approximately 15 patients in Stage 1, and an additional 
28 patients if the study proceeds to Stage 2. H0 will be rejected if a PFS 3 is observed in 
25 or more of these 43 patients. The type I error rate is 0.0481, and power is approximately 
0.8 when the true PFS 3 rate for derazantinib is p1 = 0.65.
The mITT population will be the primary analysis population.
10.6.2
Secondary efficacy parameters
Duration of response, PFS and OS will be presented through use of summary statistics 
using KM methods, to include 25th, 50th (median), and 75th percentiles and associated 
2-sided 95% CIs for the median, number of events and number of censored observations. 
PFS will be defined by RECIST v1.1, based on the date of PD that will be used to determine 
duration. ORR is defined as the achievement of confirmed CR or PR using RECIST v1.1, 
as assessed by the central radiology reviewers.
Changes in HRQOL and symptom response will be analyzed based on the EORTC 
QLQ-C30, QLQ-BIL21, and the EQ-5D VAS, primarily using descriptive statistics. 
10.6.3
Exploratory efficacy analyses
Tumor markers (CA19.9, CA125, CEA) and biomarkers (FGF19, FGF21, FGF23) will be 
analyzed using descriptive statistics by cycle or visit.
Other analyses such as correlation between tumor and biomarkers, toxicity, responses, 
outcomes with derazantinib versus prior chemotherapies, and PK parameters will be 
conducted and will be further described in the Statistical Analysis Plan.


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10.7
Determination of sample size, interim analysis, and adaptations
Substudy 1
To prove the drug effect over placebo in ORR in this single-arm pivotal study, the 
hypothesis is specified as: 
H0: ORR<= 0.10 and Ha: ORR>0.1.
The hypothesis test will be performed at a one-sided 2.5% significance level. A 10% 
response rate is chosen for the null hypothesis, which is much higher than the observed 
placebo rate of 7~8% in larger historical trials and publications (Lamarca 2014). 
A 23% response rate under the alternative hypothesis is estimated for power and sample 
size calculations.
Approximately 100 patients will be enrolled for this two-stage group sequential study with 
futility stopping. An interim analysis for futility will be done when 40 patients who satisfy 
mITT criteria have at least one post-baseline tumor evaluation. The study will be 
terminated for futility if 4 or fewer responses are observed among 40 evaluable patients. If 
the treatment is ineffective, i.e., ORR=0.1, the probability of futility stopping is 63%. If 
the true response rate ORR=0.23, the probability of futility stopping is only 3%. The design 
will provide approximately 90% power to reject the null hypothesis at one-sided 
significance level 0.025, or equivalently to have the lower bound of confidence interval of 
ORR > 10%. 
If 5 or more objective responses are observed and confirmed based on central radiology 
review prior to enrollment of 40 evaluable patients, the interim analysis may be performed 
based on fewer than 40 patients.
Substudy 2
A Simon’s two-stage design will be used in Substudy 2. The null hypothesis (H0) that the 
true 3-month rate of PFS 3 is p0 ≤ 0.45 will be tested against a one-sided alternative. In the 
first stage, approximately 15 mITT-evaluable patients will be accrued. If there are 7 or 
fewer patients with PFS 3 in these 15 patients, then Substudy 2 will be stopped. Otherwise, 
28 additional mITT-evaluable patients will be accrued for a total of up to approximately 
43. H0 will be rejected if a PFS 3 is observed in 25 or more of these 43 patients. The type 
I error rate is 0.0481, and power is approximately 0.8 when the true PFS3 rate for 
derazantinib is p1 = 0.65.
If the required number of patients alive and without disease progression is reached before 
full enrollment to Stage 1, the decision to transition from Stage 1 to Stage 2 may be taken 
before Stage 1 is fully enrolled. 
If the required number of patients alive and without disease progression is not reached at 
the time of full enrollment to Stage 1, further enrollment will be suspended to allow for all 
patients to be evaluated for PFS 3.
10.8
Data Monitoring Committee
The Data Monitoring Committee (DMC) will be established to ensure the safety of study 
patients and the validity of study results. The DMC composition and operation will be 
described in the DMC charter. The DMC may recommend study termination or 
continuation based on periodic review of safety and/or efficacy data in this study.


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COMPLIANCE WITH GOOD
CLINICAL PRACTICE AND 
ETHICAL CONSIDERATIONS
11.1
Institutional Review Board or Independent Ethics Committee approval
The protocol, any protocol modifications, the ICF, and, if applicable, permission to use 
private health information must be approved by the Investigator’s IRB/IEC in compliance 
with Federal regulations 21 CFR §56 prior to study initiation. Documentation of this 
approval must be provided to the Sponsor or its designee, and made available during an 
inspection by the FDA or other regulatory agency inspectors. The Investigator will also 
provide the Sponsor with the General Assurance Number documenting that the IRB/IEC is 
duly constituted, as well as a list of the names, occupations, and affiliations of the members 
of the IRB/IEC when available. 
Before initiating a trial, the Investigator/institution should have written and dated 
approval/favorable opinion from the IRB/IEC and, where applicable, competent 
authorities/regulatory bodies for the trial protocol/amendment(s), written ICF patient
recruitment procedures (e.g., advertisements) and written information to be provided to 
patients.
11.2
Compliance with Good Clinical Practice and ethical considerations
This study must be conducted in compliance with IRB/IEC informed consent regulation 
and the ICH GCP Guidelines. In addition, all local regulatory requirements will be adhered 
to, in particular those affording greater protection to the safety of the trial participants.
This study will also be conducted according to the current revision of the Declaration of 
Helsinki, with all subsequent revisions and with local laws and regulations relevant to the 
use of new therapeutic agents in the country of conduct.
Changes to the protocol will require written IRB/IEC and, where applicable, competent 
authorities/regulatory bodies approval/favorable opinion prior to implementation, except 
when the modification is needed to eliminate an immediate hazard(s) to patients.
11.3
Patient information and consent
The Investigator (or designee) is responsible for the content of the ICF, but the original and 
any updated versions must be approved by the Sponsor prior to submission to the IRB/IEC.
The ICF should also include any additional information required by local laws relating to 
institutional review.
Before any study-related procedures are undertaken, the Investigator or designee must 
obtain written, informed consent from each study participant in accordance with US 
Federal Regulations (21 CFR §50) and the ICH document ‘Guidance for Industry – E6 
Good Clinical Practice: Consolidated Guidance.’ Informed consent will be obtained by 
discussing with the patient the purpose of the study, the risks and benefits, the study 
procedures, and any other information relevant to the patient.
The Investigator or designee must explain to the patient that for purposes of evaluating the 
study results, that patient’s private health information obtained during the study may be 


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shared with the study Sponsor, regulatory agencies, and IRBs/IECs, before enrolling that 
patient into the study. It is the Investigator’s (or designee’s) responsibility to obtain 
permission to use private health information per the Health Information Portability and 
Accountability Act (HIPAA) from each patient, or, if appropriate, the patient’s legal 
representative.
The patient or his/her legal representative will document his/her informed consent by 
signing the current version of the written, IRB-approved ICF in the presence of a witness. 
The person who conducted the informed consent discussion with the patient and/or 
patient’s legal representative must also sign the ICF. The patient is given a fully executed 
copy of the ICF bearing all appropriate signatures, and the original must be maintained in 
the clinical master files at the site.
All active patients participating in the protocol must be re-consented each time the ICF is 
updated and re-approved by the IRB/IEC.
STUDY MANAGEMENT AND MATERIALS
The study will be initiated and conducted under the Sponsorship of Basilea. Derazantinib
capsules, clinical supplies, and eCRFs will be supplied by the Sponsor or its representative.
Representatives of the Sponsor will monitor the study to verify study data, medical records, 
and eCRFs in accordance with current ICH GCP and other applicable regulations and 
guidelines.
12.1
Monitoring, verification of data, audit, and inspection
A Sponsor monitor or designee will periodically visit each clinical study site to discuss the 
progress of the clinical trial and to review eCRFs and original source documents for 
accuracy of data recording, study drug accountability, and correspondence. The extent and 
frequency of monitoring visits will be determined by the Sponsor or designee based on the 
status of the trial and the performance of the site. When requested, the Investigator must 
be available to the study monitor for personal, one-to-one consultation.
Periodically, some or all of the facilities used in the trial may be reviewed or inspected by 
the IRB/IEC and/or regulatory authorities. An audit or inspection may include, for 
example, a review of all source documents, drug records, and original clinical medical 
notes.
The Investigator is to ensure that the trial participants are aware of and consent to the 
review of personal information during the data verification process, as part of the 
monitoring/auditing process conducted by properly authorized agents of the Sponsor, or be 
subject to inspection by regulatory authorities. In addition, participation and personal 
information is treated as strictly confidential to the extent of applicable law and is not 
publicly available.
12.2
Data recording and retention of study data
In compliance with GCP, the medical records/medical notes, and other study-related 
materials should be clearly marked and permit easy identification of participation by an 
individual in a specified clinical trial.


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The Investigator is to record all data with respect to protocol procedures, drug 
administration, laboratory data, safety data, and efficacy ratings on the eCRFs.
If the Investigator relocates or retires, or otherwise withdraws his/her responsibility for 
maintenance and retention of the master clinical study records, the Sponsor must be 
notified in writing so that adequate provision can be made with regard to the trial 
documents.
Trial documents should be retained for at least two years after the approval of a marketing 
application in an ICH region and until there are no pending or planned marketing 
applications in an ICH region, or at least two years have elapsed since the formal 
discontinuation of clinical development of derazantinib by the Sponsor. The documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirements or by an agreement with the Sponsor that it will inform the Investigator, in 
writing, as to when the retention of these documents is no longer necessary.
12.3
Electronic case report forms
An EDC system will be used to collect the data in this study. The EDC system provides 
functionality for the clinical sites to enter the data directly into the eCRFs and respond to 
data discrepancies. Once the data are entered, the information is encrypted and transmitted 
over the Internet to a clinical trial server where it is electronically reviewed. Any resulting 
data queries are immediately sent back to the site for resolution. The system automatically 
keeps a full audit trail of all data changes that occur. The clinical team will undertake 
additional manual review of the data, but all resulting data queries or clarifications will be 
entered into the EDC system for resolution. All eCRFs will be completed according to 
instructions provided in the eCRF Completion Guidelines and ICH GCP guidelines.
12.4
Confidentiality, publication, and disclosure policy
The Investigator understands that the Sponsor will use the information developed in the 
clinical study in connection with the development of derazantinib. This information may 
be disclosed to other clinical Investigators, the FDA, and other government agencies.
All information disclosed to the Investigator by the Sponsor for the purpose of having the 
Investigator conduct the clinical trial described in this protocol, or information generated 
by the Investigator as results in the clinical trial shall be treated by the Investigator as 
strictly confidential. The Investigator shall not use such information other than for the 
purpose of conducting the clinical trial and may not disclose such information to others, 
except when such disclosure is made to colleagues and/or employees who reasonably 
require the information in order to assist in carrying out the clinical trial and who are bound 
by like-obligations of confidentiality. Notwithstanding, the Investigator may use or 
disclose to others any information which: (i) was known to the Investigator prior to the 
date of its disclosure; (ii) is now, or becomes in the future, publicly available; or (iii) is 
lawfully disclosed to the Investigator on a non-confidential basis by a third party who is 
not obligated to the Sponsor or any other party to retain such information in confidence.
The Sponsor acknowledges that the Investigator has certain professional responsibilities to 
report to the scientific community on findings made in the clinical investigations they 
conduct. The Investigator shall have the right to publish the results of research performed 




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1
Consent can be obtained greater than 28 days prior to first dose and does not have to be repeated unless an updated, approved consent form is available. A 
patient can consent for tissue analysis and the full study separately or at the same time.
2
EQ-5D, EORTC QLQ-C30 and QLQ-BIL21 questionnaires should be administered on Day 1 of the first cycle, every 8 weeks (two cycles) for the first six
cycles (C3D1, C5D1, C7D1), once every 12 weeks (three cycles) thereafter (C10D1, C13D1, etc.), at the End of Treatment visit and at the 30 day Safety 
Follow-up. G-SET/HTI questionnaire should be administered on Day 1 of Cycle 3 and Day 1 of Cycle 5. EQ-5D should be completed first, followed by 
EORTC QLQ-C30, QLQ-BIL21 and G-SET/HTI, when applicable.
3
Complete opthalmological examination will be performed at C2D1, C3D1, C4D1, C5D1, at the End of Treatment visit, and at the 30-day Safety Follow-up visit,
and if clinically indicated (see Section 6.3).
4
Vital signs include weight, temperature, blood pressure, respiration rate, and pulse. At the Screening visit, height will also be measured (see Section 6.2).
5
12-lead ECG in triplicate is required at Screening., on Day 1 and Day 15 of Cycle 1 (pre-dose, and approximately 6–8 hours after the dosing), on Day 1 of 
Cycle 2 (pre-dose), on Day 1 of Cycle 3 (pre-dose, and approximately 6–8 hours after the dosing), on Day 1 of Cycle 4 and all subsequent cycles (pre-dose),
and at the End of Treatment visit (see Section 6.4).
6
Clinical safety blood samples will be forwarded to a central laboratory designated by the Sponsor for testing (see Section 6.5).
7
A serum pregnancy test, if applicable, is required at Screening within 72 hours prior to dosing, and at the End of Treatment visit. In addition, serum- or urine 
pregnancy testing will be performed monthly (on Day 1 of each treatment cycle) while the patient receives study treatment, at the 30-day Safety Follow-up 
visit, and until 120 days after the last administration of study drug. (see Section 8.8.2).
8
Blood samples for tumor markers, biomarkers, and ctDNA are only collected on Day 1 of Cycle 1 at pre-dose and every 8 weeks (two cycles) for the first 
six cycles (C3D1, C5D1, C7D1), once every 12 weeks (three cycles) thereafter (C10D1, C13D1, etc.), and at the End of Treatment visit. Blood samples for 
biomarkers and ctDNA will be collected only from patients enrolled after completion of the interim analysis, and subject to the granting of appropriate 
regulatory and IRB/IEC approval (see Section 6.7 and Appendix 3).
9
Blood for sparse PK sampling is collected on C1D1, C1D15 and C3D1 at pre-dose (− 1 hour) and 6–8 hours post-dose. Blood for PK is collected on Day 1 
of Cycles 2 and 4 at pre-dose (− 1 hour) (see Section 6.6 and Appendix 3). Blood for rich PK sampling for the PK/biomarker subgroup is collected on C1D1 
and C2D1 pre-dose (− 1 hour), and 1 (± 5 minutes), 2 (± 5 minutes), 4 (± 15 minutes), 6 (± 15 minutes), 8 (± 30 minutes), 10 (± 30 minutes), 12 (± 30 
minutes), and 24 hours after the daily dose of derazantinib (within 1 hour prior to the next dose), on C1D15 and C3D1, pre-dose (− 1 hour) and between 6 
and 8 hours after the daily dose of derazantinib, and on C4D1 pre-dose (− 1 hour); the 10 and 12 h time-points are optional (see Appendix 3).
10
In the rich PK sampling subset for urinary excretion: Urine for PK is collected on Day 1 of Cycle 2, starting from daily dose administration and until 24 h 
after dosing (immediately prior to the next dose) (see Appendix 3).
11
The patient must test positive for FGFR2 fusion (Substudy 1) or FGFR2 mutation or amplification (Substudy 2). Details of FISH and NGS testing for this 
purpose are provided in Section 6.8, and summarised in Table 1 and Table 2.
12
Tumor imaging assessments must be within 28 days prior to the first dose (see Section 6.9).


