Conditions: Carcinoma, Transitional Cell
Keywords: Urothelial carcinoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 175
Healthy volunteers: no

Brief summary:
This is a randomized, open-label, multicenter Phase 2/3 study to evaluate the efficacy and safety of rogaratinib (BAY 1163877) compared to chemotherapy in patients with FGFR-positive locally advanced or metastatic urothelial carcinoma who have received prior platinum-containing chemotherapy.

The primary objective is to demonstrate the superiority of rogaratinib over chemotherapy in terms of objective response rate (before: overall survivial) of urothelial carcinoma patients with FGFR positive tumors.

At randomization, patients will have locally advanced or metastatic urothelial carcinoma and have received at least one prior platinum-containing chemotherapy regimen. Only patients with FGFR1 or 3 positive tumors can be randomized into the study. Archival tumor tissue is adequate for testing of FGFR1 and 3 mRNA expressions, which will be determined centrally using an RNA in situ hybridization (RNA-ISH) test. Approximately 42 % of UC patients with locally advanced or metastatic UC are identified as FGFR-positive by the RNA-ISH cut-off applied.

Detailed description:

Arms:
arm 1: Rogaratinib treatment study arm, comprising

1. Pre-treatment period, including FGFR testing and screening,
2. Treatment period, and
3. Follow-up period, including active follow-up and long-term follow-up. Patients will be considered "on study" during the pre-treatment, treatment and active followup periods. During the long-term follow-up period the patients will be considered "off study". arm 2: Chemotherapy treatment study arm, comprising

1. Pre-treatment period, including FGFR testing and screening,
2. Treatment period, and
3. Follow-up period, including active follow-up and long-term follow-up. Patients will be considered "on study" during the pre-treatment, treatment and active followup periods. During the long-term follow-up period the patients will be considered "off study".

Interventions: intervention 1: Rogaratinib (BAY1163877) intervention 2: Chemotherapy
Intervention descriptions: intervention 1: Rogaratinib administered as oral (p.o.) tablets twice daily (b.i.d.) continuously intervention 2: Chemotherapy as taxane (docetaxel or paclitaxel) or vinflunine administered through intravenous (i.v.) infusion every 3 weeks (on day 1 of a 21-day cycle) The choice of the chemotherapy is at the discretion of the investigator, taking into consideration the status of the authorization or treatment guidelines in the given country.

Protocol document:
Prot_000.pdf: 
 
Document Type: 
Clinical Study Protocol 
Official Title: 
A randomized, open label, multicenter Phase 2/3 study to evaluate 
the efficacy and safety of rogaratinib (BAY1163877) compared to 
chemotherapy in patients with FGFR-positive locally advanced or 
metastatic urothelial carcinoma who have received prior platinum-
containing chemotherapy 
NCT Number: 
NCT03410693 
Document Date: 
19 NOV 2019 
 


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Cover page of the integrated protocol
A randomized, open label, multicenter Phase 2/3 study to evaluate the efficacy and 
safety of rogaratinib (BAY 1163877) compared to chemotherapy in patients with 
FGFR-positive locally advanced or metastatic urothelial carcinoma who have received 
prior platinum-containing chemotherapy
This protocol version is an integration of the following documents/sections:

Original protocol, Version 1.0, dated 29 NOV 2017

Amendment no. 3 (global amendment described in Section 15.1)
forming integrated protocol Version 2.0, dated 09 MAY 2019

Amendment no. 4 (global amendment described in Section 15.2)
forming integrated protocol Version 3.0, dated 12 NOV 2019
This document integrates the original protocol and all global amendments.
Amendments not included in the consecutive numbering of amendments are local 
amendments not forming part of this integrated global protocol. This currently includes:

Amendment no. 1 (local amendment for UK only) dated 22 JAN 2018

Amendment no. 2 (local amendment for France only) dated 19 MAR 2018


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1.
Title page
A randomized, open label, multicenter Phase 2/3 study to evaluate the efficacy and safety of 
rogaratinib (BAY 1163877) compared to chemotherapy in patients with FGFR-positive
locally advanced or metastatic urothelial carcinoma who have received prior platinum-
containing chemotherapy 
Short title:
Phase 2/3 study of rogaratinib (BAY 1163877) vs chemotherapy 
in patients with FGFR-positive locally advanced or metastatic 
urothelial carcinoma 
Acronym:
FORT-1
Test drug:
BAY 1163877 / rogaratinib 
Study purpose:
Assess the efficacy and safety of rogaratinib compared to 
chemotherapy 
Clinical study phase:
Phase 2/3
Date:
12 NOV 2019
Registration:
EudraCT: 2016-004340-11 
Version no.:
3.0
Sponsor’s study no.:
17403 
Sponsor:
Bayer AG, D-51368 Leverkusen, Germany 
US territory: Bayer HealthCare Pharmaceuticals Inc., 100 Bayer 
Boulevard, P.O. Box 915, Whippany NJ 07981-0915, USA 
Sponsor’s medical expert:
Bayer U.S. LLC
100 Bayer Blvd, PO Box 915
Whippany, NJ, 07981 USA
Telephone no.: 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements.
Confidential
The information provided in this document is strictly confidential and is intended solely for 
the guidance of the clinical investigation. Reproduction or disclosure of this 
document - whether in part or in full - to parties not associated with the clinical 
investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (, TM) may not be displayed. 
Hence, the appearance of product names without these symbols does not imply that these names 
are not protected.
PPD
PPD


PPD
PPD
PPD


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Signature of principal investigator
The signatory agrees to the content of the final clinical study protocol as presented.
Name:
Affiliation:
Date:
Signature:
Signed copies of this signature page are stored in the sponsor’s study file and in the respective 
center’s investigator site file.
In the protocol document, this page may remain unsigned.