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13
Tumor measurement (CT/MRI scan of the chest, abdomen, and pelvis) and staging will be done every 8 weeks (two cycles) for the first six cycles (C3D1, 
C5D1, C7D1) and once every 12 weeks (three cycles) thereafter (C10D1, C13D1, etc.). Post-dose BS / WBMRI will be performed only if clinically 
indicated. If a scan shows CR/PR, a confirmation scan must be performed 4-5 weeks after the last scan was performed (see Section 6.9).
14
Tumor measurement and staging will be performed at the End of Treatment visit only if the previous scan was not done within four weeks (28 days) prior to 
the End of Treatment visit or if the previous scan did not show radiographic disease progression (see Section 6.9).
15
All medications taken within 30 days prior to the first dose are to be recorded.
16
To avoid unnecessary waste of derazantinib capsules, in cases where treatment was interrupted and/or dose was reduced, the patient can continue dosing 
from the previously dispensed bottle until the next drug dispensing visit where re-supply is needed to maintain the protocol dosing regimen.
17
Survival contact can be in person, via phone, or, where applicable, by checking regional/national death registries. All patients and/or family will be contacted 
at 3 month intervals (± 14 days) to record the patient status as Alive (date); Dead (date); Alive, but withdrew consent for further follow up; Lost to Follow 
Up. Survival updates may be made more often than every 3 months if the patient is seen at the investigational site for other reasons and for study level 
survival sweep(s) (see Section 5.6).


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Appendix 2
ECOG Performance Status
ECOG Performance Status scale
Grade
Descriptions
0
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work).
2
In bed < 50% of the time. Ambulatory and capable of all self-care, but unable to 
carry out any work activities. Up and about more than 50% of waking hours.
3
In bed > 50% of the time. Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair.
5
Dead.


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Appendix 3
Pharmacokinetic and pharmacodynamic sampling schedules
BLOOD COLLECTION SCHEDULES FOR PHARMACOKINETIC ASSESSMENTS
IN THE RICH PK SUBSET OF PATIENTS

Cycle 1, Day 1 (FASTED): nine samples
–
One blood draw prior to the first dose of derazantinib (−1 hour)
–
One blood draw each, 1 (± 5 minutes), 2 (± 5 minutes), 4 (± 15 minutes), 
6 (± 15minutes), 8 (± 30 minutes), 10 (± 30 minutes), 12 (± 30 minutes), and 24 hours 
after the first dose of derazantinib (within 1 hour  prior to the next dose); the 10 and 
12 hour time-points are optional.

Cycle 1, Day 15: two samples
–
One blood draw before the daily dose of derazantinib (−1 hour)
–
One blood draw between 6 and 8 hours after the daily dose of derazantinib

Cycle 2, Day 1: nine samples
–
One blood draw prior to the daily dose of derazantinib (−1 hour)
–
One blood draw each, 1 (± 5 minutes), 2 (± 5 minutes), 4 (± 15 minutes), 
6 (± 15 minutes), 8 (±30 minutes), 10 (±30 minutes), 12 (±30 minutes), and 24 hours 
after the first dose of derazantinib (within 1 hour prior to the next dose); the 10 and 12 
hour time-points are optional.

Cycle 3, Day 1: two samples
–
One blood draw before the daily dose of derazantinib (−1 hour)
–
One blood draw between 6 and 8 hours after the daily dose of derazantinib

Cycle 4, Day 1: one sample
–
One blood draw before the daily dose of derazantinib (−1 hour)
URINE COLLECTION SCHEDULE FOR URINARY EXCRETION ASSESSMENTS
IN THE SUBSET OF PATIENTS WITH URINE PK COLLECTION

Cycle 2, Day 1: one pooled sample
–
Patient urinates normally (to waste) prior to administration 
–
Starting from daily dose administration and until 24 h after the daily dose of 
derazantinib, urine is collected; at 24 h the patient voluntarily empties his/her bladder 


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BLOOD COLLECTION SCHEDULES FOR PHARMACOKINETIC ASSESSMENTS
IN ALL OTHER PATIENTS

Cycle 1, Day 1: two samples
–
One blood draw prior to the first dose of derazantinib (−1 hour)
–
One blood draw between 6 and 8 hours after the first dose of derazantinib

Cycle 1, Day 15: two samples
–
One blood draw before the daily dose of derazantinib (−1 hour)
–
One blood draw between 6 and 8 hours after the daily dose of derazantinib

Cycle 2, Day 1: one sample
–
One blood draw before the daily dose of derazantinib (−1 hour)

Cycle 3, Day 1: two samples
–
One blood draw before the daily dose of derazantinib (−1 hour)
–
One blood draw between 6 and 8 hours after the daily dose of derazantinib

Cycle 4, Day 1: one sample (−1 hour)
–
One blood draw before the daily dose of derazantinib
BLOOD COLLECTION SCHEDULES FOR PHARMACODYNAMIC ASSESSMENTS*

Cycle 1, Day 1: pre-dose sample

Cycle 3, Day 1

Cycle 5, Day 1

Cycle 7, Day 1 

Cycle 10, Day 1 and every three cycles (12 weeks) thereafter

End of Treatment
*Note: Blood samples for tumor markers will be collected for all enrolled patients. Blood 
samples for biomarkers and ctDNA will be collected only from patients enrolled after 
completion of the interim analysis, and subject to the granting of appropriate regulatory 
and IRB/IEC approval.


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Appendix 4
Examples of in vivo substrates, inhibitors, and inducers for specific CYP 
enzymes
Inhibitors can be classified by their potency, such as:

Strong inhibitor being one that causes at least a 5-fold increase in the plasma area under 
the curve (AUC) values, or more than 80% decrease in clearance.

Moderate inhibitor being one that causes at least a 2-fold increase in the plasma AUC 
values, or 50–80% decrease in clearance.

Weak inhibitor being one that causes at least a 1.25-fold but less than 2-fold increase in the 
plasma AUC values, or 20–50% decrease in clearance.
Selected inducers, inhibitors, and substrates of CYP2C8
Substrates
Inhibitors
Inducers

Amodiaquine (anti-malarial)

Cerivastatin (statin)

Paclitaxel (anti-tumoral)

Repaglinide (anti-diabetic)

Sorafenib (anti-tumoral)

Torsemide (diuretic)
Strong: 

Gemfibrozil (lipid lowering)
Moderate

trimethoprim (antibiotic)
Unspecified potency:

glitazones (anti-diabetic)

montelukast (anti-asthmatic)

quercetin (antioxidant, supplement)

rifampin  (antibiotic)
Selected inducers, inhibitors, and substrates of CYP1A2
Substrates
Inhibitors
Inducers

many antidepressants 
o
amitriptyline (tricyclic 
antidepressant) 
o
clomipramine (tricyclic 
antidepressant) 
o
imipramine (tricyclic 
antidepressant) 
o
agomelatine 

some atypical antipsychotics 
o
clozapine 
o
olanzapine 

haloperidol (typical 
antipsychotic) 

caffeine (stimulant) 

ropivacaine (local anaesthetic) 

theophylline (xanthine, in 
respiratory diseases) 

zolmitriptan (serotonin receptor 
agonist) 

melatonin (antioxidant, sleep-
inducer) 

tamoxifen (SERM) 

erlotinib (Tarceva, a tyrosine 
kinase inhibitor) 
Strong: 

ciprofloxacin (fluoroquinolone 
bactericidal) 

many other fluoroquinolones (broad-
spectrum antibiotics) 

fluvoxamine (SSRI antidepressant) 

verapamil (calcium channel blocker) 
Weak

cimetidine (H2-receptor antagonist) 
Unspecified potency:

amiodarone (antiarrhythmic agent) 

interferon (antiviral, antiseptic, 
antioncogenic) 

methoxsalen (in psoriasis) 

mibefradil (calcium channel blocker) 

Some foods
o
grapefruit juice (its bitter 
flavanone naringenin)
o
cumin 
o
turmeric 

tobacco 

Some foods
o
broccoli 
o
brussels sprouts 
o
chargrilled meat 
o
cauliflower 

insulin (in diabetes) 

methylcholanthrene 
(carcinogen) 

modafinil (eugeroic) 

nafcillin (beta-lactam 
antibiotic) 

beta-Naphthoflavone 
(chemopreventive) 

omeprazole (proton 
pump inhibitor) 


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Selected inducers, inhibitors, and substrates of CYP1A2
Substrates
Inhibitors
Inducers

cyclobenzaprine (muscle 
relaxant, depressant) 

estradiol (in hypoestrogenism) 

fluvoxamine (SSRI 
antidepressant) 

mexiletine (antiarrhythmic 
agent) 

naproxen (NSAID) 

ondansetron (5-HT3 antagonist) 

phenacetin (analgesic) 

paracetamol (analgesic, 
antipyretic) 

propranolol (beta blocker) 

riluzole (in amyotrophic lateral 
sclerosis) 

tacrine (parasympathomimetic) 

tizanidine (α-2 adrenergic 
agonist) 

verapamil (calcium channel 
blocker) 

warfarin (anticoagulant) 

zileuton (in asthma) 
Selected inducers, inhibitors, and substrates of CYP2D6
Substrates
↑ = bioactivation by CYP2D6
Inhibitors
Inducers

All tricyclic antidepressants, e.g. 
o
imipramine 
o
amitriptyline 
o
etc. 

Most SSRIs (antidepressant), e.g. 
o
fluoxetine 
o
paroxetine 
o
fluvoxamine 

venlafaxine (SNRI antidepressant) 

mianserin (tetracyclic 
antidepressant) 

opioids 
o
codeine↑ into morphine 
o
tramadol↑ 
o
oxycodone 

antipsychotics, e.g. 
o
haloperidol
o
risperidone 
o
perphenazine 
o
thioridazine 
o
zuclopenthixol 
o
iloperidone 
Strong:

SSRIs 
o
fluoxetine 
o
paroxetine 

bupropion (non-SSRI 
antidepressant) 

quinidine (class I antiarrhythmic 
agent) 

cinacalcet (calcimimetic) 

ritonavir (antiretroviral) 
Moderate

sertraline (SSRI) 

duloxetine (SNRI)

terbinafine (antifungal) 
Weak:

buprenorphine (in opioid addiction) 

amiodarone (antiarrhythmic) 

cimetidine (H2-receptor antagonist) 
Unspecified potency:

antipsychotics 
o
haloperidol 

dexamethasone
(glucocorticoid) 

rifampicin (bactericidal) 
Strong:

glutethimid


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Selected inducers, inhibitors, and substrates of CYP2D6
Substrates
↑ = bioactivation by CYP2D6
Inhibitors
Inducers
o
aripiprazole 
o
chlorpromazine 
o
levomepromazine 
o
remoxipride 

minaprine (RIMA antidepressant) 

tamoxifen↑ (SERM) 

beta-blockers 
o
metoprolol 
o
timolol 
o
alprenolol 
o
carvedilol 
o
bufuralol 
o
nebivolol 
o
propranolol 

debrisoquine (antihypertensive) 

Class I antiarrhythmics 
o
flecainide 
o
propafenone 
o
encainide 
o
mexiletine 
o
lidocaine 
o
sparteine 

ondansetron (antiemetic) 

donepezil (acetylcholinesterase 
inhibitor) 

phenformin (antidiabetic) 

tropisetron (5-HT3 receptor 
antagonist) 

amphetamine (in ADHD, 
narcolepsy) 

atomoxetine (in ADHD) 

chlorphenamine (antihistamine) 

dexfenfluramine (serotoninergic 
anorectic) 

dextromethorphan (antitussive) 
into psychoactive dextrorphan 

duloxetine (SNRI) 

metoclopramide (dopamine 
antagonist) 

Methoxyamphetamine 

perhexiline (antianginal agent) 

phenacetin (analgesic) 

promethazine (antihistamine 
antiemetic) 
o
perphenazine 
o
thioridazine 
o
zuclopenthixol 
o
risperidone 
o
chlorpromazine 

bicalutamide 

hyperforin (St. John’s Wort) 

antihistamines (H1-receptor 
antagonists) 
o
Promethazine 
o
chlorphenamine 
o
diphenhydramine 
o
hydroxyzine 
o
tripelennamine 

some SSRI antidepressants 
o
citalopram 
o
escitalopram 

clemastine (antihistamine and 
anticholinergic) 

celecoxib (NSAID) 

clomipramine (tricyclic 
antidepressant) 

cocaine (stimulant) 

doxorubicin (chemotherapeutic) 

metoclopramide (antiemetic, 
prokinetic) 

methadone (analgesic and anti-
addictive) 

moclobemide (antidepressant) 

ranitidine (H2-receptor antagonist) 

doxepin (tricyclic antidepressant, 
anxiolytic) 

halofantrine (in malaria) 

levomepromazine (antipsychotic) 

mibefradil (calcium channel 
blocker) 

midodrine (α1 agonist) 

ticlopidine (antiplatelet) 
Source: http://medicine.iupui.edu/clinpharm/ddis/table.aspx


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Appendix 5
Examples of in vivo substrates, inhibitors, and inducers of P-glycoprotein
Examples of In Vivo Substrates, Inhibitors, and Inducers of P-glycoprotein1
Transporter
Substrates
Inhibitors2
Inducers3
P-gp
(Gene ABCB1)
Aliskiren 
ambrisentan 
colchicine 
dabigatran etexilate
digoxin 
everolimus 
fexofenadine 
imatinib 
lapatinib 
maraviroc, 
nilotinib 
posaconazole 
ranolazine 
saxagliptin 
sirolimus 
sitagliptin 
talinolol 
tolvaptan 
topotecan 
Amiodarone
azithromycin4
captopril
carvedilol
clarithromycin
conivaptan
cyclosporine
diltiazem
dronedarone
erythromycin5
felodipine
itraconazole
ketoconazole4
lopinavir and ritonavir
quercetin4
quinidine
ranolazine
ticagrelor 
verapamil
Avasimibe6
carbamazepine7
phenytoin
rifampin
St John’s wort8
tipranavir/ritonavir
Source: Guidance for Industry: Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing, 
and Labeling Recommendations (http://www fda.gov/downloads/Drugs/GuidanceComplianceRegulatory
Information/Guidances/UCM292362.pdf ).
1
Not an exhaustive list. For an updated list, see the following link: 
http://www fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabelin
g/ucm080499 htm
2
Inhibitors listed for P-gp are those that showed >25% increase in digoxin AUC or otherwise indicated if 
substrate is other than digoxin
3
Inducers listed for P-gp are those that showed >20% decrease in digoxin AUC or otherwise indicated if 
substrate is other than digoxin
4
Inhibitors listed are those that showed >25% increase in fexofenadine AUC
5
Inhibitors listed are those that showed >25% increase in talinolol AUC
6
Not a marketed drug
7
Inducers listed are those that showed >20% decrease in fexofenadine AUC
8
Herbal product


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Appendix 6
Assessment of anti-tumor activity per RECIST v. 1.1
Assessment of tumor responses may be performed following the revised RECIST guidelines, 
version 1.1. Some of these definitions and criteria are highlighted below.
Measurability of tumor baseline

CT with intravenous (IV) contrast and MRI are the best currently available and 
reproducible methods to measure target lesions selected for response assessment.
Conventional CT and MRI should be performed with cuts of 10 mm or less in slice 
thickness contiguously. Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm.

Standard imaging studies should be performed according to the imaging manual provided 
by the central imaging laboratory designated by the Sponsor.
Definitions
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows:
Measurable 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:

10 mm by CT scan (CT scan slice thickness no greater than 5 mm).

10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable).

20 mm by chest X-ray.
Measurable malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed. See also notes below on ‘Baseline documentation 
of target and non-target lesions’ for information on lymph node measurement.
Non-measurable
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with ≥10 to < 15 mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin (nevi) or 
lung, and abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques.


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Special considerations regarding lesion measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment:
Bone lesions
Bone scan, PET scan, or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions.
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above.
Blastic bone lesions are non-measurable.
Cystic lesions
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if noncystic lesions are 
present in the same patient, these are preferred for selection as target lesions.
Lesions with prior local treatment
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are not considered measurable unless there has been demonstrated 
progression in the lesion. 
Specifications by methods of measurements
Measurement of lesions
All measurements should be recorded in metric notation, using calipers if clinically assessed. 
All baseline evaluations should be performed as close as possible to the treatment start and 
NEVER more than 4 weeks before the beginning of the treatment.
Method of assessment
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation 
should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam.
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and ≥ 10 mm diameter as assessed using calipers (e.g., skin (nevi) nodules). For the case of 
skin (nevi) lesions, documentation by color photography including a ruler to estimate the size 
of the lesion is suggested. As noted above, when lesions can be evaluated by both clinical exam 
and imaging, imaging evaluation should be undertaken since it is more objective and may also 
be reviewed at the end of the study.


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Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung.
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. When CT scans have a 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g., for body scans). 
Tumor response evaluation
Assessment of overall tumor burden and measurable disease
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. In this study, 
only patients with measurable disease at baseline should be included in the study. 
Baseline documentation of ‘target’ and ‘non-target’ lesions
When more than one measurable lesion is present at baseline, all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved 
organs should be identified as target lesions and will be recorded and measured at baseline 
(this means in instances where patients have only one or two organ sites involved, a maximum 
of two and four lesions respectively will be recorded). 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), 
be representative of all involved organs, but in addition should be those that lend themselves 
to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance the next largest lesion 
which can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. As noted above, pathological nodes which 
are defined as measurable and may be identified as target lesions must meet the criterion of a 
short axis of ≥ 15 mm by CT scan. Only the short axis of these nodes will contribute to the 
baseline sum. The short axis of the node is the diameter normally used by radiologists to judge 
if a node is involved by solid tumor. Nodal size is normally reported as two dimensions in the 
plane in which the image is obtained (for CT scan this is almost always the axial plane; for 
MRI the plane of acquisition may be axial, sagittal, or coronal). The smaller of these measures 
is the short axis. For example, an abdominal node which is reported as being 20 mm × 30 mm 
has a short axis of 20 mm and qualifies as a malignant, measurable node. In this example, 20 
mm should be recorded as the node measurement. All other pathological nodes (those with 
short axis ≥ 10 mm but < 15 mm) should be considered non-target lesions. Nodes that have a 
short axis < 10 mm are considered non-pathological and should not be recorded or followed.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum of the diameters. If lymph nodes 
are to be included in the sum, then as noted above, only the short axis is added into the sum. 


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The baseline sum of the diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be identified 
as non-target lesions and should also be recorded at baseline. Measurements are not required 
and these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression’ (more details to follow). In addition, it is possible to record multiple non-target 
lesions involving the same organ as a single item on the case record form (e.g., ‘multiple 
enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
Response criteria
This section provides the definitions of the criteria used to determine objective tumor response 
for target lesions.
Evaluation of target lesions

Complete Response: Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm.

Partial Response: At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters.

Progressive Disease: At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more 
new lesions is also considered progression).

Stable Disease: Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. In this study, 
the minimum duration for SD is defined as 8 weeks (± 2 days).
Special notes on the assessment of target lesions
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short 
axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study. This means that when lymph 
nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if complete 
response criteria are met, since a normal lymph node is defined as having a short axis of < 10 
mm. For PR, SD, and PD, the actual short axis measurement of the nodes is to be included in 
the sum of target lesions.
Target lesions that become ‘too small to measure’. While on study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each Response 
Criteria subsequent evaluation, even when very small (e.g., 2 mm). However, sometimes 
lesions or lymph nodes which are recorded as target lesions at baseline become so faint on CT 
scan that the radiologist may not feel comfortable assigning an exact measure and may report 
them as being ‘too small to measure’. When this occurs, it is important that a value be recorded 
on the case report form. If it is the opinion of the radiologist that the lesion has likely 
disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should be assigned 


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(Note: It is less likely that this rule will be used for lymph nodes since they usually have a 
definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too 
small to measure, a default value of 5 mm should be assigned in this circumstance as well). 
This default value is derived from the 5 mm CT slice thickness (but should not be changed 
with varying CT slice thickness). The measurement of these lesions is potentially non-
reproducible, therefore providing this default value will prevent false responses or progressions 
based upon measurement error. To reiterate, however, if the radiologist is able to provide an 
actual measure, that should be recorded, even if it is below 5 mm.
Lesions that split or coalesce on treatment. When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion 
sum. Similarly, as lesions coalesce, a plane between them may be maintained that would aid 
in obtaining maximal diameter measurements of each individual lesion. If the lesions have 
truly coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the ‘coalesced lesion’.
Evaluation of non-target lesions
This section provides the definitions of the criteria used to determine the tumor response for 
the group of non-target lesions. While some non-target lesions may actually be measurable, 
they need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol. 

Complete Response: Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis).

Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits.

Progressive Disease: Unequivocal progression (see comments below) of existing non-
target lesions. (Note: the appearance of one or more new lesions is also considered 
progression).
Special notes on the assessment of progression of non-target disease
The concept of progression of non-target disease requires additional explanation as follows:
When the patient also has measurable disease. In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in the presence of SD or PR in target disease, 
the overall tumor burden has increased sufficiently to merit discontinuation of therapy (see 
further details below). A modest ‘increase’ in the size of one or more non-target lesions is 
usually not sufficient to quality for unequivocal progression status. The designation of overall 
progression solely on the basis of change in non-target disease in the face of SD or PR of target 
disease will therefore be extremely rare. 




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Missing assessments and inevaluable designation
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements is made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not 
change the assigned time point response. This would be most likely to happen in the case of 
PD. For example, if a patient had a baseline sum of 50 mm with three measured lesions and at 
follow-up only two lesions were assessed, but those gave a sum of 80 mm, the patient will 
have achieved PD status, regardless of the contribution of the missing lesion. 
Best overall response: all time points
The best overall response is determined once all the data for the patient are known.
Best response determination in trials where confirmation of complete or partial response IS 
NOT required: Best response in these trials is defined as the best response across all time points 
(for example, a patient who has SD at first assessment, PR at second assessment, and PD on 
last assessment has a best overall response of PR). When SD is believed to be the best response, 
it must also meet the protocol specified minimum time from baseline of 8 weeks. If the 
minimum time is not met when SD is otherwise the best time point response, the patient’s best 
response depends on the subsequent assessments. For example, a patient who has SD at the 
first assessment, PD at second the assessment, and does not meet the minimum duration for 
SD, the patient will have a best response of PD. The same patient lost to follow-up after the 
first SD assessment would be considered inevaluable.
Special notes on response assessment
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ 
size (< 10 mm), they may still have a measurement reported on scans. This measurement 
should be recorded even though the nodes are normal in order not to overstate progression 
should it be based on increase in the size of the nodes. As noted earlier, this means that patients 
with CR may not have a total sum of ‘zero’ on the eCRF.
For patients with PR or CR, the Investigator should make every attempt to perform the 
confirmation scan 4 to 5 weeks after the last scan was performed. Radiographic disease 
progression must be confirmed by central radiology prior to treatment discontinuation if 
progression is seen on first or second post-treatment scan.
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’. Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy. The objective response status of 
such patients is to be determined by evaluation of target and non-target disease.
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.


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Frequency of tumor re-evaluation
In this study, tumor measurement will be conducted at baseline, and once every 8 weeks (every 
two cycles) from the day of the first dose for the first 6 months and once every 12 weeks (every 
three cycles) thereafter while the patient is on treatment or as clinically indicated until 
progression of disease, withdrawal of consent, or death. Tumor measurement will also be 
performed during the End of Treatment visit if it is not done within 28 days of the End of 
Treatment visit date or if prior scan did not show radiographic disease progression.
Baseline tumor assessments must be performed within three weeks (21 days) of the first dose 
of treatment. 
All efforts must be made to ensure consistency between the baseline measurements and all 
subsequent measurements in reference to utilization of scanning methods, equipment, 
technique (including slice thickness and field of view), and the radiographic interpreter.
The radiological evaluation must include CT or MRI scanning of the chest, abdomen, and 
pelvis. Any additional suspected sites of disease should also be imaged. All evaluations must
meet the standard of care for imaging of lesions in the respective organ(s). 
All target and non-target sites are evaluated at each time point of tumor assessment. 
Confirmatory measurement/duration of response
Confirmation
Confirmation of PR and CR is required 4–5 weeks after the initial scan showing PR or CR. 
Duration of overall response
the duration of overall response is measured from the time measurement criteria are first met 
for CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease 
is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded on study).
The duration of overall complete response is measured from the time measurement criteria that 
are first met for CR until the first date that recurrent disease is objectively documented.
Duration of stable disease
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest sum on study (if the baseline sum is the smallest, this is 
the reference for calculation of PD). In this study, the minimum duration for SD is defined as 
8 weeks (± 3 days).


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Appendix 7
Patient-reported outcomes guidelines
These guidelines assume that an appropriate person has been designated to facilitate the self-
administration of the questionnaire.
When and how should the questionnaire be administered?
The QLQ-C30, QLQ-BIL21, EQ-5D, and the G-SET/HTI should be completed by the patient
without assistance during his or her scheduled visits at the clinic. They should be administered 
at the start of the visit, before the patient sees the physician, and on day C1D1 prior to the first 
dose of study medication, so that any interaction between the patient and physician will not 
influence the patient’s responses to the questionnaire. The questionnaires should also be 
administered before the patient is asked about adverse experiences and concurrent illnesses, 
again so that any discussions of health problems do not influence the patient’s responses. The 
QLQ-C30, QLQ-BIL21, and EQ-5D are to be administered on Day 1 of the first cycle, every 
8 weeks (two cycles) for the first six cycles, once every 12 weeks (three cycles) thereafter, and 
at the End of Treatment visit, and at the 30-day Safety Follow-up visit. The G-SET/HTI will 
be administered after 8 weeks (at Cycle 3 Day 1) and 16 weeks (at Cycle 5 Day 1).
A quiet place should be provided for the patient to complete the questionnaire. It is important 
that the patient completes the questionnaire alone, without any advice from family members 
or friends who may accompany them. On average, it takes less than 10 minutes to complete 
each questionnaire.
Patients must have basic fluency in the language of their country in order to complete the QLQ-
C30, QLQ-BIL21, and EQ-5D. If a patient is not able to speak/read the language of his/her 
country, check if the patient has basic fluency in any of the languages in which the 
questionnaire is currently available and which has been approved by the sites IRB/IEC. 
How should the questionnaire be introduced?
A sample script for introducing the questionnaire is given below.
‘Your doctor would like to better understand how you feel, how well you are able to do your 
usual activities, and how you rate your health. To help us better understand these things about 
you, please complete the questionnaires about your health. The questionnaires are easy to fill 
out. The instructions are at the beginning of each questionnaire. You should read each question 
and then circle the appropriate number that matches your answer. Remember that this is not a 
test and there are no right or wrong answers. Choose the answer that best describes the way 
you feel. I will quickly review the questionnaire when you are finished to make sure that all of 
the questions have been answered. You should answer these questions by yourself. Your 
spouse or other family members should not help you when you answer the questionnaire. I will 
be nearby in case you want to ask me any questions. Please return the questionnaires to me 
when you have finished.’
What to do if the patient asks for clarification?
Some patients may ask the meaning of specific questions. If this happens, the staff member 
can assist the patient by re-reading the question for them verbatim. If the patient asks what 
something means, do not try to explain what the question means, but tactfully suggest that the 
patient use his/her own interpretation of the question. All patients should answer the questions 
based on what they think the questions mean, or the study results may be biased.


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17 November 2020
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Page 107 of 114
Questionnaire completion 
When the patient returns the questionnaires, check that all of the questions have been answered. 
If the questionnaires are not complete, point out to the patient that some of the questions were 
not answered. If the patient does not quickly volunteer to answer these items, ask him/her 
whether she had any difficulty completing the questionnaire. If the patient says that he/she had 
trouble understanding a question, ask him/her why he/she had difficulty with that item. Re-
read the question for him/her verbatim, but do not attempt to explain or reword the question, 
as explained before. If the patient is still unable to answer the question, accept the questionnaire 
as is.
Some patients may be confused by the response choices. They may want to respond with 
‘I don’t know’ or some other response choice that is not available. If this happens, try to help 
the patient choose one of the response categories by saying something like: ‘I know that it may 
be difficult for you to choose an answer, but which of these answers do you think comes closest 
to the way that you are thinking or feeling?’ If the patient still cannot select an answer, accept 
the questionnaire as is.
Occasionally, patients may not report having difficulty with a question or the response choices, 
but still may hesitate or refuse to answer an item or items. If this happens, accept the 
questionnaire as is.
If a patient asks for interpretation of his/her responses or asks for his/her scores on the 
questionnaire, tell him/her that you are not trained to score or interpret the questionnaire.
Emphasize that their answers will be kept confidential.
Completed questionnaires
Thank the patient once he/she has completed the questionnaires and you have checked it for 
completeness.


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Clinical Study Protocol
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Protocol Version 9.0
17 November 2020
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 108 of 114
Appendix 8 FGFR2 genetic aberrations eligible for enrollment in Substudy 2
NGS testing will be performed or commissioned by the respective study site using, as
applicable, US FDA-approved and/or fully CE-marked industrial-scale assays. For enrollment 
of patients in the EU, assays must be either fully CE-marked or CE-marked for analytical 
performance, unless assays are exempt from this requirement by the
IVDD
(Directive 98/79/EC), i.e., manufactured and appropriately validated within health-institution 
laboratories for use in that environment and not subject to commercial transactions.
Eligible FGFR2 amplifications
All levels of FGFR2 amplifications. 
Eligible FGFR2 mutations (small variants)
Missense point mutations (substitutions), in-frame deletions, and insertions.
The presence of the following FGFR2 genetic aberrations is an Exclusion criterion even 
in the presence of an eligible mutation/amplification:

Any concurrent FGFR2 translocations.
Note: If the NGS test used cannot identify FGFR2 translocations, a FISH test is mandatory to 
confirm that none are present.

Nonsense and frame-shift variants in exons 1–16, 17 (up to amino acid 761).

Loss-of-function mutations H213Y, V248D, K517R, D530N, I642V, A648T, and R759X.

Large deletions involving exons 11–17.

Splice variants in introns 11–16.


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Protocol Version 9.0
17 November 2020
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Appendix 9
Drugs with the potential to prolong QT and/or cause Torsades de Pointes
Known risk of Torsades de Pointes*
Generic name
Brand name
Generic name
Brand name
Aclarubicin
Aclacin and others
Ibogaine
None
Amiodarone
Cordarone and others
Ibutilide
Corvert
Anagrelide
Agrylin and others
Levofloxacin
Levaquin and others
Arsenic trioxide
Trisenox
Levomepromazine 
(methotrimeprazine)
Nosinan and others
Astemizole
Hismanal
Levomethadyl acetate
Orlaam
Azithromycin
Zithromax and others
Levosulpiride
Lesuride and others
Bepridil
Vascor
Mesoridazine
Serentil
Chloroquine
Aralen
Methadone
Dolophine and others
Chlorpromazine
Thorazine and others
Moxifloxacin
Avelox and others
Cilostazol
Pletal
Ondansetron
Zofran and others
Ciprofloxacin
Cipro and others
Oxaliplatin
Eloxatin
Cisapride
Propulsid
Papaverine HCl 
(Intra-coronary)
None
Citalopram
Celexa and others
Pentamidine
Pentam
Clarithromycin
Biaxin and others
Pimozide
Orap
Cocaine
Cocaine
Probucol
Lorelco
Disopyramide
Norpace
Procainamide
Pronestyl and others
Dofetilide
Tikosyn
Propofol
Diprivan and others
Domperidone
Motilium and others
Quinidine
Quinaglute and others
Donepezil
Aricept
Roxithromycin
Rulide and others
Dronedarone
Multaq
Sevoflurane
Ultane and others
Droperidol
Inapsine and others
Sotalol
Betapace and others
Erythromycin
E.E.S. and others
Sparfloxacin
Zagam
Escitalopram
Cipralex and others
Sulpiride
Dogmatil and others
Flecainide
Tambocor and others
Sultopride
Barnetil and others
Fluconazole
Diflucan and others
Terfenadine
Seldane
Gatifloxacin
Tequin
Terlipressin
Teripress and others
Grepafloxacin
Raxar
Terodiline
Micturin and others
Halofantrine
Halfan
Thioridazine
Mellaril and others
Haloperidol
Haldol and others
Vandetanib
Caprelsa
* Source: CredibleMeds® (https://www.crediblemeds.org).