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2.
Synopsis
Title
A randomized, open label, multicenter, Phase 2/3 study to evaluate the 
efficacy and safety of rogaratinib (BAY 1163877) compared to 
chemotherapy in patients with FGFR-positive locally advanced or 
metastatic urothelial carcinoma who have received prior platinum-
containing chemotherapy 
Short title
Phase 2/3 study of rogaratinib (BAY 1163877) vs chemotherapy in patients 
with FGFR-positive locally advanced or metastatic urothelial carcinoma 
Acronym
FORT-1
Clinical study phase
Phase 2/3 
Study objectives
The original objectives of the study are provided below:
Primary objective:

To demonstrate the superiority of rogaratinib over chemotherapy in 
terms of prolonging overall survival of urothelial carcinoma patients 
with FGFR positive tumors. 
Secondary objectives:

To evaluate additional efficacy including the following variables:
o
progression-free survival (PFS)
o
objective response rate (ORR)
o
disease control rate (DCR)
o
duration of response (DOR)

To evaluate the safety of rogaratinib (adverse events) 
Tertiary objectives:

Patient-reported outcome (PRO) 

Evaluate biomarkers to investigate the drug (i.e. mode-of-action-
related effect and/or safety) and/or the pathomechanism of the disease 

Pharmacokinetics
The objective for the Phase 2 part of the study is to demonstrate the 
efficacy of rogaratinib over chemotherapy in terms of objective response 
rate of urothelial carcinoma patients with FGFR positive tumors. The 
Phase 3 part of the study will no longer be conducted, therefore OS will be 
considered an exploratory efficacy variable for the Phase 2.
Test drug
BAY 1163877 
Name of active ingredient
Rogaratinib (BAY 1163877) 
Dose(s)
600 mg twice daily (b.i.d.), continuously 


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Route of administration
oral 
Duration of treatment
Patients may continue on study treatment until any of the following events 
occur:

Radiological disease progression according to RECIST v.1.1 as 
assessed by independent central radiology review. 
o
At the investigator’s discretion, study treatment may continue 
beyond centrally confirmed radiological progression as defined by 
RECIST v.1.1 if the clinical condition of the patient is stable or the 
patient is improving symptomatically, and the investigator expects 
continued clinical benefit for the patient

Clinical progression

Unacceptable toxicity

Death

Withdrawal of consent

Withdrawal from the study treatment at the discretion of the 
investigator or designated associate(s)
Comparator drugs
Taxane (docetaxel or paclitaxel) 
Vinflunine 
The choice of the chemotherapy is at the discretion of the investigator, 
taking into consideration the status of the authorization or treatment 
guidelines in the given country.
Name of active ingredient
Taxane (docetaxel or paclitaxel) 
Vinflunine 
Doses
Docetaxel 75 mg/ m²
Paclitaxel 175 mg/ m²
Every three weeks on D1 of the cycle
Vinflunine 320 mg/ m²
Every three weeks on D1 of the 
cycle
Route of administration
intravenous infusion 
intravenous infusion 
Duration of treatment
See test drug above.
Indication
Patients with FGFR-positive locally advanced or metastatic urothelial 
carcinoma who have received prior platinum-containing chemotherapy 
Diagnosis and main criteria for 
inclusion /exclusion
Patients with FGFR-positive locally advanced or metastatic urothelial 
carcinoma who have received prior platinum-containing chemotherapy 
Main inclusion criteria:

Existence of archival or fresh biopsy for FGFR testing. Mandatory 
FGFR testing of patients will be performed prior to start of screening. 
The timing of the FGFR test is at the discretion of the investigator. 
Investigators should ensure all patients will be eligible in terms of 
disease status and lines of treatment within this timeframe.

Male or female patients ≥ 18 years of age


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
Documented urothelial carcinoma (transitional cell carcinoma) 
including urinary bladder, renal pelvis, ureters, urethra meeting all of 
the following criteria 
o
Histologically confirmed 

Patients with mixed histologies are required to have a 
dominant transitional cell pattern. 
o
Locally advanced (T4, any N; or any T, N 2−3) or metastatic 
disease (any T, any N and M1). 
Locally advanced bladder cancer must be unresectable i.e. 
invading the pelvic or abdominal wall (stage T4b) or presenting 
with bulky nodal disease (N2-3). 

ECOG Performance Status of 0 or 1

Disease progression during or following treatment with at least one 
platinum-containing regimen (patients should have been treated for at 
least 2 cycles). In patients who received prior adjuvant/neoadjuvant 
platinum-containing chemotherapy, progression had to occur within 12 
months of treatment. 

High FGFR1 or 3 mRNA expression levels in archival or fresh tumor 
biopsy specimen quantified as outlined in the lab manual

At least 1 measurable lesion according to Response Evaluation Criteria 
in Solid Tumors (RECIST v.1.1) in contrast enhanced (unless 
contraindicated) CT or MRI
Main exclusion criteria:

Previous or concurrent cancer except 
o
cervical carcinoma in situ 
o
treated basal-cell or squamous cell skin carcinoma 
o
any cancer curatively treated > 3 years before randomization
o
Curatively treated incidental prostate cancer (T1/T2a) 

Ongoing or previous anti-cancer treatment within 4 weeks before 
randomization. 

More than two prior lines of systemic anti-cancer therapy for urothelial 
carcinoma given for advanced unresectable/metastatic disease.

Ongoing or previous treatment with anti-FGFR directed therapies (e.g. 
receptor tyrosine kinase inhibitors including rogaratinib or FGFR-
specific antibodies) or with taxanes or vinflunine

Unresolved toxicity higher than National Cancer Institute’s Common 
Terminology Criteria for Adverse Events, version 4.03 (CTCAE 
v.4.03) Grade 1 attributed to any prior therapy/procedure excluding 
alopecia, anemia and/or hypothyroidism

History or current condition of an uncontrolled cardiovascular disease 
including any of the following conditions: 
o
Congestive heart failure (CHF) NYHA > Class 2
o
Unstable angina (symptoms of angina at rest) or new-onset angina 


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(within last 3 months before randomization) 
o
Myocardial infarction (MI) within past 6 months before 
randomization 
o
Unstable cardiac arrhythmias requiring anti-arrhythmic therapy. 
Patients with arrhythmia under control with anti-arrhythmic 
therapy such as beta-blockers or digoxin are eligible. 