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Clinical Study Protocol
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Protocol Version 9.0
17 November 2020
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
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Possible risk of  Torsades de Pointes*
Generic name
Brand name
Generic name
Brand name
Abarelix
Plenaxis
Dexmedetomidine
Precedex and others
Alfuzosin
Uroxatral
Dextromethorphan/
Quinidine
Nuedexta
Apalutamide
Erleada
Dolasetron
Anzemet
Apomorphine
Apokyn and others
Efavirenz
Sustiva and others
Aripiprazole
Abilify and others
Eliglustat
Cerdelga
Artemether + Lumefantrine
Coartem
Encorafenib
Braftovi
Artenimol+piperaquine
Eurartesim
Epirubicin
Ellence and others
Asenapine
Saphris and others
Eribulin mesylate
Halaven
Atomoxetine
Strattera
Ezogabine (Retigabine)
Potiga and others
Bedaquiline
Sirturo
Felbamate
Felbatol
Bendamustine
Treanda and others
Fingolimod
Gilenya
Benperidol
Anquil and others
Fluorouracil (5-FU)
Adrucil and others
Betrixaban
Bevyxxa
Flupentixol
Depixol and others
Bortezomib
Velcade and others
Gemifloxacin
Factive
Bosutinib
Bosulif
Glasdegib
Daurismo
Buprenorphine
Butrans and others
Granisetron
Kytril and others
Cabozantinib
Cometriq
Hydrocodone - ER
Hysingla ER and others
Capecitabine
Xeloda
Iloperidone
Fanapt and others
Ceritinib
Zykadia
Imipramine (melipramine) Tofranil
Clofazimine
Lamprene
Inotuzumab ozogamicin
Besponsa
Clomipramine
Anafranil
Isradipine
Dynacirc
Clotiapine
Entumine
Ketanserin
Sufrexal
Clozapine
Clozaril and others
Lacidipine
Lacipil and others
Crizotinib
Xalkori
Lapatinib
Tykerb and others
Cyamemazine 
(cyamepromazine)
Tercian
Lenvatinib
Lenvima
Dabrafenib
Tafinlar
Leuprolide
Lupron and others
Dasatinib
Sprycel
Lithium
Eskalith and others
Degarelix
Firmagon and others
Lopinavir and ritonavir
Kaletra and others
Delamanid
Deltyba
Maprotiline
Ludiomil and others
Desipramine
Pertofrane and others
Melperone
Bunil and others
Deutetrabenazine
Austedo
Memantine
Namenda XR and others
(Continued)
* Source: CredibleMeds® (https://www.crediblemeds.org).


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17 November 2020
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Possible risk of  Torsades de Pointes (continued)*
Generic name
Brand name
Generic name
Brand name
Midostaurin
Rydapt
Rilpivirine
Edurant and others
Mifepristone
Korlym and others
Risperidone
Risperdal
Mirabegron
Myrbetriq
Romidepsin
Istodax
Mirtazapine
Remeron
Saquinavir
Invirase(combo)
Moexipril/HCTZ
Uniretic and others
Sertindole
Serdolect and others
Necitumumab
Portrazza
Sorafenib
Nexavar
Nicardipine
Cardene
Sunitinib
Sutent
Nilotinib
Tasigna
Tacrolimus
Prograf and others
Norfloxacin
Noroxin and others
Tamoxifen
Nolvadex and others
Nortriptyline
Pamelor and others
Telavancin
Vibativ
Nusinersen
Spinraza
Telithromycin
Ketek
Ofloxacin
Floxin
Tetrabenazine
Nitoman and others
Osimertinib
Tagrisso
Tiapride
Tiapridal and others
Oxytocin
Pitocin and others
Tipiracil and Trifluridine
Lonsurf
Paliperidone
Invega and others
Tizanidine
Zanaflex and others
Palonosetron
Aloxi
Tolterodine
Detrol and others
Panobinostat
Farydak
Toremifene
Fareston
Pasireotide
Signifor
Tramadol
Crispin and others
Pazopanib
Votrient
Trimipramine
Surmontil and others
Perflutren lipid 
microspheres
Definity and others
Tropisetron
Navoban and others
Perphenazine
Trilafon and others
Valbenazine
Ingrezza
Pilsicainide
Sunrythm
Vardenafil
Levitra
Pimavanserin
Nuplazid
Vemurafenib
Zelboraf
Pipamperone
Dipiperon and others
Venlafaxine
Effexor and others
Primaquine phosphate
None
Vorinostat
Zolinza
Promethazine
Phenergan
Zotepine
Losizopilon and others
Prothipendyl
Dominal and others
Zuclopent(h)ixol
Cisordinol and others
Ribociclib
Kisqali
* Source: CredibleMeds® (https://www.crediblemeds.org).


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Clinical Study Protocol
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Protocol Version 9.0
17 November 2020
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 112 of 114
Conditional risk of  Torsades de Pointes*
Generic name
Brand name
Generic name
Brand name
Amantadine
Symmetrel and others
Ketoconazole
Nizoral and others
Amisulpride
Solian and others
Lansoprazole
Prevacid
Amitriptyline
Elavil and others
Loperamide
Imodium and many other 
OTC and Rx brands
Amphotericin B
Fungilin and others
Metoclopramide
Reglan and others
Amsacrine (acridinyl 
anisidide)
Amsidine
Metolazone
Zytanix and others
Atazanavir
Reyataz and others
Metronidazole
Flagyl and many others
Bendroflumethiazide or 
bendrofluazide
Aprinox and others
Nelfinavir
Viracept
Chloral hydrate
Aquachloral and others
Olanzapine
Zyprexa and others
Cimetidine
Tagamet and others
Omeprazole
Losec and others
Diphenhydramine
Benadryl and others
Pantoprazole
Protonix and others
Doxepin
Sinequan and others
Paroxetine
Paxil and others
Eperisone
Myonal and others
Piperacillin/Tazobactam
Tazosyn and Zosyn
Esomeprazole
Nexium and others
Posaconazole
Noxafil and others
Famotidine
Pepcid and others
Propafenone
Rythmol SR and others
Fluoxetine
Prozac and others
Quetiapine
Seroquel
Fluvoxamine
Faverin and others
Quinine sulfate
Qualaquin
Furosemide (frusemide)
Lasix and others
Ranolazine
Ranexa and others
Galantamine
Reminyl and others
Sertraline
Zoloft and others
Garenoxacin
Geninax
Solifenacin
Vesicare
Hydrochlorothiazide
Apo-Hydro and others
Telaprevir
Incivo and others
Hydroxychloroquine
Plaquenil and others
Torsemide (torasemide)
Demadex and others
Hydroxyzine
Atarax and others
Trazodone
Desyrel and others
Indapamide
Lozol and others
Voriconazole
VFend
Itraconazole
Sporanox and others
Ziprasidone
Geodon and others
Ivabradine
Procoralan and others
* Source: CredibleMeds® (https://www.crediblemeds.org).


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Clinical Study Protocol
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Protocol Version 9.0
17 November 2020
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 113 of 114
Appendix 10 Sponsor’s signature
Study Title:
A pivotal study of derazantinib in patients with inoperable or 
advanced intrahepatic cholangiocarcinoma and FGFR2 gene 
fusions or FGFR2 gene mutations or amplifications
Study Number:
DZB-CS-301
Version / Date:
Protocol Version 9.0 / 17 November 2020


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Clinical Study Protocol
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Protocol Version 9.0
17 November 2020
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 114 of 114
Appendix 11 Investigator’s signature
Study Title:
A pivotal study of derazantinib in patients with inoperable or 
advanced intrahepatic cholangiocarcinoma and FGFR2 gene 
fusions or FGFR2 gene mutations or amplifications
Study Number:
DZB-CS-301
Version / Date:
Protocol Version 9.0 / 17 November 2020
I have read the protocol described above. I agree to comply with all applicable regulations and 
to conduct the study as described in the protocol. 
Signed by:
Printed Name of Investigator
Signature:
Date:
Investigator
DD/MMM/YYYY

SAP_001.pdf: 
 
 
 
 
 
BASILEA PHARMACEUTICA 
STATISTICAL ANALYSIS PLAN 
A PIVOTAL STUDY OF DERAZANTINIB IN PATIENTS WITH INOPERABLE OR 
ADVANCED INTRAHEPATIC CHOLANGIOCARCINOMA AND FGFR2 GENE 
FUSIONS OR FGFR2 GENE MUTATIONS OR AMPLIFICATIONS  
 
DZB-CS-301 (formerly ARQ 087-301) 
LABCORP STUDY ID: 000000154565 
DOCUMENT VERSION: Final 
DOCUMENT DATE: 23 August 2022 
 
AUTHOR: 
 
 
 
 
LABCORP CLINICAL DEVELOPMENT LIMITED 
 
 


 
 
 
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STATISTICAL ANALYSIS PLAN 
 
 
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BASILEA PHARMACEUTICA: DZB-CS-301 
 
 
 
     PAGE 2 OF 35 
 
 
 
 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................................................... 4 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................ 6 
1.1 
STUDY DESIGN .............................................................................................................................. 6 
1.2 
OBJECTIVES ................................................................................................................................ 11 
1.2.1 
Primary objective ........................................................................................................................... 11 
1.2.2  
Secondary objectives ..................................................................................................................... 11 
1.2.3 
Exploratory objectives .................................................................................................................... 11 
1.3 
STUDY ENDPOINTS ..................................................................................................................... 12 
1.3.1 
Primary Endpoints ......................................................................................................................... 12 
1.3.2 
Secondary Efficacy Endpoints ....................................................................................................... 12 
1.3.3 
Exploratory Efficacy Endpoints ...................................................................................................... 12 
1.3.4 
Safety Endpoints ............................................................................................................................ 13 
1.4 
SAMPLE SIZES AS PER PROTOCOL, INTERIM ANALYSIS AND DATA MONITORING 
COMMITTEE ................................................................................................................................. 13 
2 
ANALYSIS POPULATIONS ......................................................................................................... 15 
2.1 
SAFETY/INTENT-TO-TREAT POPULATION (ITT) ...................................................................... 15 
2.2 
MODIFIED INTENT-TO-TREAT (MITT) POPULATION ................................................................ 15 
2.3 
PER PROTOCOL (PP) POPULATION .......................................................................................... 15 
3 
STATISTICAL AND ANALYTICAL PROCEDURES .................................................................... 16 
3.1 
GENERAL STATISTICAL CONSIDERATIONS ............................................................................ 16 
3.1.1 
Statistical Methods ......................................................................................................................... 16 
3.1.2 
Definition of Baseline ..................................................................................................................... 16 
3.1.3 
Visit Windows ................................................................................................................................ 16 
3.1.4 
Handling of Dropouts and Missing Data ........................................................................................ 16 
3.2 
STATISTICAL METHODS ............................................................................................................. 17 
3.2.1 
Disposition of Patients and Analysis Populations .......................................................................... 17 
3.2.2 
Demographics and Baseline Characteristics ................................................................................. 17 


 
 
 
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3.2.3 
Medical History (Non-Cancer Related) .......................................................................................... 18 
3.2.4 
Cancer-Related Medical History .................................................................................................... 18 
3.2.5 
Prior and Concomitant Medications, and Non-Drug Treatments/Procedures ............................... 18 
3.2.6 
Study Drug Exposure and Compliance ......................................................................................... 19 
3.2.7 
Analyses of Efficacy Variables ...................................................................................................... 20 
3.2.7.1 
Analysis of Primary Efficacy Variable ............................................................................................ 20 
3.2.7.2 
Analyses of Secondary Efficacy Variables .................................................................................... 25 
3.2.7.3 
Exploratory Analyses ..................................................................................................................... 29 
3.2.8 
Analyses of Safety Data ................................................................................................................ 30 
3.2.8.1 
Adverse Events .............................................................................................................................. 30 
3.2.8.2 
Laboratory Variables ...................................................................................................................... 31 
3.2.8.3 
Vital Sign Variables ........................................................................................................................ 32 
3.2.8.4 
Electrocardiogram (ECG) .............................................................................................................. 32 
3.2.8.5 
ECOG ............................................................................................................................................ 33 
3.2.8.6 
Other Safety Variables ................................................................................................................... 33 
4 
CHANGES FROM PLANNED ANALYSIS ................................................................................... 34 
5 
REFERENCES .............................................................................................................................. 35 
 


 
 
 
 
 
 
                                      
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical (drug classification system) 
BICR 
Blinded Independent Central Review 
BMI 
Body mass index 
CCG 
Clinical change group 
cm 
centimeter 
CR 
Complete response 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating tumor deoxyribonucleic acid 
DCR 
Disease control rate 
DMC 
Data monitoring committee 
DoR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
End of treatment 
EORTC 
European Organization for Research and Treatment of Cancer 
EQ-5D (5L) 
EuroQol five-dimension scale five-level 
FISH 
Fluorescence in situ hybridization 
GA 
Genetic aberration 
G-SET 
Global Self Evaluated Transition  
H0 
Null hypothesis  
HA 
Alternative hypothesis  
HRQoL 
Health-related quality of life 
HTI 
Health Transition Index  
iCCA 
Intrahepatic cholangiocarcinoma 
IEC 
Independent Ethics Committee 
IPD 
Important protocol deviation 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
kg 
Kilogram 
kg/m2 
Kilogram per meter squared 
LDH 
Lactate dehydrogenase 
LLN 
Lower limit of normal 
LFT 
Liver function test(s) 
m2 
Meter squared 
max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
Minimum 


 
 
 
 
 
 
                                      
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MID 
Minimally important difference 
mITT 
Modified intent-to-treat 
mg 
Milligram 
mmHg 
Millimeter of mercury 
MRI 
Magnetic resonance imaging 
n 
Number of available observations 
NE 
Not evaluable  
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NGS 
Next-generation sequencing 
OR 
Objective response 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression free survival 
PFS3 
Progression free survival at 3 months 
PK 
Pharmacokinetics 
PopPK 
Population pharmacokinetics 
PP 
Per protocol 
PR 
Partial response 
PT 
Preferred term 
Q1 
First quartile 
Q3 
Third quartile 
QD 
Once daily 
QTc 
Corrected QT Interval 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RS 
Raw score 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
s.d. 
Standard deviation 
SD 
Stable disease 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
TTP 
Time to progression 
ULN 
Upper limit of normal  
VAS 
Visual analog scale 
WHODRUG 
Who Drug Dictionary 


 
 
 
 
 
 
                                      
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1 
OVERVIEW AND INVESTIGATIONAL PLAN 
This statistical analysis plan (SAP) was created based on Protocol DZB-CS-301, Version 9.0, Amendment 
8.0 dated 17 November 2020. It provides a comprehensive and detailed description of the planned statistical 
analysis for the above mentioned protocol. 
1.1 
STUDY DESIGN 
This is a multi-center, open label, single arm, Phase 2 study evaluating derazantinib in adult patients with 
inoperable or advanced intrahepatic cholangiocarcinoma (iCCA) and FGFR2 genetic aberrations (GAs). 
 Substudy 1 enrolls patients with FGFR2 fusions.   
 Substudy 2 enrolls patients with FGFR2 mutations or amplifications 
Substudy 1 was considered pivotal and will enroll approximately 100 patients to determine the objective 
response rate (ORR). 
Substudy 2 will use a Simon’s two-stage design, with approximately 15 modified intent-to-treat (mITT) -
evaluable patients in Stage 1, and an additional 28 mITT-evaluable patients if the study proceeds to Stage 2.   
Patient eligibility will be assessed in two steps: 1) Molecular pre-screening to confirm FGFR2 GA status 
(FGFR2 fusions, or FGFR2 mutations/amplifications; see Table 1 and Table 2, and Appendix 8 from the 
protocol) using validated/approved genetic testing devices; and 2) clinical screening procedures to confirm 
study treatment eligibility is confirmed by the tumor’s FGFR2 GA status. 
Molecular pre-screening for FGFR2 fusions in Substudy 1 may be based on local or central testing. If 
pre-screening is performed based on a local test, then a central confirmation by the FGFR2 break-apart 
fluorescence in situ hybridization (FISH) Probe Kit test is required for Substudy 1 (FGFR2 fusions). 
Molecular pre-screening for FGFR2 mutations/amplifications in Substudy 2 should be based on 
next-generation sequencing (NGS) testing performed or commissioned by the respective study site.  
Patients may be prescreened for the tumor’s FGFR2 GA status (prior to initiation of or during ongoing 
systemic therapy). If the patient is still receiving prior systemic therapy, clinical screening procedures will 
be delayed until radiographically confirmed disease progression or intolerance to the ongoing systemic 
therapy is documented. After the study treatment eligibility is confirmed, patients will be enrolled and 
treated with continuous 300 mg once daily (QD) of derazantinib capsules. A treatment cycle is defined as 28 
days. Patients will receive treatment with derazantinib capsules until death, radiographic disease 
progression, unacceptable toxicity, or until another of the specified criteria is met for stopping therapy. 
If the locally-documented FGFR2 gene fusion positive status was tested and not confirmed by FISH 
(Substudy 1) by the central laboratory designated by the Sponsor after the commencement of study 
treatment, these patients will be assessed on a case-by-case basis. 
It is expected that most patients will receive between 1 and 8 months of treatment with derazantinib 
capsules. Dose delays and/or reductions will be allowed when derazantinib-related toxicity is observed.  
During the treatment period, patients will be evaluated every 2 weeks for the first cycle (Cycle 1 Days 1 and 
15), and once every cycle thereafter (Day 1 of each cycle). 


 
 
 
 
 
 
                                      
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Tumor measurements will be done at Screening (within 28 days prior to the first dose of derazantinib), once 
every 8 weeks (two cycles) from the day of the first dose for the first 6 cycles and once every 12 weeks 
(three cycles) thereafter. For patients with partial response (PR) or complete response (CR), the Investigator 
should perform a confirmation tumor measurement 4 to 5 weeks after the scan showing PR or CR. For 
patients with progressive disease (PD) per Investigator assessment, a central radiology reviewer 
confirmation should be received prior to the patient’s discontinuation from the study drug if progression is 
seen on the first or second on-treatment scan. Patients who discontinue study drug for a reason other than 
radiographic disease progression, withdrawal of consent, death, or loss to follow-up, and have not had their 
end of treatment (EOT) visit, should continue tumor evaluation visits if possible every 8–12 weeks until they 
start another anti-cancer therapy, experience disease progression, withdraw consent, die, or are lost to 
follow-up.  
Pharmacodynamic assessment will include evaluation of tumor markers (CA19.9, CA125, CEA), 
biomarkers (FGF19, FGF21, FGF23), and cell-free circulating tumor deoxyribonucleic acid (ctDNA). Blood 
samples for tumor markers will be collected for all enrolled patients. Blood samples for PD assessments will 
be collected only from patients enrolled after completion of the interim analysis, and subject to the granting 
of appropriate regulatory and Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
approval. These blood samples will be collected on Day 1 of the first cycle, every 8 weeks (two cycles) for 
the first six cycles, once every 12 weeks (three cycles) thereafter, and at the End of Treatment visit. All 
collected samples will be evaluated in batches either during or at the end of the study. 
Archival tumor tissue samples will be obtained for all patients to enable additional molecular analyses with 
regard to the identified GAs and markers predictive of response at the laboratories selected by the Sponsor.  
In addition, further information on the molecular status of the tumor, including available full NGS reports 
will be collected. 
To determine the population pharmacokinetics (PopPK) parameters of derazantinib, blood samples will be 
collected on Day 1 and Day 15 of Cycle 1, and on Day 1 of Cycles 2, 3, and 4. Exploratory assessments of 
metabolites of derazantinib will also be investigated from these PK plasma samples.  
All patients will be scheduled for sparse PK sampling. A subset of up to 20 patients (PK subgroup) will be 
asked to participate in rich PK sampling and/or urinary PK sampling. 
Health-related quality of life (HRQoL) and symptom response will be measured using the QLQ-C30, 
QLQ-BIL21, and the EuroQol five-dimension scale five-level (EQ-5D) (5L). The Global Self Evaluated 
Transition (G-SET) / Health Transition Index (HTI) is a single item, and will be used as an external anchor 
to determine the minimal important difference of the EQ-5D visual analog scale (VAS), European 
Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, and QLQ-BIL21 scales. 
Safety follow-up will be conducted at least 30 days after the administration of the last dose of study drug. 
Safety follow-up will include collection of adverse events (AEs) and changes in concomitant medication. 
Survival follow-up will start the day of the last dose of derazantinib; it will continue until the study has 
completed or other discontinuation criteria are met. 
Assessments and procedures during all cycles are performed according to the Schedule of Assessments in 
Table 1 unless otherwise indicated. 
Note: C1D1 denotes Cycle 1, Day 1, CXDX denotes Cycle X, Day X. 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 1 Schedule of Assessments 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1 Consent can be obtained greater than 28 days prior to first dose and does not have to be repeated unless an updated, approved consent form is available. A patient can 
consent for tissue analysis and the full study separately or at the same time. 
2 EQ-5D, EORTC QLQ-C30 and QLQ-BIL21 questionnaires should be administered on Day 1 of the first cycle, every 8 weeks (two cycles) for the first six cycles (C3D1, 
C5D1, C7D1), once every 12 weeks (three cycles) thereafter (C10D1, C13D1, etc.), at the End of Treatment visit and at the 30 day Safety Follow-up. G-SET/HTI 
questionnaire should be administered on Day 1 of Cycle 3 and Day 1 of Cycle 5. EQ-5D should be completed first, followed by EORTC QLQ-C30, QLQ-BIL21 and G-
SET/HTI, when applicable. 
3 Complete opthalmological examination will be performed at C2D1, C3D1, C4D1, C5D1, at the End of Treatment visit, and at the 30-day Safety Follow-up visit, and if 
clinically indicated (see Section 6.3 from the protocol). 
4 Vital signs include weight, temperature, blood pressure, respiration rate, and pulse. At the Screening visit, height will also be measured (see Section 6.2 from the protocol). 
5 12-lead ECG in triplicate is required at Screening., on Day 1 and Day 15 of Cycle 1 (pre-dose, and approximately 6–8 hours after the dosing), on Day 1 of Cycle 2 (pre-
dose), on Day 1 of Cycle 3 (pre-dose, and approximately 6–8 hours after the dosing), on Day 1 of Cycle 4 and all subsequent cycles (pre-dose), and at the End of Treatment 
visit (see Section 6.4 from the protocol). 
6 Clinical safety blood samples will be forwarded to a central laboratory designated by the Sponsor for testing (see Section 6.5 from the protocol). 
7 A serum pregnancy test, if applicable, is required at Screening within 72 hours prior to dosing, and at the End of Treatment visit. In addition, serum- or urine pregnancy 
testing will be performed monthly (on Day 1 of each treatment cycle) while the patient receives study treatment, at the 30-day Safety Follow-up visit, and until 120 days after 
the last administration of study drug. (see Section 8.8.2 from the protocol). 
8 Blood samples for tumor markers, biomarkers, and ctDNA are only collected on Day 1 of Cycle 1 at pre-dose and every 8 weeks (two cycles) for the first six cycles (C3D1, 
C5D1, C7D1), once every 12 weeks (three cycles) thereafter (C10D1, C13D1, etc.), and at the End of Treatment visit. Blood samples for biomarkers and ctDNA will be 
collected only from patients enrolled after completion of the interim analysis, and subject to the granting of appropriate regulatory and IRB/IEC approval (see Section 6.7 and 
Appendix 3 from the protocol). 
9 Blood for sparse PK sampling is collected on C1D1, C1D15 and C3D1 at pre-dose (− 1 hour) and 6–8 hours post-dose. Blood for PK is collected on Day 1 of Cycles 2 and 
4 at pre-dose (− 1 hour) (see Section 6.6 and Appendix 3). Blood for rich PK sampling for the PK/biomarker subgroup is collected on C1D1 and C2D1 pre-dose (− 1 hour), 
and 1 (± 5 minutes), 2 (± 5 minutes), 4 (± 15 minutes), 6 (± 15 minutes), 8 (± 30 minutes), 10 (± 30 minutes), 12 (± 30 minutes), and 24 hours after the daily dose of 
derazantinib (within 1 hour prior to the next dose), on C1D15 and C3D1, pre-dose (− 1 hour) and between 6 and 8 hours after the daily dose of derazantinib, and on C4D1 
pre-dose (− 1 hour); the 10 and 12 h time-points are optional (see Appendix 3 from the protocol). 
10 In the rich PK sampling subset for urinary excretion: Urine for PK is collected on Day 1 of Cycle 2, starting from daily dose administration and until 24 h after dosing 
(immediately prior to the next dose) (see Appendix 3 from the protocol). 
11 The patient must test positive for FGFR2 fusion (Substudy 1) or FGFR2 mutation or amplification (Substudy 2). Details of FISH and NGS testing for this purpose are 
provided in Section 6.8, and summarised in Table 1 and Table 2 from the protocol. 
12 Tumor imaging assessments must be within 28 days prior to the first dose (see Section 6.9 from the protocol). 
13 Tumor measurement (CT/MRI scan of the chest, abdomen, and pelvis) and staging will be done every 8 weeks (two cycles) for the first six cycles (C3D1, C5D1, C7D1) 
and once every 12 weeks (three cycles) thereafter (C10D1, C13D1, etc.). Post-dose BS / WBMRI will be performed only if clinically indicated. If a scan shows CR/PR, a 
confirmation scan must be performed 4-5 weeks after the last scan was performed (see Section 6.9 from the protocol). 
14 Tumor measurement and staging will be performed at the End of Treatment visit only if the previous scan was not done within four weeks (28 days) prior to the End of 
Treatment visit or if the previous scan did not show radiographic disease progression (see Section 6.9 from the protocol). 
15 All medications taken within 30 days prior to the first dose are to be recorded. 
16 To avoid unnecessary waste of derazantinib capsules, in cases where treatment was interrupted and/or dose was reduced, the patient can continue dosing from the 
previously dispensed bottle until the next drug dispensing visit where re-supply is needed to maintain the protocol dosing regimen. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
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17 Survival contact can be in person, via phone, or, where applicable, by checking regional/national death registries. All patients and/or family will be contacted at 3 month 
intervals (± 14 days) to record the patient status as Alive (date); Dead (date); Alive, but withdrew consent for further follow up; Lost to Follow Up. Survival updates may be 
made more often than every 3 months if the patient is seen at the investigational site for other reasons and for study level survival sweep(s) (see Section 5.6 from the 
protocol). 
 


 
 
 
 
 
 
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1.2 
OBJECTIVES 
1.2.1 Primary objective 
Substudy 1 
• 
To evaluate the anti-cancer activity of ORR by central radiology review as per Response Evaluation 
Criteria in Solid Tumors (RECIST) version 1.1 in patients with inoperable or advanced iCCA whose 
tumors harbor FGFR2 fusions and who received at least one prior regimen of systemic therapy. 
Substudy 2 
• 
To evaluate the anti-tumor activity of derazantinib by progression-free survival (PFS) at 3 months 
(PFS3) based on survival status or central radiology review (RECIST version 1.1) in patients with 
inoperable or advanced iCCA whose tumors harbor FGFR2 mutations or amplifications, and who 
received at least one prior regimen of systemic therapy. 
1.2.2  Secondary objectives 
Substudy 1 and Substudy 2 
• 
To evaluate PFS by central radiology review and overall survival (OS) 
• 
To evaluate duration of response (DoR) by central radiology review 
• 
To evaluate the safety profile (toxicities) of derazantinib in this patient population 
• 
To evaluate changes, and assess the minimally important difference, in HRQoL and symptom 
response from baseline using the EORTC QLQ-C30, QLQ-BIL21, G-SET / HTI, and the EQ-5D 
VAS  
 
Substudy 2 
 
• 
To evaluate the anti-cancer activity by ORR by central radiology review as per RECIST version 1.1 
in patients with inoperable or advanced iCCA whose tumors harbor FGFR2 mutations or 
amplifications, and who received at least one prior regimen of systemic therapy  
1.2.3 Exploratory objectives 
The exploratory efficacy objectives of this study are: 
• 
To evaluate disease control rate (DCR) by central radiology review 
• 
To evaluate time to progression (TTP) by central radiology review 
• 
To compare TTP on the first and/or the last prior line of systemic therapy (reported) versus TTP on 
derazantinib by central radiology review (TTP will be calculated from the first date of receiving 
study drug or prior line of systemic therapy until radiographic disease progression) 
• 
To evaluate ORR, PFS, DCR and TTP by investigator radiology review 
• 
To evaluate the non-confirmed central and local ORR and DCR 
• 
To explore the concordance of local FISH or NGS genomic testing compared to central FISH testing 
results  
The exploratory PK and pharmacodynamic objectives of this study are: 
• 
To evaluate changes in pharmacodynamic biomarkers   
• 
To evaluate ORR, PFS, OS, and DoR by pharmacodynamic biomarkers 


 
 
 
 
 
 
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• 
To evaluate the relationship between derazantinib exposure and effectiveness, toxicity and 
pharmacodynamic biomarkers  
• 
To evaluate PopPK 
• 
To evaluate the urinary excretion of derazantinib, and possibly its metabolites, in a subset of patients 
The PK and pharmacodynamic objectives and planned analyses will be further detailed in a separate plan. 
PK and pharmacodynamic data available at time of database lock and final analysis will be only be listed.  
1.3 
STUDY ENDPOINTS 
1.3.1 Primary Endpoints 
Substudy 1 
ORR was selected as the primary endpoint of this study. This endpoint is an acceptable surrogate endpoint 
of clinical benefit in this disease. ORR will be the proportion of patients with confirmed complete responses 
and partial responses by central radiology review as per RECIST version 1.1. 
Substudy 2 
PFS 3 will be the proportion of patients who have progression-free survival at 3 months from the first date 
of receiving study drug as assessed by survival status and central radiology review as per RECIST version 
1.1. 
1.3.2 Secondary Efficacy Endpoints 
Substudy 1 and Substudy 2 
 PFS will be calculated from the first date of receiving study drug until radiographic disease 
progression by central radiology review or death 
 OS will be calculated from the first date of receiving study drug until death. 
 DoR will be calculated from the first date of documented tumor response to disease progression by 
central radiology review. 
 Changes in HRQOL and symptom response will be evaluated using the EORTC QLQ-C30, QLQ-
BIL21, and EQ-5D VAS. 
Substudy 2 
 ORR will be the proportion of patients with confirmed complete responses and partial responses by 
central radiology review as per RECIST version 1.1. 
1.3.3 Exploratory Efficacy Endpoints 
Substudy 1 and Substudy 2 
 DCR by central radiology. DCR will be the proportion of patients with confirmed complete or partial 
responses or stable disease by central radiology review as per RECIST version 1.1. 
 TTP will be calculated based on central radiology review from the first date of receiving study drug 
until radiographic disease progression 
 TTP will be assessed for the first and/or the last prior line of systemic therapy (reported) and will be 
compared to TTP on derazantinib 
 ORR, PFS, DCR and TTP by investigator radiology review 
 Non-confirmed central and local ORR and DCR 
 Concordance of local FISH or NGS genomic testing compared to central FISH testing results 


 
 
 
 
 
 
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1.3.4 Safety Endpoints 
Toxicities will be evaluated using National Cancer Common Terminology Criteria for Adverse Event (NCI 
CTCAE) version 4.03 criteria. 
1.4 
SAMPLE SIZES AS PER PROTOCOL, INTERIM ANALYSIS AND DATA MONITORING 
COMMITTEE 
Data Monitoring Committee (DMC) 
 
The DMC was established to ensure the safety of study patients and the validity of study results. The DMC 
composition and operation was as described in the DMC Charter. The DMC may recommend study 
termination or continuation based on periodic review of safety and/or efficacy data in this study. 
Substudy 1 
To prove the drug effect over placebo in ORR in this single-arm pivotal study, the hypothesis was specified 
as  
H0: ORR<= 0.10 and Ha: ORR > 0.10. 
The hypothesis test will be performed at a one-sided 2.5% significance level. A 10% response rate is chosen 
for the null hypothesis (H0), which is much higher than the observed placebo rate 7~8% in larger historical 
trials and publications (Lamarca 2014). The 23% response rate under the alternative hypothesis is estimated 
for power and sample size calculations. 
Approximately 100 patients will be enrolled for this two-stage group sequential study with futility stopping.  
An interim analysis for futility was planned to be performed when 40 patients who satisfy mITT criteria had 
at least one post baseline tumor evaluation. The study was to be terminated for futility if 4 or fewer 
responses were observed among 40 evaluable patients. If the treatment was ineffective, i.e., ORR=0.1, the 
probability of futility stopping was 63%. If the true response rate ORR=0.23, the probability of futility 
stopping was only 3%. The design provided approximately 90% power to reject the null hypothesis at 
one-sided significance level 0.025, or equivalently to have the lower bound of confidence interval of ORR > 
10%. If 5 or more objective responses (OR) were observed and confirmed based on central radiology review 
prior to enrollment of 40 evaluable patients, the interim analysis was to be performed based on fewer than 
40 patients.  
The interim analysis was performed on 29 patients satisfying the mITT criteria. At the time of analysis 6 
patients (21%) had a confirmed central PR, and futility was rejected per DMC recommendation. 
Substudy 2  
A Simon’s two-stage design will be used in Substudy 2. The null hypothesis (H0) that the true 3-month rate 
of PFS 3 is p0 ≤ 0.45 will be tested against a one-sided alternative. In the first stage, approximately 15 
mITT-evaluable patients will be accrued. If there are 7 or fewer patients with PFS 3 in these 15 patients, 
then Substudy 2 will be stopped. Otherwise, 28 additional mITT-evaluable patients will be accrued for a 
total of up to approximately 43. H0 will be rejected if a PFS 3 is observed in 25 or more of these 43 patients. 