Arterial or venous thrombotic events or embolic events such as 
cerebrovascular accident (including transient ischemic attacks), deep 
vein thrombosis or pulmonary embolism within 3 months before 
randomization 

Current evidence of endocrine alteration of calcium phosphate 
homeostasis (e.g. parathyroid disorder, history of parathyroidectomy, 
tumor lysis, tumoral calcinosis, paraneoplastic hypercalcemia) 

Any hemorrhage / bleeding event ≥ CTCAE v.4.03 Grade 3 within 4 
weeks before randomization 

Current diagnosis of any retinal detachment, retinal pigment epithelial 
detachment (RPED), serous retinopathy or retinal vein occlusion
For the complete list of inclusion and exclusion criteria, please refer to 
Sections 6.1 and 6.2 of this protocol.
Study design
Randomized, open-label, multicenter Phase 2/3 study.  
The study is composed of the following periods:

Pre-treatment period, including
o
FGFR testing 
The FGFR1&3 RNA in situ hybridization (RNA-ISH) test is used 
for the detection of FGFR1 and FGFR3 mRNA levels in formalin-
fixed, paraffin-embedded (FFPE) tumor tissue from urothelial 
carcinoma patients.
Mandatory FGFR testing will be performed prior to start of 
screening (signing of informed consent for study treatment 
eligibility). The timing of the FGFR test is at the discretion of the 
investigator.
During the FGFR testing period, and after a positive FGFR test 
result was obtained, these samples are also tested for presence or 
absence of potential FGFR inhibitor resistance mutations in 
phosphoinositide 3-kinase catalytic subunit alpha isoform 
(PIK3CA) and/or in the human orthologues of rat sarcoma (RAS) 
encoding genes. The outcome of the mutation testing will not 
affect the study eligibility, it will be used for patient stratification.
o
Screening
Only patients with FGFR positive tumors are eligible to continue 
to the screening which will be scheduled within 28 days before 
randomization.

Treatment period


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Patients who meet all the eligibility criteria at screening will be 
randomized 1:1 using an Interactive Voice/Web Response System 
(IxRS) to receive either an oral regimen of continuous rogaratinib b.i.d. 
or chemotherapy (docetaxel, paclitaxel or vinflunine) administered 
through intravenous (i.v.) infusion every 3 weeks as a comparator drug 
(investigators choice). Randomization will be stratified by PIK3CA 
and/or RAS activating mutations (presence vs. absence), prior 
immunotherapy (yes vs. no), and modified 4-factor Bellmunt risk score 
(high vs. low). 

Follow-up period, including
o
Active follow-up
Safety information is collected for all discontinued patients for at 
least 30 (up to +7) days after the last administration of study 
treatment, and both safety and efficacy information is collected for 
patients who discontinue study treatment without disease 
progression. Follow-up tumor evaluations will be performed (by 
CT or MRI) until progression of malignancy and/or start of 
subsequent systemic anti-cancer treatment, whichever comes first, 
or any other criterion for withdrawal is met.
o
Long-term follow-up 
Patients will be contacted (telephone contact is sufficient) every 
month (±7 days) to determine survival status and obtain 
information on subsequent systemic anti-cancer treatment until 
either data maturation for the final planned OS analysis is reached, 
death of the patient or any other criterion for withdrawal is met.
Phase 2/3 design
This study follows a Phase 2/3 design with interim analysis, meaning the 
patients recruited to the Phase 2 part of the study will automatically 
continue to the Phase 3 part without interruption if futility is not 
demonstrated at the 1st interim ORR analysis. 
The Phase 2 part will end at the time of the cut-off for the 1st interim ORR
analysis. To help structure the protocol flow, we present this Phase 2/3 
study as one study protocol with two interim analyses, while the first 
interim indicates the end of the Phase 2 part, and the second and final 
analyses are considered the Phase 3 part including Phase 2 patients in the 
analyses.
The Phase 2 part of the study ends when the first approximately 116 
confirmed FGFR positive patients with wild-type PIK3CA and RAS 
biomarkers have completed 4.5 months of treatment, at which time the 
analysis of Phase 2 part will be triggered. A DMC meeting will be 
scheduled to review the Phase 2 data. Decisions on trial termination, 
amendment or cessation of patient recruitment based on risk benefit 
assessments will be made after recommendations from the DMC have been 
assessed by the sponsor. In the meantime, the study will continue its routine 
recruitment until trial termination or recruitment cessation decisions are 
announced.
If the decision is made to continue the study at the end of Phase 2 period, 
the study moves on to Phase 3 part of the study. Randomization and 
treatment continue the same as the Phase 2 part of the study until 390 