 
 
 
 
 
 
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The type I error rate is 0.0481, and power is approximately 0.8 when the true PFS 3 rate for derazantinib is 
p1 = 0.65. 
If the required number of patients alive and without disease progression is reached before full enrollment to 
Stage 1, the decision to transition from Stage 1 to Stage 2 may be taken before Stage 1 is fully enrolled.  
If the required number of patients alive and without disease progression is not reached at the time of full 
enrollment to Stage 1, further enrollment will be suspended to allow for all patients to be evaluated for PFS 
3. 
The analysis was performed on 14 patients satisfying the mITT criteria. The protocol defined threshold for 
stage transition and study continuation was achieved with 8 patients out of 14 patients in mITT population 
meeting the PFS3 criterion. 
 


 
 
 
 
 
 
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2 
ANALYSIS POPULATIONS 
Three analysis populations will be defined as follows: 
2.1 
SAFETY/INTENT-TO-TREAT POPULATION (ITT) 
The Safety/ITT population for Substudy 1 will include all patients with locally or centrally confirmed 
FGFR2 fusions/rearrangements who receive any amount of study drug.    
The Safety/ITT population for Substudy 2 will include all patients with locally confirmed FGFR2 mutations 
or amplifications who receive any amount of study drug.    
All data from patients enrolled but not fulfilling the molecular entry criteria (and therefore not included in 
the Safety/ITT population) will only be listed.  
2.2 
MODIFIED INTENT-TO-TREAT (MITT) POPULATION 
The mITT population will include all patients in the Safety/ITT population, who have at least one post-
baseline disease assessment (at least one post-baseline imaging assessment in accordance with RECIST 1.1, 
or documented clinical progression [every effort should be made to objectively assess radiographic 
progression]), or reported death during the treatment period  
2.3 
PER PROTOCOL (PP) POPULATION 
The PP population will include all patients in the mITT population who have no important protocol 
deviations (IPD) which are determined to potentially impact efficacy analyses during the study. Protocol 
deviations will be identified prior to database lock and final analysis. 


 
 
 
 
 
 
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3 
STATISTICAL AND ANALYTICAL PROCEDURES 
3.1 
GENERAL STATISTICAL CONSIDERATIONS 
3.1.1 Statistical Methods 
Summary statistics will be presented as follows. For continuous variables, number of available observations 
(n), mean, standard deviation (s.d), median, first quartile (Q1), third quartile (Q3), minimum (min), and 
maximum (max) will be provided; 95% confidence interval for the median will be added as specified. For 
categorical variables, the number and percentage in each category will be displayed; missing categories will 
be added accordingly. Percentages will be based on the number of patients in the relevant analysis 
population.  
Time-to-event data will be summarized using the Kaplan-Meier method. 
By-patient data listings will be produced for data collected through the study (e.g., case report form, lab). All 
data listings that contain an evaluation date will contain a relative study day (Study Day). Pre-treatment and 
on-treatment study days are numbered relative to the day of the first dose of study drug, which is designated 
as Day 1. The preceding day is Day -1, the day before that is Day -2, etc.  
All statistical analyses will be performed in SAS Version 9.4 or higher. 
3.1.2 Definition of Baseline  
Assessment of change from baseline will include only those patients with both baseline and post-baseline 
measurements. The last evaluable/non-missing observation/assessment, including unscheduled visits taken 
before the first dose of study drug will be used as the baseline, unless otherwise specified.  
3.1.3 Visit Windows 
All data will be tabulated per the evaluation visit as recorded on the electronic case report form, even if the 
assessment is outside of the visit window. With the exception of the baseline definition, unless otherwise 
stated in the analysis sections below, unscheduled visits will only be included in data listings.  
3.1.4 Handling of Dropouts and Missing Data 
In general, unless otherwise specified, missing values will not be imputed for data analysis. Patients whose 
clinical response is unknown or not reported will be treated as non-responders. 
If any laboratory value falls above or below the upper or lower level of quantification, the following rule 
will be applied for summary statistics: values reported as <XX or ≤XX will be analyzed as XX/2; values 
reported as >XX or ≥XX will be analyzed as XX (e.g., <0.2 will become 0.1, >0.2 will become 0.2). 
Reported values will be listed.  
All dates are expected to be completed with day, month, and year. For efficacy analyses, if the day/month of 
death or tumor assessment or last contact date is missing, the 1st of the month/year will be used. 
 


 
 
 
 
 
 
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3.2 
STATISTICAL METHODS 
3.2.1  Disposition of Patients and Analysis Populations  
Patient disposition will be presented by substudy and overall. Tabulation will include the following: 
 Number (%) of patients treated  
 Number (%) of patients who discontinued treatment and primary reason for discontinuation of treatment  
 Treatment phase duration (months)  
- 
Where the treatment phase duration will be calculated as the time from C1D1 to EOT visit. If 
EOT visit was not performed, then the last study visit prior to EOT will be analyzed. 
 Number (%) of patients who performed the 30-day Safety Follow-up visit 
 Number (%) of patients who entered Survival Follow-up, their last outcome at time of analysis (alive, 
continuing in follow-up, dead, lost to follow-up, alive, withdrawal of consent from study follow-up) 
 Study duration (months) 
- 
Where the study duration will be calculated as the time from C1D1 to last survival follow-up 
date, or death. If last survival follow-up date, or death is missing, then the last date of contact will 
be analyzed. 
 
The table will be based on the Safety/ITT Population. 
 
The number and percentage of patients in each analysis populations (Safety/ITT, mITT, PP), including 
reasons for exclusion from each analysis population will be presented for all patients enrolled i.e. patients 
signed with informed consent. 
 
The number of patients by country and site will be presented by the Safety/ITT population. 
The following by-patient listings will be presented by substudy, 
• 
Patient eligibility with inclusion and exclusion criteria details 
• 
Patient enrollment 
• 
Patient disposition 
• 
Analysis populations 
• 
IPDs 
 
3.2.2 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by the Safety/ITT, mITT and PP populations. 
The following variables will be listed and summarized in the demographic and baseline characteristic 
summary table using both continuous and categorical descriptive statistics. 
• 
gender,  
• 
race (White, Black or African American, Asian, American Indian or Alaska Native, Native Hawaiian 
or Other Pacific Islander, Other, not allowed to record per local regulation, unknown)  
• 
ethnicity (Hispanic or Latino, not Hispanic or Latino, not reported),  
• 
age (years) at baseline,  
• 
baseline Eastern Cooperative Oncology Group (ECOG),  
• 
baseline vital signs: height (cm), weight (kg), body mass index (BMI) (kg/m2) – calculated as weight 
(kg) / height (m)2  
• 
tumor’s genomic status (FGFR2 fusion for Substudy 1, and FGFR2 mutations or amplification or 


 
 
 
 
 
 
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Substudy 2) 
Concordance of local FISH or NGS genomic testing compared to central FISH testing results will be 
summarized descriptively. 
By patient listing of demographics, pregnancy test, tumor’s genomic status will be produced,   
 
 
3.2.3 
Medical History (Non-Cancer Related) 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) version 23.0 
or later and will be summarized by system organ class (SOC) and preferred term (PT) for the Safety/ITT 
population. Patients will be counted only once for each SOC or PT in the event that they have multiple 
records of the same SOC or PT in the database. All medical history data will be listed. 
 
3.2.4 
Cancer-Related Medical History   
Cancer-related medical history will be summarized for the Safety/ITT population. Descriptive statistics on 
cancer-related medical history will be presented for the following: 
 Cancer history for iCCA 
 Prior systemic cancer therapies 
 Prior iCCA local therapies 
 Prior iCCA cancer surgery/procedure 
 Prior liver resection: 
 Prior iCCA radiation therapies: 
All cancer-related medical history data will be listed. 
 
3.2.5 
Prior and Concomitant Medications, and Non-Drug Treatments/Procedures  
Prior and concomitant medications will be summarized for the Safety/ITT population. All prior and 
concomitant medications will be included in by-patient data listings. 
Non-drug treatments/procedures will only be listed for the Safety/ITT population. 
Prior medication will be defined as any medication taken and stopped prior to the first dose of study drug. 
Concomitant medication will be defined as any medication ongoing at time of first dose of study drug or 
taken after the first dose of study drug.  
Medications missing both start and stop dates, or having a start date prior to the first dose of study drug and 
missing the stop date, or having a stop date on or after the last dose of study drug and missing start date will 
be counted as concomitant. 
For partial dates, the following approach will be taken: 
• 
If the start day is missing but the start month and year are complete, a medication will be excluded as 
being concomitant only if the start month/year is before the month/year of study drug administration and if 
the stop date (either full date, month and year if missing day, or year if missing month and day) is before 
study drug administration. 


 
 
 
 
 
 
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• 
If the start day and month are missing but the start year is complete, a medication or procedure will be 
excluded as concomitant only if the start year is before the year of study drug administration and if the stop 
date (either: full date, month and year if missing day, or year if missing month and day) is before study drug 
administration.  
Prior and concomitant medications will be coded using the WHO Drug Dictionary (WHODRUG Global B3 
Sep2019 or above), and patient incidence will be tabulated by Anatomic Therapeutic Class (ATC) level 2,  
level 4 and PT. Patients will be counted only once for each ATC or PT in the event that they have multiple 
records of the same ATC or PT in the database.  
 
3.2.6 
Study Drug Exposure and Compliance 
Study drug exposure and compliance will be presented using the Safety/ITT population. 
Exposure to study drug will be presented cumulatively.  
The number of cycles of study drug received is defined as the total number of cycles where the patient has 
received at least 1 dose of study drug in each cycle, and excluding any cycle(s) where the patient has not 
been dosed. The study drug exposure is recorded for each cycle where the number of capsules dispensed and 
number of capsules returned will be entered; where the number of capsules returned is equal to the number 
of capsules dispensed, then this indicates that the patients were not dosed at this specific cycle.  
Duration of study drug is defined as: (date of last dose – date of first dose) + 1. If the date of last dose is 
missing then this will be imputed as the date of the last study drug dispensed.  
Dose intensity (%) is defined as the percentage of the study drug a patient has taken compared to the amount 
of study drug the patient was meant to take. This will be calculated as: 
Total cumulative dose received (mg) / total cumulative dose planned (mg) *100 
Total cumulative dose received (mg) is defined as the sum of all dose (mg) as recorded from the study drug 
administration eCRF page using each entry (date of last dose –date of first dose) + 1 * dose in mg. If the 
date of last dose is missing then this will be imputed with the date of the last study drug dispensed.  
Similarly, the total cumulative dose planned (mg) is defined as the sum of all planned dose (mg) as recorded 
from the study drug administration eCRF page using each entry (date of last dose –date of first dose) + 1 * 
300 mg.  If the date of last dose is missing then this will be imputed with the date of the last study drug 
dispensed. 
Treatment compliance is defined as the percent of actual amount of drug taken relative to the planned 
amount.  It is calculated according to the following formula for the entire study: 
 
% compliance = (# of capsules dispensed - # of capsules returned)/{(# of days in the dosing 
interval)*(# capsules per daily dose)}*100 
where the # of days in the dosing interval excludes any days that the patient was instructed to hold dosing 
due to an AE. 
Treatment compliance will also be summarized categorically, considering cut-offs of 80% and 120% for 
compliance. 
The number of cycles of study drug received, total duration of study drug (weeks), dose density (%), total 
cumulative dose received (mg) and treatment compliance (%) will be summarized using continuous 
statistics. Treatment compliance (%), the number of patients with at least 1 dose change/interruption during 


 
 
 
 
 
 
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the duration of the study, and the reasons for dose change/interruption will be summarized as categorical 
variables.  
Study drug administration, drug accountability, exposure and compliance will be presented by patient 
listings. 
 
3.2.7 
Analyses of Efficacy Variables 
All efficacy data will be summarized by substudy as detailed below, and listed.  
For Substudy 1, the Safety/ITT population will be used to analyze the efficacy data, with the mITT and PP 
population used for sensitivity analyses. For Substudy 2, the mITT population will be used to analyze the 
efficacy data, with the ITT and PP population used for the sensitivity analyses.   
Assessments by Blinded Independent Central Review (BICR) consider two readers. Should there be 
disagreement between these two readers, an adjudicator decides which reader is correct. As such, all 
analyses which consider BICR assessments will be based upon the first reader by default, unless the second 
reader is selected following adjudication. BICR and local assessment will be analyzed and listed. 
Waterfall plots, spider plots and swimmer plots will be produced to accompany efficacy analyses. 
3.2.7.1 Analysis of Primary Efficacy Variable 
Substudy 1 
The primary efficacy endpoint for Substudy 1 will be ORR, defined as the achievement of confirmed CR or 
PR using RECIST v1.1(Eisenhauer 2009) as assessed by BICR. 
Per protocol inclusion criteria, only patients with measurable disease by RECIST version 1.1 criteria should 
be enrolled. If a patient without measurable disease is enrolled, the ITT principle requires including these 
patients in the analyses. Hence, analyses will be based on patients with either measurable or non-measurable 
disease. For this purpose, non-CR/non-PD in patients with non-measurable disease will be considered 
equivalent to SD in patients with measurable disease, and the same rules will be applied.  
Classification of best confirmed response is done according to the following hierarchy and rules: 
1. CR: requires two consecutive CR response assessments a minimum of four weeks apart 
2. PR: requires two consecutive PR response assessments OR a PR response followed by a consecutive CR 
response assessment (a minimum of four weeks apart) 
3. SD: requires only one SD response assessment (provided minimum criteria for SD duration met) 
4. Non-CR/Non-PD (non-measurable disease patients only): requires only one Non-CR/Non-PD response 
assessment (provided minimum criteria for Non-CR/Non-PD duration met) 
5. PD: requires only one PD response assessment 
The minimum duration for SD and Non-CR/Non-PD is defined as at least 6 weeks i.e. 42 days, where the 
duration is calculated from the start of treatment until the criteria of SD is met. 
The classification as per RECIST 1.1 (Eisenhauer 2009) is summarized in Table 1 below. 


 
 
 
 
 
 
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Table 1: Best overall response when confirmation of CR and PR required. 
Overall response 
BEST overall response 
First time point Subsequent 
time point 
CR 
CR 
CR 
CR 
PR 
SD, PD or PR* 
CR 
SD 
SD provided minimum criteria for SD duration met, otherwise PD 
CR 
PD 
SD provided minimum criteria for SD duration met, otherwise PD 
CR 
NE 
SD provided minimum criteria for SD duration met, otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, otherwise PD 
PR 
NE 
SD provided minimum criteria for SD duration met, otherwise NE 
NE 
NE 
NE 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = 
inevaluable. 
* If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have 
reappeared after CR). Best response would depend on whether minimum duration for SD was met. 
However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely still 
present and in fact the patient had PR, not CR at the first time point. Under these circumstances, the 
original CR should be changed to PR and the best response is PR. 
For patients with non-measurable disease, SD should be replaced by non-CR/Non-PD  
If the best overall response has any special cases or difficulty from unexpected data, then these may be 
checked and discussed with the study team to decide which best overall response is best suited. 
As specified in RECIST 1.1, repeated ‘NE’ time point assessments complicate best response determination. 
Should a CR/PR be followed by one or more NE response and then a CR/PR, then confirmed response 
would be achieved (as an example PR-NE-PR will be considered as a confirmed response). 
Patients without efficacy assessments are considered non-responders, and included in the analysis. 
Hypothesis testing (null hypothesis [H0] versus alternative hypothesis [HA]) were performed at the interim 
and will be performed in the final analyses as specified below: 
Null Hypothesis H0: ORR <= 0.10 and  
Alternative Hypothesis HA: ORR > 0.10  
The hypothesis testing will be performed using exact test for binomial proportion at a one-sided 2.5% 
significance level. Point estimates and exact 2-sided 95% confidence intervals (Clopper-Pearson) will be 
provided. If the p-value is ≤ to 2.5% (one-sided), or equivalently the lower limit of the confidence interval is 
> 10%, the null hypothesis will be rejected.  
Considering the number of patients per site planned in this study, the site effect and treatment by site 
interaction will not be evaluated. 
 