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deaths are seen in the PIK3CA and RAS WT patients.
Before achieving the criteria for the first interim analysis, the study
recruitment was put on hold after a recommendation of the study DMC. 
The sponsor decided to perform a full analysis and review of all study data
and stopped the recruitment permanently. Due to the stop of enrollment and 
full data analysis, the study will not move forward to its Phase 3 and will 
remain as Phase 2. The study will remain open until the survival data is 
considered adequate for analysis by the sponsor.
Methodology
Efficacy
For OS (original primary variable planned for the Phase 3 part), all patients 
who end study treatment for any reason (except death) will be contacted to 
assess survival until death, or any other criterion for withdrawal is met. 
The secondary efficacy endpoints (PFS, ORR, DCR, and DOR) will be 
assessed based on central radiological tumor evaluation. Tumor 
assessments will be performed by contrast-enhanced (unless 
contraindicated) computed tomography (CT) or magnetic resonance 
imaging (MRI) of chest/abdomen/pelvis at screening, every 6 weeks (± 7 
days) starting from Cycle 1 Day 1 up to week 18, and thereafter, every 9 
weeks (± 7 days). A minimum of at least 6 weeks from start of treatment is 
mandatory for the 1st “on treatment” tumor assessment. In addition, brain 
and bone scans are required at screening. The brain and bone scans need to 
be repeated only if metastases or symptoms are present. Tumor scans are 
evaluated using RECIST v.1.1. All images need to be submitted 
continuously for independent central imaging review.
The efficacy endpoint for the Phase 2 part of the study is ORR.
OS data will be collected as an exploratory efficacy endpoint for the 
Phase 2. All patients who end study treatment for any reason (except death) 
will be contacted to assess survival until death, or any other criterion for 
withdrawal is met.
Safety
Safety and tolerability evaluations will be included in results of physical 
examinations, vital signs, 12-lead electrocardiogram (ECG) readings, 
adverse events, concomitant medications and laboratory tests. In addition, 
ophthalmological examinations will be performed. Each patient will be 
regularly monitored for potential adverse events and disease related signs 
and symptoms. AEs will be graded according to The Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.03. Laboratory toxicities
will be graded according to CTCAE v.4.03 based on numerical laboratory 
values only.
Patient reported outcome (PRO)
Patient reported outcomes will be assessed using EORTC QLQ-C30 and 
EQ-5D-3L (at screening, on Day 1 of every cycle, at the EOT, and at the 
safety assessment visit of the active follow-up). 
Pharmacokinetics
Plasma samples for measurement of rogaratinib (BAY 1163877) 
concentrations will be collected on Day 1 of Cycle 1, 2, 3, 4 and 5 at pre-
dose (before supervised dose administration) and 1 (±0.5) hour post-dose.


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Main biomarker investigations
For all patients to be enrolled, a biomarker analysis will be done before 
randomization on either a fresh or archival tumor biopsy sample to confirm 
high expression levels of fibroblast growth factor receptor (FGFR) mRNA 
using FGFR1&3 RNA in situ hybridization (RNA-ISH) test. The tumor 
biopsy sample will also be used to test for presence or absence of potential 
FGFR inhibitor resistance mutations in PIK3CA and/or RAS-encoding 
genes in FGFR-positive patients. The detection of activating mutations in 
PIK3CA and/or RAS-encoding genes will be conducted using 
commercially available assays. 
Type of control
Active control: chemotherapy (docetaxel, paclitaxel or vinflunine). The 
choice of the chemotherapy is at the discretion of the investigator taking 
into consideration the status of the authorization or treatment guidelines in 
the given country. 
Data Monitoring Committee
Yes 
Number of patients
Although both PIK3CA and/or RAS mutant and wild type (WT) patients 
are recruited, this study is powered for the PIK3CA and RAS WT 
subgroup. Therefore, the recruitment will stop when approximately 450 
PIK3CA and RAS WT patients who meet all selection criteria are randomly 
assigned in a 1:1 ratio, using IxRS, to one of the following treatment arms:

Rogaratinib, or

Chemotherapy
Based on a current assumption that roughly 75% of all study population are 
PIK3CA and RAS WT patients, at the time when 450 WT patients are 
randomized, approximately a total of 600 patients (450 WT + 150 mutant 
patients) will be randomized in the all study population.
Primary variable
The primary efficacy variable of Phase 2 is ORR, and will be analyzed 
based on central review assessment. 
Overall survival (defined as the time from randomization until death from 
any cause) will be considered an exploratory efficacy variable for the Phase 
2, since the Phase 3 part of the study will no longer be conducted.
Time point/frame of 
measurement for primary 
variable(s)
Due to the stop of enrollment and full data analysis, the study will not move 
forward to its Phase 3 and will remain as Phase 2. The study will remain 
open until the survival data is considered adequate for analysis by the 
sponsor.
Originally planned analyses are given below as reference to the original 
design. 
Final OS analysis: at approx. 390 deaths in WT population (approx. 
43 months after the start of randomization).
In addition, two interim analyses are planned:

1st interim ORR analysis (Phase 2 part): at approx. the first 116 
confirmed FGFR positive patients with wild-type PIK3CA and RAS 
biomarkers complete 4.5 months of treatment


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
2nd interim OS analysis (Phase 3 part): at approx. 195 deaths in 
PIK3CA and RAS WT patients (50% of 390 total death events in WT 
population, approx. 22 months after start of randomization)
Plan for statistical analysis
The formal statistical analyses will be both descriptive and inferential. 
Summaries will be provided for each of the treatment arms, rogaratinib and 
chemotherapy in both PIK3CA and RAS WT and all study population. In 
addition, descriptive summaries of population characteristics will be 
provided for the total study population. 
Efficacy analyses
In Phase 3, the primary efficacy variable is overall survival (OS). OS data 
will be considered mature and the final OS analysis (i.e. primary 
completion) will be performed when approximately a total of 390 PIK3CA 
and RAS WT patients have died, in accordance with the power calculations 
specified for the full analysis set (FAS). For the primary efficacy variable 
of overall survival, a stratified log-rank test controlling type I error at a 
level of 0.025 (one-sided) will be conducted for the WT population first 
(step 1). A full alpha of 0.025 (one-sided) will be passed on to OS in all 
study population and some selected secondary endpoints (step 2), if and 
only if the null hypothesis of OS for WT population is rejected. Details on 
controlling family-wise type I error within step 2 for OS in all study 
population and selected secondary endpoints will be specified in the 
Statistical Analysis Plan (SAP).
In addition, the hazard ratio (rogaratinib / chemotherapy) for OS and its 
95% confidence interval will be calculated using the Cox model, stratified 
by the same factors used for randomization, for both PIK3CA and RAS WT 
and all study population (referred as “both populations” below). Kaplan-
Meier (KM) estimates for OS and KM survival curves will also be 
presented for each treatment arm and both populations. The KM estimates 
at time points such as 3 months, 6 months etc. together with corresponding 
95% confidence intervals as well as the differences of these estimates will 
also be calculated between the rogaratinib arm and the chemotherapy arm 
for both populations.
The primary efficacy variable of Phase 2 is ORR, and will be analyzed 
based on central review assessment. Due to the stop of enrollment and full 
data analysis, the study will not move forward to its Phase 3 and will 
remain as Phase 2. The study will remain open until the survival data is 
considered adequate for analysis by the sponsor.
Secondary efficacy variables include PFS, DCR and DOR based on central 
review assessments. Formal testing procedure with respect to PFS in WT 
and all study population will be specified in a separate Statistical Analysis 
Plan (SAP) document. Since the responders are not a randomized group, no 
statistical testing will be performed for DOR. Analysis of DOR will be 
descriptive in nature. 
Safety analyses
Summary of adverse events (AEs) is considered a secondary objective for 
the study. Descriptive tables will be presented by treatment arm for both 
populations. AEs will be summarized by the Medical Dictionary for 
Regulatory Activities (MedDRA) terms (v.20.0 or later) and worst grade 
based on the National Cancer Institute (NCI) Common Terminology 