 
 
 
 
 
 
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Substudy 2 
The primary efficacy endpoint for Substudy 2 will be the proportion of patients who have PFS at 3 months 
from the first date of receiving study drug as assessed by survival status or central radiology review RECIST 
1.1.  
PFS will be calculated as the time from first dose of study drug until disease progression as assessed by 
BICR, or death from any cause, whichever occurs first. Patients who either have no baseline tumor 
evaluation or have no post-baseline tumor evaluation will be censored at date of first dose. Patients who 
discontinue treatment due to reasons other than disease progression by BICR or death will be censored in the 
PFS analyses as the date of their last tumor evaluation prior to EOT. Patients who progress or die after 
missing ≥2 consecutive scheduled tumor assessments will be censored at the date of the last tumor 
evaluation prior to progression or death. Any disease progression as assessed by BICR, or death occurring 
after end of treatment visit are not taken into account as a PFS event. For missing end of treatment visit date, 
a +7 day window compared to the maximum of last dose date, last on treatment visit date will be applied to 
create a tentative end of treatment visit date and a cut-off for death occurring after this date.  
The rules for censoring PFS are summarized in the table below: 
Table 2: Censoring scheme for PFS 
Situation 
Date of progression or censoring 
Outcome 
No baseline tumor assessments  
Date of first dose  
Censored 
No post-baseline tumor evaluation  
Date of first dose 
Censored 
Documented radiological 
progression  
Date of radiological assessment of measured 
lesions up to EOT 
Progressed 
No radiological progression 
Date of last radiological assessment of measured 
lesions up to EOT 
Censored 
Treatment discontinuation for 
reasons other than radiological 
disease progression by BICR or 
death 
Date of last radiological assessment of measured 
lesions up to EOT 
Censored 
Death before first PD assessment 
Date of death 
Progressed 
Death between adequate assessment 
visits  
Date of death 
Progressed 
Death or radiological progression 
after more than two missed tumor 
assessment or after end of treatment  
 
Date of last radiological assessment of measured 
lesions prior to progression or death 
Censored 
The hypothesis being tested is:  
Null Hypothesis H0: PFS 3 ≤ 0.45 and  
Alternative Hypothesis HA: PFS 3 > 0.45  
Where PFS 3 is the proportion of patients with a PFS > 3 months (i.e. > 91 days). 
A Simon’s two-stage design will be used, with approximately 15 patients in Stage 1, and an additional 28 
patients if the study proceeds to Stage 2. H0 will be rejected if a PFS 3 is observed in 25 or more of these 43 
patients. The type I error rate is 0.0481, and power is approximately 0.8 when the true PFS 3 rate for 
derazantinib is p1 = 0.65. 


 
 
 
 
 
 
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Point estimates, exact 2-sided 95% confidence intervals (Clopper-Pearson) and associated p-value will be 
provided.  
PFS will be analyzed using Kaplan-Meier methodology (Kaplan & Meier 1958). The median duration of 
PFS will be presented along with the standard error and 2-sided 95% CI.  If they are calculable, the 25th and 
75th percentiles and the 2-sided 95% CIs around the percentiles will be presented. Kaplan-Meier estimates at 
3, 6, 9 and 12 months will also be presented. The Kaplan-Meier survival curves will also be presented. 
Additional PFS sensitivity analyses which consider alternative censoring methods as outlined in FDA 
guidelines (FDA 2018, FDA 2015) will be conducted in the same manner, as described above. These will be 
performed for the Safety/ITT and mITT populations: 
- 
Sensitivity analysis 1 in Table 3 uses a conservative approach by assigning the date of 
discontinuation, or missed tumor assessment followed by PD or death as an event date.  
- 
Sensitivity analysis 2 in Table 4 includes clinical progression as an event.  
- 
Sensitivity analysis 3 in Table 5 evaluates PFS including post EOT radiological assessments.  
Table 3: Censoring scheme for PFS - sensitivity analysis 1 (any change considered as progression 
event) 
Situation 
Date of progression or censoring 
Outcome 
No baseline tumor assessments  
Date of first dose 
Censored 
No post-baseline tumor evaluation 
Date of first dose 
Censored 
Documented radiological progression 
between scheduled visits 
Date of radiological assessment of 
measured lesions  
Progressed 
No radiological progression 
Date of last radiological assessment 
of measured lesions  
Censored 
Treatment discontinuation for reasons 
other than radiological disease progression 
by BICR or death 
Date of discontinuation  
Progressed 
Death before first PD assessment 
Date of death 
Progressed 
Death between adequate assessment visits  
Date of death 
Progressed 
Death or radiological progression after 
more than two missed tumor assessment   
 
Date of first missed tumor 
assessment 
Progressed 
 


 
 
 
 
 
 
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Table 4: Censoring scheme for PFS - sensitivity analysis 2 (includes clinical progression) 
Situation 
Date of progression or censoring 
Outcome 
No baseline tumor assessments  
Date of first dose 
Censored 
No post-baseline tumor evaluation  
Date of first dose 
Censored 
Documented radiological progression  
Date of radiological assessment of 
measured lesions up to EOT   
Progressed 
No radiological progression, no clinical 
progression 
Date of radiological assessment of 
measured lesions up to EOT   
Censored 
Clinical progression 
Date of clinical progression 
Progressed 
Treatment discontinuation for reasons 
other than radiological disease progression 
by BICR, clinical progression or death 
Date of radiological assessment of 
measured lesions up to EOT   
Censored 
Death before first PD assessment 
Date of death 
Progressed 
Death between adequate assessment visits  
Date of death 
Progressed 
Death or radiological progression or 
clinical progression after more than two 
missed tumor assessment or after end of 
treatment  
 
Date of last radiological assessment 
of measured lesions prior to 
progression or clinical progression 
or death 
Censored 
 
Table 5: Censoring scheme for PFS - sensitivity analysis 3 (including post EOT assessments) 
Situation 
Date of progression or censoring 
Outcome 
No baseline tumor assessments  
Date of first dose 
Censored 
No post-baseline tumor evaluation 
Date of first dose 
Censored 
Documented radiological progression  
Date of radiological assessment of 
measured lesions  
Progressed 
No progression, or new anticancer 
treatment started 
Earliest date of: 
- 
last radiological 
assessment of measured 
lesions, including post 
EOT 
- 
new anticancer 
treatment  
Censored 
Death before first PD assessment 
Date of death 
Progressed 
Death between adequate assessment visits  
Date of death 
Progressed 
Death or progression after more than two 
missed tumor assessment  
 
Date of last radiological assessment 
of measured lesions prior to 
progression or death 
 
Censored 
 


 
 
 
 
 
 
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3.2.7.2 Analyses of Secondary Efficacy Variables 
3.2.7.2.1 PFS (Substudy 1 and Substudy 2) 
PFS as assessed by BICR will be analyzed as detailed in Section 3.2.7.1 for primary efficacy analysis for 
Substudy 2.  
3.2.7.2.2 DoR (Substudy 1 and Substudy 2) 
DoR (months) will be calculated from the first date of documented objective tumor response (confirmed CR 
or PR) to disease progression as assessed by BICR or death. If a patient is discontinued or is lost to follow-
up with no documentation of progressive disease, DoR is defined as the time from the date of the first 
documentation of OR to the date of the last tumor assessment as a censored value.  
DoR will be derived only for patients who have the best overall response of CR or PR. 
DoR will be analyzed using Kaplan-Meier methodology (Kaplan & Meier 1958). The median DoR will be 
presented along with the standard error and 2-sided 95% CI. If they are calculable, the 25th and 75th 
percentiles and the 2-sided 95% CIs around the percentiles will be presented. Kaplan-Meier estimates at 3, 
6, 9 and 12 months will also be presented. The Kaplan-Meier survival curves will also be presented. 
The date of first study drug dose, documented objective tumor response, disease progression, death, last 
tumor assessment, last contact and DoR days will be reported in a by-patient listing. 
3.2.7.2.3 OS (Substudy 1 and Substudy 2) 
OS time (months) will be calculated from the first date of receiving study drug until death from any cause.   
Any patient without a date of death in the database at the time the survival analyses are performed will be 
censored at the time of their last study contact. OS will be performed for the Safety/ITT population. 
OS will be analyzed using Kaplan-Meier methodology (Kaplan & Meier 1958). The median duration of OS 
will be presented along with the standard error and 2-sided 95% CI.  If they are calculable, the 25th and 75th 
percentiles and the 2-sided 95% CIs around the percentiles will be presented. Kaplan-Meier estimates at 3, 
6, 9 and 12 months will also be presented. The Kaplan-Meier survival curves will also be presented.  
The date of first study drug dose, death, last study contact and OS days will be reported in a by-patient 
listing. 
3.2.7.2.4 ORR (Substudy 2) 
ORR will be considered a secondary efficacy endpoint in Substudy 2 and analyzed in the same way as stated 
in Section 3.2.7.1. 
3.2.7.2.5 PRO Assessments (Substudy 1 and Substudy 2) 
For each assessment the minimally important difference (MID) in a score at C3D1 and C5D1 will be 
determined following the recent protocol by the EORTC Quality of Life Group (Musoro 2018). Patients 
with complete data will be categorized into five mutually exclusive clinical change groups (CCG) reflecting 
the five possible levels of change. For each pair of timepoints (Change in summary score from baseline at 


 
 
 
 
 
 
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C3D1 and Change in summary score from C3D1 at C5D1), a patient can thus belong to only one CCG 
category. Two methods for determining the MID will be explored: 
 
1. Mean Change Method 
For a given mean absolute change in PRO assessment scale summary score: the MID for improvement is 
equal to the mean summary score of the ‘small positive change’ CCG (somewhat better now than 6 
weeks ago) and the MID for deterioration is equal to the mean summary score of the ‘small negative 
change’ CCG (somewhat worse now than 6 weeks ago). The mean summary score of the ‘small change’ 
CCGs and that of the ‘no change’ CCG will be compared and reported. If the mean summary score for 
‘no change’ CCG is similar to any of the two ‘small change’ CCGs, the estimated MID may be 
considered doubtful. No a priori rule will be established to determine if mean summary scores are 
sufficiently similar to determine MID to be doubtful. 
 
2. Linear Regression 
For a given absolute change in PRO assessment scale summary score: the estimate of the numerical 
change in summary score that is associated with the transition between adjacent CCG categories will be 
determined using linear regression. Separate models will be fitted for improving and deteriorating scores 
based on the anchor. The outcome variable is the PRO assessment summary score, and the covariate is a 
binary anchor variable; coded as ‘no change’=0 and ‘small positive change’=1 for model on 
improvement (Other CCG categories are excluded from the linear regression model), and ‘no change’=0 
and ‘small negative change’=1 for model on deterioration (Other CCG categories are excluded from the 
linear regression model. The resulting β’s (i.e. slope parameters) correspond to the MIDs for 
improvement and deterioration respectively. No other covariates will be included in these models. 
 
PRO analysis will be performed for the Safety/ITT population. 
3.2.7.2.5.1 G-SET/HTI  
G-SET/HTI is a single item, and will be used as an external anchor to determine the minimal important 
difference of EQ-5D-VAS, EORTC QLQ-C30, and QLQ-BIL21 scales. The G-SET/HTI is a patient-rated 
change in health between two time periods using a five-point ordinal scale (1=much better now than 8 weeks 
ago; 2=somewhat better now than 8 weeks ago; 3=about the same as 8 weeks ago; 4=somewhat worse now 
than 8 weeks ago; 5=much worse now than 8 weeks ago). G-SET/HTI will be summarized at Cycle 3, Day 
1, and Cycle 5, Day 1 by categorical and continuous descriptive statistics. 
3.2.7.2.5.2  EORTC QLQ-C30   
EORTC QLQ-C30 was developed to assess the quality of life of cancer patients and is the most widely used 
cancer-specific HRQoL instrument. It contains 30 items and measures five functional scales (physical, role, 
cognitive, emotional, and social); three symptom scales (fatigue, pain, and nausea and vomiting); six single 
symptom items (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea and financial impact) and a 
global health and quality-of-life scale. The global health and quality of life items uses a 7-point scale scoring 
from 1 (very poor) to 7 (excellent). The other items are scored on a 4-point scale from 1 (not at all) to 4 
(very much). A high score for a functional scale represents a high/healthy level of functioning. A high score 
for the global health status represents a high QoL. However, a high score for a symptom scale/item 
represents a high level of symptomatology/problems. The scoring method is outlined in Table 6 and the 
following paragraphs. 


 
 
 
 
 
 
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Table 6: Scoring the QLQ-C30 version 3.0 
 
Scale 
Number 
of items 
Item 
range 
Version 3.0 
Item 
numbers  
Function 
scales 
Global health Status /QoL 
QL 
2 
6 
29, 30 
 
Functional Scales 
Physical functioning 
PF 
5 
3 
1 to 5 
F 
Role functioning 
RF 
2 
3 
6,7 
F 
Emotional functioning 
EF 
4 
3 
21 to 24 
F 
Cognitive functioning 
CF 
2 
3 
20, 25 
F 
Social function 
SF 
2 
3 
26, 27 
F 
Symptom scales/items 
Fatigue 
FA 
3 
3 
10, 12, 18 
 
Nausea and vomiting 
NV 
2 
3 
14,15 
 
Pain 
PA 
2 
3 
9, 19 
 
Dyspnea 
DY 
1 
3 
8 
 
Insomnia 
SL 
1 
3 
11 
 
Appetite loss 
AP 
1 
3 
13 
 
Constipation 
CO 
1 
3 
16 
 
Diarrhea 
DI 
1 
3 
17 
 
Financial difficulties 
FI 
1 
3 
28 
 
Raw score (RS) is calculated as the average of item score when at least half of the items are not missing. A 
linear transformation to 0–100 will then be applied to get the score (S) using the item range provided in 
Table 6. 
For functional scales S = (1-(RS-1)/range) x 100 
For symptom scales/items and global health status S = ((RS-1)/range) x 100 
Each scale will be summarized at each visit as a continuous variable using descriptive statistics per substudy 
for the total scores, change from baseline and percent change from baseline for all visits where the EORTC 
QLQ-C30 is collected. In addition, at C5D1, the change from C3D1 at C5D1 and the percentage change at 
C5D1 from C3D1 will also be reported. For each of the functional scales, the minimally important change 
from baseline at C3D1 and change from C3D1 at C5D1 will be determined using the two methods detailed 
in Section 3.2.7.2.5. 
3.2.7.2.5.3 EORTC QLQ-BIL21   
The EORTC QLQ-BIL21 comprises five multi-item measures of cholangiocarcinoma and gallbladder 
cancer-associated symptoms (eating symptoms, jaundice, tiredness, pain symptoms, anxiety), and three 
single items on treatment side effects, difficulties with drainage bags/tubes, and concerns regarding weight 
loss. The response is a four-point Likert scale. 


 
 
 
 
 
 
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Table 7: Scoring the QLQ-BIL21 
 
Number of items 
Version 3.0 Item numbers  
Eating 
4 
31, 32, 33, 34 
Jaundice 
3 
35, 36, 37 
Tiredness 
3 
38, 39, 40 
Pain 
4 
41, 42, 43, 44 
Anxiety 
4 
45, 46, 47, 48 
Treatment Side Effects 
1 
49 
Drainage Bag/Tube Difficulties 
1 
50 
Weight Loss Concerns 
1 
51 
Raw score (RS) is calculated as the average of item score when at least half of the items are not missing. A 
linear transformation to 0–100 will then be applied to get the score (S) using the item range provided in 
Table 7. 
For functional scales S = (1-(RS-1)/range) x 100 
For symptom scales/items and global health status S = ((RS-1)/range) x 100 
Each scale will be summarized at each visit as a continuous variable using descriptive statistics per substudy 
for the total scores, change from baseline and percent change from baseline for all visits where the EORTC 
QLQ-BIL21 is collected. In addition, at C5D1, the change from C3D1 at C5D1 and the percentage change at 
C5D1 from C3D1 will also be reported. For each of the functional scales, the minimally important change 
from baseline at C3D1 and change from C3D1 at C5D1 will be determined using the two methods detailed 
in Section 3.2.7.2.5. 
3.2.7.2.5.4 EQ-5D (5L)  
The EQ-5D (5L) is a standardized instrument for use as a measure of health outcome. The five health state 
dimensions in this instrument include the following: mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression. Each dimension is rated on a five-point scale from 1 (no problem) to 5 (extreme 
problem). The EQ-5D (5L) also includes a graded (0 to 100) VAS on which the patient rates his or her 
general state of health at the time of the assessment. 
The 5 questions will be summarized descriptively as categorical variables for all visits where the EQ-5D 
(5L) is collected. The VAS will be summarized as a continuous variable using descriptive statistics for the 
total scores, change from baseline and percent change from baseline for all visits where the EQ-5D (5L) is 
collected. In addition, at C5D1, the change from C3D1 at C5D1 and the percentage change at C5D1 from 
C3D1 will also be reported. The minimally important change from baseline at C3D1 and change from C3D1 
at C5D1 of the EQ-5D (5L) VAS will be determined using the two methods detailed in Section 3.2.7.2.5. 
Missing VAS scores will not be included in summary statistics and only patients with both an observation at 
the specified visit and at baseline will be included in change from baseline summaries. 


 
 
 
 
 
 
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3.2.7.3 Exploratory Analyses  
3.2.7.3.1 Disease Control Rate (Substudy 1 and Substudy 2) 
Disease control rate (DCR) is defined as the achievement of confirmed CR or PR or SD (or Non-CR/Non-
PD for patients with non-measurable disease) using RECIST 1.1 as assessed by BICR. Point estimates and 
exact 2-sided 95% CIs (Clopper-Pearson) will be provided by the Safety/ITT Population.  
DCR by investigator assessment will also be analyzed for the Safety/ITT Population. 
3.2.7.3.2 Investigator Assessed Best Overall Response (Substudy 1 and 2) 
In the primary analysis, tumor response will be based upon measurements evaluation by the BICR. 
However, an initial assessment of tumor response will be made by investigators at site. As an exploratory 
measure, analyses of best overall response will be conducted considering investigator assessment only, these 
will be summarized by the Safety/ITT, mITT and PP population. 
3.2.7.3.3 Investigator Assessed PFS (Substudy 1 and 2) 
PFS as assessed by the investigators will be analyzed similarly as detailed in Section 3.2.7.2.1 for the 
Safety/ITT and mITT Population. 
3.2.7.3.4 TTP (Substudy 1 and 2) 
TTP will be calculated as follows: 
a. TTP (on derazantinib): TTP will be calculated from the first date of receiving study drug until 
first radiographic disease progression per BICR. 
b. TTP (on the first prior line of systemic therapy): TTP will be calculated from the date of first 
prior line of systemic therapy until date of radiographic disease progression reported for that 
regimen  
c. TTP (on the last prior line of systemic therapy): TTP will be calculated from the date of last prior 
line of systemic therapy until date of first radiographic disease progression reported for that 
regimen  
 
Missing dates for the prior line of systemic therapy will be imputed as detailed in Section 3.1.4. The dates 
for the prior lines will be sorted by ascending dates to determine the first and last lines of systemic therapy. 
Censoring of the TTP variables are summarized in Table 8, 9 and 10 below: 
Table 8: Censoring scheme for TTP (on derazantinib) 
Situation 
Date of progression or censoring 
Outcome 
No baseline tumor assessments  
Date of first dose  
Censored 
No post-baseline tumor evaluation 
Date of first dose 
Censored 
Radiological progression on or prior 
to EOT 
Date of radiological assessment of measured 
lesions prior to EOT 
Progressed 
No radiological progression 
Date of last radiological assessment of measured 
lesions prior to EOT 
Censored 
Treatment discontinuation for 
reasons other than radiological 
Date of last radiological assessment of measured 
lesions prior to EOT 
Censored 


 
 
 
 
 
 
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disease progression by BICR  
Death 
Date of last radiological assessment of measured 
lesions prior to EOT 
Censored 
Radiological progression after more 
than two missed tumor assessment 
or after end of treatment  
 
Date of last radiological assessment of measured 
lesions prior to radiological progression, or EOT  
Censored 
Table 9: Censoring scheme for TTP (first line) 
Situation 
Date of progression or censoring 
Outcome 
No radiological progression reported 
for first regimen 
Date of last dose of treatment for the regimen 
Censored 
Table 10: Censoring scheme for TTP (last line) 
Situation 
Date of progression or censoring 
Outcome 
No radiological progression reported 
for last progression 
Date of last dose of treatment for the regimen 
Censored 
 
This will be analyzed using Kaplan-Meier methodology (Kaplan & Meier 1958). The median duration of TTP 
will be presented along with the standard error and 2-sided 95% CI.  If they are calculable, the 25th and 75th 
percentiles and the 2-sided 95% CIs around the percentiles will be presented. Kaplan-Meier estimates at 3, 
6, 9 and 12 months will also be presented. The Kaplan-Meier survival curves will also be presented. 
TTP by line of prior systemic therapy will also be performed similarly. 
TTP assessed on the first and the last prior line of systemic therapy (reported) and TTP on derazantinib will 
be presented by a Kaplan-Meier survival curve.  
 
3.2.8 
Analyses of Safety Data 
Safety analyses will be performed for the Safety/ITT population. 
3.2.8.1 Adverse Events 
AEs will be coded using the MedDRA and assigned the grades (severities) based on NCI CTCAE, Version 
4.03. For AEs not listed in the NCI CTCAE version 4.03, a similar grading system should be used as 
follows: 
 Grade 1: Mild AE 
 Grade 2: Moderate AE 
 Grade 3: Severe AE 
 Grade 4: Life-threatening or disabling AE 
 Grade 5: Death 
A treatment-emergent adverse event (TEAE) is defined as an AE with start date on or after the date of first 
dose and up to 30 days after last dose of study treatment (or until the start of a new anticancer therapy, 
whichever occurs earlier). 


 
 
 
 
 
 
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An overall TEAE incidence summary table will be produced and will include the number and percentage of 
patients with any TEAE, with any TEAE assessed by the Investigator as related to drug (related/not related), 
and with any serious TEAEs, drug-related serious TEAEs, TEAEs leading to permanent study drug 
discontinuation, drug-related TEAEs leading to permanent study drug discontinuation, TEAEs leading to 
study drug dose reduction or interruption, TEAEs leading to study drug dose reduction, TEAEs leading to 
study drug interruption, drug-related TEAEs leading to study drug dose reduction or interruption, drug-
related TEAEs leading to study drug dose reduction, drug-related TEAEs leading to study drug interruption 
TEAEs leading to death, drug-related TEAEs leading to death will be summarized. The number of events 
will also be displayed. 
For all event types listed above in the overall AE incidence summary table, tabulations by SOC and PT will 
also be produced. These will be presented by SOC and PT, sorted by decreasing frequency. Furthermore, 
TEAE, and drug-related TEAEs will also be summarized by SOC, PT, and maximum CTCAE grade, and 
sorted by decreasing frequency. Patients with more than one AE within a particular SOC are counted only 
once for that SOC. Similarly, patients with more than one AE within a particular PT are counted only once 
for that PT. For summaries by maximum CTCAE grade, patients with multiple AEs within a particular SOC 
or PT will be counted under the category of their most severe AE within that SOC or PT. AEs with missing 
CTCAE grade will be included in the missing counts. 
The following TEAEs and drug-related TEAEs of special interest will also be presented by SOC and PT and 
sorted by decreasing frequency: Transaminase elevations, hyperphosphatemia, blood creatinine increased, 
nail toxicity, dry eye, corneal, and specific eye TEAEs (keratitis, retinal events, asthenia/fatigue, dry 
eye/xerophthalmia).   
No formal hypothesis-testing analysis of AE incidence rates will be performed. 
TEAEs will be listed in patient data listings. By-patient listings also will be provided for the following: 
patient deaths, serious adverse events (SAEs), and AEs leading to withdrawal. 
3.2.8.2 Laboratory Variables  
Local laboratory results will only be listed. 
Central laboratory results will be summarized with descriptive statistics at each scheduled time and for the 
change from baseline. Repeated or unscheduled tests will not be summarized for each scheduled visit (with 
the exception of baseline which may include unscheduled visits). Baseline values and values at each visit for 
each laboratory parameter collected be descriptively summarized and plotted over time using a boxplot.  
Laboratory data will also be summarized using shift tables where appropriate. Each patient’s continuous 
laboratory safety parameter values will be flagged as “low”, “normal”, “high” or “missing” relative to the 
normal ranges. Each patient’s categorical laboratory safety parameter values will be flagged as “abnormal” 
or “normal”. This categorical data will be summarized in shift tables comparing the minimum post-baseline 
value, maximum post-baseline value and all other relevant post-baseline visits with those at the baseline 
visit. Note that minimum post-baseline will only be displayed in the instances where there is a range with 
lower limit of normal (LLN) >0. For parameters that have gradings for both low and high values, low and 
high will be summarized separately.  
In the shifts of low values, any high values will be classified as normal and the worst low grade will be 
summarized. And in the shifts of high values, any low values will be classified as normal and the worst high 
grade will be summarized. 


 
 
 
 
 
 
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In addition, CTCAE grade and hyperphosphatemia grade will be summarized. Shift tables of grade from 
baseline to maximum or minimum on-treatment as applicable will be produced.  
 
Since hyperphosphatemia is not defined by CTCAE v. 4.03, as per protocol hyperphosphatemia is defined 
as: 
Grade 1: > upper limit of normal (ULN) to < 7.0 mg/dL (<2.26 mmol/L) 
Grade 2: Non-invasive intervention required (e.g., withhold drug or modify dose) or between 7.0 – 9.0 mg/dL 
(2.26 – 2.90 mmol/L)  
Grade 3: Severe or medically significant, but not immediately life threatening, or > 9.0 – 10.0 mg/dL (˃ 2.90 
– 3.23 mmol/L)  
Grade 4: Life-threatening consequences, urgent intervention indicated e.g., dialysis, or > 10.0 mg/dL (> 3.23 
mmol/L) 
Central and local laboratory results will be included in by-patient listings and will include CTCAE grade and 
hyperphosphatemia grade at each visit, as well as change from baseline at each visit. 
Hy’s law  
 
Patients who have elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total 
bilirubin post baseline will be summarized descriptively as follows and Hy’s law cases identified.  
 
 ALT and AST: > 3x ULN, > 5x ULN, > 10x ULN, > 20x ULN  
 Total bilirubin >2x ULN  
 ALT or AST: > 3x ULN and Total bilirubin >2x ULN 
 
Plots of ALT and AST vs. Total bilirubin by module will also be produced with reference lines at 3×ULN 
for ALT, AST, and 2×ULN for total bilirubin. In each plot, peak total bilirubin x ULN will be on the vertical 
axis and peak ALT or AST x ULN will be on the horizontal axis. 
3.2.8.3 Vital Sign Variables 
Values and change from baseline for vital signs, including systolic blood pressure, diastolic blood pressure, 
heart rate, respiratory rate, body temperature, and weight will be summarized by scheduled time of 
evaluation.  Repeated or unscheduled tests will not be summarized for each scheduled visit.  
By patient listings for all vital signs will also be presented. 
3.2.8.4 Electrocardiogram (ECG) 
The actual value and change from baseline to each visit and at end of study will be descriptively summarized 
by visit for ECG parameters (e.g., heart rate, RR interval, PR interval, QRS duration, QT interval, QTcF 
interval and QTcB interval).  For all patients, a standard, triplicate, 12-lead ECG must be performed at all 
study visits using the pre-programmed device provided by the Sponsor. Summary tables will consider the 
mean of the triplicate measurements at each visit as the single reported value. 
A categorical analysis of QTcF interval and QTcB interval correction will also be presented, based on the 
number and percentage of patients meeting or exceeding specific thresholds for absolute QTcF/QTcB 
interval prolongation and change from baseline in QTcF/QTcB interval. In this analysis, the mean of the 
triplicate measurements will not be used; instead, the maximum at each timepoint will be considered.  


 
 
 
 
 
 
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For absolute QTcF/QTcB interval prolongation, the number and percentage of patients within the following 
thresholds will be summarized at each visit. The worst (largest) value will also be summarized. 
 Interval ≤450 ms 
 Interval >450 ms and ≤480 ms 
 Interval >480 ms and ≤500 ms 
 Interval >500 ms 
The change from baseline in QTcF/QTcB interval to the worst (largest) post-baseline observation and at 
each study visit will also be summarized, considering the following thresholds: 
 Interval increased from baseline ≤30 ms 
 Interval increased from baseline >30ms and ≤60 ms 
 Interval increased from baseline >60 ms  
For the analysis of change from baseline, the mean of the triplicate measurements will be used for baseline, 
but the maximum of triplicate measurements will be used for post-baseline values. 
Local and central ECG data will be presented separately in the summary tables, and will be presented by 
timepoint. All ECG data will be provided in a by-patient listing. 
3.2.8.5 ECOG 
ECOG performance status will be summarized in a shift table, which will summarize values at baseline, 
each visit and the maximum values during the study.  
All ECOG performance assessments will be provided in a by-patient listing. 
 
3.2.8.6 Other Safety Variables 
By patient listings for physical examination, eye examination, and pregnancy test will be presented.  
 


 
 
 
 
 
 
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4 
CHANGES FROM PLANNED ANALYSIS 
 The protocol indicates the primary analysis population is restricted to FISH performed by a 
central laboratory. However, this was not the case and therefore reference to central FISH has 
been removed  
 Safety/ITT Population has been updated from "All patients who receive any amount of study 
drug” to 2 separate definitions for each substudy to take into consideration the substudy that each 
patient was enrolled in: 
o The Safety/ITT population for Substudy 1 will include all patients with locally or 
centrally confirmed FGFR2 fusions/rearrangements who receive any amount of study 
drug.    
o The Safety/ITT population for Substudy 2 will include all patients with locally confirmed 
FGFR2 mutations or amplifications who receive any amount of study drug.    
 The mITT population definition was updated from “All patients who receive any amount of study 
drug and have at least one post-baseline disease assessment.” to “All patients in the Safety/ITT 
population, and have at least one post-baseline disease assessment (at least one post-baseline 
imaging assessment in accordance with RECIST 1.1, or documented clinical progression [every 
effort should be made to objectively assess radiographic progression]). Patients who have 
primary reason for discontinuation as death will be included in the mITT population.” 
 The PP population was updated from “All patients in the mITT Population who have no major 
protocol violations during the study, receive at least one cycle (28 doses) of ARQ 087, have at 
least one post-baseline efficacy measurement, and test positive for FGFR2 gene fusion by the 
central laboratory” to “will include all patients in the mITT population who have no important 
protocol (IPD) deviations which are determined to potentially impact efficacy analyses during the 
study. Protocol deviations will be identified prior to final analysis.” This was to reflect the 
Labcorp standard to use “important” rather than “major”, and furthermore to allow flexibility in 
defining those IPDs that may affect the efficacy endpoints. 
 DCR has been added as an exploratory efficacy endpoint, and is defined as the achievement of 
confirmed CR or PR or SD (or Non-CR/Non-PD for patients with non-measurable disease).   
 The minimum duration of SD in the protocol had referenced both 8 weeks (+/-2 days) on page 
101 and 8 weeks (+/- 3 days) on page 105 of the protocol. Following client discussion, it was 
decided that the minimum duration of SD should instead be at least 6 weeks i.e. 42 days as per 
RECIST guidelines. This minimum duration will also apply to Non-CR/Non-PD. 
 Although RECIST does not expect the best overall response to include non-CR/non-PD (NN) for 
non-measurable disease, in the event that this happens it will be treated as its only entity and in 
terms of hierarchy it will fall between SD and PD. 
 Exploratory endpoints have been added to take into consideration of investigator assessments for 
ORR, PFS and DCR. 
 


 
 
 
 
 
 
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5 
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