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Criteria Adverse Event (CTCAE), version 4.03. For all events, the 
relationship to treatment and the severity of the event will be determined by 
the investigator and summarized by treatment for both populations. 
Further efficacy and safety analyses details will be outlined in Section 10 of 
this protocol and in the Statistical Analysis Plan (SAP).


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Table of contents
Cover page of the integrated protocol.................................................................................... 1
1.
Title page............................................................................................................................ 2
Signature of the sponsor’s medically responsible person..................................................... 3
Signature of principal investigator......................................................................................... 4
2.
Synopsis.............................................................................................................................. 5
Table of contents..................................................................................................................... 14
Table of tables......................................................................................................................... 17
Table of figures....................................................................................................................... 18
List of abbreviations............................................................................................................... 19
3.
Introduction..................................................................................................................... 24
3.1
Background.................................................................................................................... 24
3.2
Rogaratinib..................................................................................................................... 24
3.2.1
Mode of action............................................................................................................ 24
3.2.2
Clinical experience with rogaratinib........................................................................... 25
3.3
Chemotherapy................................................................................................................ 26
3.4
Rationale of the study .................................................................................................... 27
3.5
Benefit-risk assessment.................................................................................................. 27
4.
Study objectives............................................................................................................... 29
5.
Study design..................................................................................................................... 29
5.1
Design overview ............................................................................................................ 29
5.2
Study periods ................................................................................................................. 33
5.2.1
Pre-treatment period ................................................................................................... 33
5.2.2
Treatment period......................................................................................................... 33
5.2.3
Follow-up periods....................................................................................................... 34
5.2.3.1
Active follow-up ..................................................................................................... 34
5.2.3.2
Long-term follow-up............................................................................................... 34
5.3
Primary variable............................................................................................................. 35
5.4
Justification of the design .............................................................................................. 35
5.5
End of study................................................................................................................... 37
5.6
Primary completion........................................................................................................ 38
6.
Study population ............................................................................................................. 38
6.1
Inclusion criteria ............................................................................................................ 39
6.2
Exclusion criteria ........................................................................................................... 42
6.3
Justification of selection criteria.................................................................................... 46
6.4
Withdrawal of patients from study ................................................................................ 46
6.4.1
Withdrawal ................................................................................................................. 46
6.4.1.1
Screening failure ..................................................................................................... 46
6.4.1.2
Re-screening............................................................................................................ 47


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6.4.1.3
Withdrawal criteria.................................................................................................. 47
6.4.1.4
General procedures.................................................................................................. 50
6.4.2
Replacement ............................................................................................................... 51
6.5
Patient identification...................................................................................................... 51
7.
Treatments....................................................................................................................... 51
7.1
Treatments to be administered....................................................................................... 51
7.2
Identity of study treatment............................................................................................. 51
7.2.1
Rogaratinib (test drug)................................................................................................ 52
7.2.2
Chemotherapy (comparator drugs)............................................................................. 53
7.3
Treatment assignment.................................................................................................... 54
7.4
Dosage and administration............................................................................................. 54
7.4.1
Doses, dosing schedule and route of administration .................................................. 54
7.4.2
Justification of selected doses..................................................................................... 56
7.4.3
Dose modifications..................................................................................................... 56
7.4.3.1
Dose modifications of rogaratinib........................................................................... 56
7.4.3.2
Dose modifications of chemotherapy (comparator drugs)...................................... 60
7.4.4
Treatment duration ..................................................................................................... 64
7.5
Blinding ......................................................................................................................... 65
7.6
Drug logistics and accountability................................................................................... 65
7.7
Treatment compliance.................................................................................................... 66
8.
Non-study therapy........................................................................................................... 66
8.1
Prior and concomitant therapy....................................................................................... 66
8.2
Post-study therapy.......................................................................................................... 68
9.
Procedures and variables ............................................................................................... 69
9.1
Tabular schedule of evaluations .................................................................................... 69
9.2
Visit description............................................................................................................. 76
9.2.1
Pre-treatment period ................................................................................................... 76
9.2.1.1
FGFR testing ........................................................................................................... 76
9.2.1.2
Screening................................................................................................................. 77
9.2.2
Treatment period......................................................................................................... 79
9.2.2.1
Day 1 of Cycle 1...................................................................................................... 80
9.2.2.2
Day 8 of Cycle 1...................................................................................................... 82
9.2.2.3
Day 15 of Cycle 1.................................................................................................... 82
9.2.2.4
Day 1 of Cycle 2...................................................................................................... 83
9.2.2.5
Day 15 of Cycle 2.................................................................................................... 85
9.2.2.6
Day 1 of Cycle ≥ 3 .................................................................................................. 85
9.2.2.7
Tumor assessments during treatment period........................................................... 87
9.2.2.8
End-of-treatment (EOT) visit.................................................................................. 88
9.2.3
Follow-up periods....................................................................................................... 89
9.2.3.1
Active follow-up ..................................................................................................... 89
9.2.3.2
Long-term follow-up............................................................................................... 91
9.3
Population characteristics .............................................................................................. 91
9.3.1
Demographic .............................................................................................................. 91
9.3.2
Medical history........................................................................................................... 92


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9.3.3
Other baseline characteristics..................................................................................... 92
9.4
Efficacy.......................................................................................................................... 94
9.4.1
Radiological tumor assessments................................................................................. 95
9.5
Pharmacokinetics / pharmacodynamics......................................................................... 97
9.6
Safety ............................................................................................................................. 98
9.6.1
Adverse events............................................................................................................ 98
9.6.1.1
Definitions............................................................................................................... 98
9.6.1.2
Classifications for adverse event assessment........................................................ 100
9.6.1.3
Assessments and documentation of adverse events .............................................. 102
9.6.1.4
Reporting of serious adverse events ...................................................................... 104
9.6.1.5
Expected adverse events........................................................................................ 105
9.6.1.6
Adverse events of special safety interest............................................................... 105
9.6.2
Pregnancies............................................................................................................... 105
9.6.3
Further safety............................................................................................................ 106
9.6.3.1
Laboratory evaluations.......................................................................................... 106
9.6.3.2
Physical examinations........................................................................................... 107
9.6.3.3
12-lead ECG.......................................................................................................... 108
9.6.3.4
Vital signs (including height and body weight) .................................................... 109
9.6.3.5
ECOG performance status..................................................................................... 109
9.6.3.6
Ophthalmological examination ............................................................................. 110
9.7
Other procedures and variables.................................................................................... 111
9.7.1
Biomarker investigations.......................................................................................... 111
9.7.2
Patient-reported outcomes (PRO)............................................................................. 113
9.7.3
Healthcare resource utilization................................................................................. 114
9.8
Appropriateness of procedures / measurements .......................................................... 114
10. Statistical methods and determination of sample size ............................................... 114
10.1
General considerations................................................................................................. 114
10.2
Analysis sets ................................................................................................................ 115
10.3
Variables and planned statistical analyses................................................................... 116
10.3.1
Efficacy variables ..................................................................................................... 116
10.3.1.1
Primary efficacy variable ...................................................................................... 116
10.3.1.2
Secondary efficacy variables................................................................................. 117
10.3.1.3
Subgroup analyses................................................................................................. 118
10.3.2
Safety variables......................................................................................................... 118
10.3.2.1
Adverse events (AEs)............................................................................................ 118
10.3.2.2
Deaths and serious adverse events (SAEs) ........................................................... 119
10.3.2.3
AEs leading to discontinuation of study treatment and/or withdrawal from the 
study and other significant AEs ............................................................................ 119
10.3.2.4
Clinical laboratory evaluations.............................................................................. 119
10.3.2.5
Other safety measures ........................................................................................... 120
10.3.3
Other variables.......................................................................................................... 120
10.3.3.1
Pharmacokinetic variables..................................................................................... 120
10.3.3.2
Biomarker variables .............................................................................................. 120
10.3.3.3
Patient-reported outcomes (PRO) ......................................................................... 120


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10.4
Determination of sample size....................................................................................... 121
10.5
Planned interim analyses ............................................................................................. 122
11. Data handling and quality assurance.......................................................................... 123
11.1
Data recording.............................................................................................................. 123
11.2
Monitoring ................................................................................................................... 126
11.3
Data processing............................................................................................................ 126
11.4
Missing data................................................................................................................. 127
11.5
Audit and inspection .................................................................................................... 127
11.6
Archiving ..................................................................................................................... 127
12. Premature termination of the study ............................................................................ 128
13. Ethical and legal aspects............................................................................................... 129
13.1
Investigator(s) and other study personnel.................................................................... 129
13.2
Funding and financial disclosure ................................................................................. 130
13.3
Ethical and legal conduct of the study......................................................................... 131
13.4
Patient information and consent .................................................................................. 131
13.4.1
PI/ICF for FGFR testing........................................................................................... 131
13.4.2
PI/ICF for study treatment eligibility ....................................................................... 132
13.4.3
PI/ICF for collection of data on pregnancy and birth............................................... 133
13.4.4
PI/ICF on study updates ........................................................................................... 133
13.5
Publication policy and use of data ............................................................................... 133
13.6
Compensation for health damage of patients / insurance ............................................ 134
13.7
Confidentiality ............................................................................................................. 134
14. Reference list.................................................................................................................. 135
15. Protocol amendments.................................................................................................... 138
15.1
Amendment no.3.......................................................................................................... 138
15.2
Amendment no.4.......................................................................................................... 146
16. Appendices..................................................................................................................... 148
16.1
CYP3A4 inhibitors and inducers ................................................................................. 148
16.2
Response Evaluation Criteria in Solid Tumors (RECIST) .......................................... 148
16.3
New York Heart Association (NYHA) classification.................................................. 153
16.4
Estimated glomerular filtration rate (eGFR) calculation ............................................. 153
Table of tables
Table 7–1: Identity of test drug (IMP): rogaratinib (BAY 1163877) ...................................... 53
Table 7–2: Dose levels of rogaratinib (BAY 1163877)........................................................... 56
Table 7–3: Criteria for dose modification of rogaratinib due to toxicity (excluding 
hyperphosphatemia, liver toxicity, retinal disorders)............................................ 57
Table 7–4: Dose modifications of rogaratinib and management for hyperphosphatemia....... 58
Table 7–5: Dose modifications of rogaratinib for liver toxicity .............................................. 59
Table 7–6: Dose delay for subsequent cycles of vinflunine due to toxicity ............................ 61


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Table 7–7: Vinflunine dose adjustments due to toxicity.......................................................... 62
Table 7–8: Vinflunine dose adjustments due to toxicity in renal impaired or elderly patients 63
Table 9–1: Tabular schedule of evaluations............................................................................. 70
Table 9–2: Guidance for calculating modified 4-factor Bellmunt risk score........................... 94
Table 9–3: Definitions for ECOG PS grading ....................................................................... 110
Table 10–1: Summary of planned interim and final analyses................................................ 123
Table 16–1: Strong CYP3A4 inhibitors and inducers............................................................ 148
Table 16–2: Target and non-target lesion response ............................................................... 151
Table 16–3: New York Heart Association (NYHA) categories............................................. 153
Table of figures
Figure 5–1: Study 17403 – Design overview........................................................................... 31
Figure 5–2: Overview of the original Phase 2/3 design........................................................... 32


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List of abbreviations
ADL
Activities of Daily Living
AE
Adverse event
AESI
Adverse event of special interest
AG
Joint stock company, Aktiengesellschaft
AJCC
American Joint Committee on Cancer
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AML
Acute myeloid leukemia
ANC
Absolute neutrophil count
ANCOVA
Analysis of covariance
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
AUC
Area under the curve
AZD4547
Fibroblast growth factor receptor (FGFR) tyrosine kinase family inhibitor
b.i.d.
Twice daily, bis in die
BCRP
Breast cancer resistance protein
BP
Blood pressure
BSA
Body surface area
BSC
Best supportive care
BUN
Blood urea nitrogen
°C
Degree(s) Celsius
CA
California
CD8A
Cluster of differentiation 8A (T-cell surface glycoprotein)
CDL
Clinical Development Leader
CHF
Congestive heart failure
CI
Confidence interval
Cmax
Maximal plasma concentration
cMet
Tyrosine-protein kinase Met
CMH
Cochran-Mantel-Haenszel
cMyc
v-Myc myelocytomatosis viral oncogene homolog
CNS
Central nervous system
CR
Complete response
CrCl
Creatinine clearance
CRO
Contract research organization
CSR
Central serous retinopathy
CT
Computed tomography
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
Circulating tumor DNA
CTLA-4
Cytotoxic T-lymphocyte–associated antigen 4
CxDx
Cycle x Day x
CYP
Cytochrome P450


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CYP3A4
Cytochrome P450, family 3, subfamily A, polypeptide 4
DCR
Disease control rate
DICOM
Digital Imaging and Communications in Medicine
dL
Deciliter
DLT
Dose-limiting toxicity
DMC
Data monitoring committee
DNA
Deoxyribonucleic acid
DOR
Duration of response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic data capture
e.g.
For example, exempli gratia
eGFR
Estimated glomerular filtration rate
EORTC
European Organisation for Research and Treatment of Cancer
EOT
End of treatment
EQ-5D-3L
EuroQol Group’s five dimensions questionnaire
ERK
Extracellular-signal-regulated kinase
eTMF
Electronic trial master file
EU
European Union
EudraCT
European Clinical Trials Database
°F
Degree(s) Fahrenheit
FACP
Fellow of the American College of Physicians
FAS
Full analysis set
FDA
Food and Drug Administration
FDG
Fludeoxyglucose
FFPE
Formalin-fixed, paraffin-embedded
FGF(R)
Fibroblast growth factor (receptor)
FIM
First-in-man
FRACP
Fellow of the Royal Australasian College of Physicians
FSH
Follicle stimulating hormone
FU
Follow-up
g
Gram
GC
Gemcitabine/cisplatin
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
GGT
Gamma-glutamyl transferase
GMP
Good Manufacturing Practice
HCG
β-human chorionic gonadotropin
HDPE
High-density polyethylene
HIV
Human immunodeficiency virus
HNSCC
Head and neck squamous-cell carcinoma
HR
Hazard ratio
HRAS
Harvey rat sarcoma viral oncogene homolog


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HRQoL
Health-related Quality of Life
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International Council for Harmonization
IDMS
Isotope dilution mass spectroscopy
i.e.
That is, id est
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
IMP
Investigational medicinal product
INN
International Nonproprietary Names
INR
International normalized ratio
IR
Immediate release
IRC
Imaging review charter
IRB
Institutional Review Board
ISH
In situ hybridization
ITT
Intent to treat
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
i.v.
Intravenous(ly)
IVRS
Interactive voice response system
IWRS
Interactive web response system
IxRS
Interactive voice/web response system
KM
Kaplan-Meier
KRAS
Kirsten rat sarcoma
LAC
Lung adenocarcinoma
LDH
Lactic dehydrogenase
LLT
MedDRA lowest level term
LPLV
Last patient’s last visit
LSF
Liquid service formulation
LSH
Life Science Data Hub
m
Meter
m2
Square meter
MBBS
Bachelor of Medicine and Bachelor of Surgery
MD
Medical doctor
MDRD
Modification of Diet in Renal Disease
MDS
Myelodysplastic syndrome
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
MI
Myocardial infarction
microRNA
Micro ribonucleic acid
min
Minute
mL
Milliliter
mm
Millimeter
mm3
Cubic millimeter


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MRI
Magnetic resonance imaging
mRNA
Messenger ribonucleic acid
M&S
Modeling and simulation
mUC
Metastatic urothelial carcinoma
M-VAC
Methotrexate, vinblastine, adriamycin or doxorubicin, and cisplatin
NA
Not applicable
NCI
National Cancer Institute
ng
Nanogram
NJ
New Jersey
No.
Number
NOAC
Novel oral anticoagulant
NRAS
Neuroblastoma rat sarcoma oncogene
NSCLC
Non-small-cell lung carcinoma
NYHA
New York Heart Association
OCT
Optical coherence tomography
ORR
Objective response rate
OS
Overall survival
p53
Tumor suppressor
PD
Progressive disease
PD-1
Programmed death protein 1
PD-L1
Programmed death-ligand 1
pERK
Extracellular-signal-regulated kinase protein
PET
Positron emission tomography
P-gp
P-glycoprotein
PFS
Progression-free survival
pH
Hydrogen ion concentration
PhD
Doctor of Philosophy
PID
Patient identification number
PI/ICF
Patient information/informed consent form
PIK3CA
Phosphoinositide 3-kinase, catalytic subunit alpha isoform
PK
Pharmacokinetic(s)
p.o.
Orally, per os
PP
Polypropylene
PR
Partial response
PRES
Posterior reversible encephalopathy syndrome
PRO
Patient-reported outcome
PS
Performance status
PSA
Prostate-specific antigen
PT
Prothrombin time
PTEN
Phosphatase and tensin homolog
PTT
Partial thromboplastin time
QA
Quality assurance
QLQ-C30
30 item Quality of Life Questionnaire
QoL
Quality of Life


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QT
QT interval in ECG (time between the start of the Q wave and the end of the T wave)
QTc
Corrected QT interval
RAS
Rat sarcoma
RAVE
Data collection tool
RBC
Red blood cell (count)
RECIST
Response evaluation criteria in solid tumors
RNA
Ribonucleic acid
ROS
Roll-over study
RoW
Rest of World
RPED
Retinal pigment epithelial detachment
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical Analysis Plan
SAS
Statistical Analysis Software
SC
Steering Committee
SCR
Serum creatinine level
SD
Stable disease
SmPC
Summary of product characteristics
sqNSCLC
Squamous non-small-cell lung carcinoma
SSU
Smallest shippable unit
SUSAR
Suspected, unexpected, serious adverse reaction
T3
Triiodothyronine
T4
Thyroxine
TC-99m
Technetium-99m
TEAE
Treatment-emergent adverse event
TM
Trade mark
TNM
Classification of Malignant Tumors (T = tumor, N = lymph node, M = metastasis)
TSH
Thyroid-stimulating hormone
UC
Urothelial carcinoma
ULN
Upper limit of normal
US / USA
United States / United States of America
USC
University of Southern California
VAS
Visual analog scale
WBC
White blood cell (count)
WOCBP
Women of childbearing potential
WT
Wild type


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3.
Introduction
In addition to the information provided below please also refer to the latest available version 
of the investigator’s brochure (IB) for rogaratinib (BAY 1163877) and any additional data 
supplied by the sponsor.
3.1
Background
Bladder cancer is the ninth most common cancer worldwide with an estimated 439,000 new 
cases and approximately 165,000 death cases in 2012 (1); it is the sixth most common cancer 
in the United States with an estimated 77,000 new cases in 2016 (2). Approximately three 
times more men than women are diagnosed with bladder cancer; the majority of patients are 
> 65 years old.
Bladder cancer can be divided into non-muscle-invasive and muscle-invasive tumors. 
Approximately 90% of all muscle-invasive bladder cancers are urothelial (transitional) tumors 
which can occur in the bladder, renal pelvis, ureter and urethra.
Patients with locally advanced or metastatic urothelial carcinoma are not treatable with a 
curative intent. Standard-of-care systemic treatment for those who are fit enough to tolerate 
cisplatin includes cisplatin-containing combination chemotherapy, e.g. GC 
(gemcitabine/cisplatin) or M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) (3). 
Overall efficacy is similar between GC and M-VAC, but GC shows a better safety profile. 
Dose-dense M-VAC has a better toxicity profile and is more efficacious in terms of response 
rate and 2-year overall survival rate than conventional M-VAC. However, median overall 
survival is similar between the two regimens (4).
After relapse, no standard-of-care treatment exists. Most of the data are derived from 
uncontrolled trials and are variable depending on patient selection. Potential treatment options 
after failure of platinum-containing chemotherapy include single-agent chemotherapy 
(docetaxel, paclitaxel or vinflunine) (5-7). Gemcitabine has also shown good response rates, 
but most patients already receive this drug as part of their first-line therapy (8). For selected 
patients, combination chemotherapy can be considered. Recently, several PD-1 and PD-L1 
inhibitors, including atezolizumab, pembrolizumab, nivolumab, durvalumab and avelumab
have been approved by the FDA for treatment of relapsed patients.
Despite emerging new therapies the majority of patients will eventually progress and die from 
their disease. Thus there is a clear unmet medical need for the development of additional 
treatment options.
3.2
Rogaratinib
3.2.1
Mode of action
Rogaratinib (BAY 1163877) is an oral pan-FGFR inhibitor. It shows potent FGFR1, -2, -3 
and -4 inhibition in biochemical assays that translates into strong inhibition of cellular 
downstream pERK resulting in inhibition of FGF2-stimulated tumor cell proliferation. 
Inhibition of cell proliferation by rogaratinib strongly correlates with expression of mRNA of 
FGFR isoforms as well as activation by somatic mutations. The high in-vitro potency and 


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mode of action translates into strong in-vivo efficacy in tumor models which have an activated 
FGFR signaling in non-small-cell lung cancer, small-cell lung cancer, bladder, head and neck 
as well as breast cancer. In vivo efficacy is correlated with effective inhibition of tumor FGFR 
phosphorylation and inhibition of FGFR downstream signaling as shown by pERK inhibition. 
Moreover, rogaratinib exhibits strong in vivo anti-tumor efficacy in monotherapy in FGFR 
mRNA overexpressing xenograft models with good tolerability. Efficacy in inhibition of 
tumor growth as well as the respective mode of action of inhibition of FGFR signalling such 
as phosphorylation of ERK1/2 was also strongly correlated with abundant expression levels of 
FGFR isoforms in tumor cells or tumor tissues. In addition, rogaratinib demonstrated additive 
activity with standard-of-care therapy in lung and urothelial carcinoma models.
Rationale for the quantification of mRNA levels of tumor FGFR1 and 3 as predictive
biomarker 
FGFR3 is the FGFR isoform which is most frequently overexpressed in urothelial carcinoma
(overexpressed in up to 50% of all cases) (9, 10). In addition, FGFR3-activating mutations 
have been frequently observed in early stages of urothelial carcinoma and in advanced 
metastatic muscle invasive urothelial carcinoma with a lower prevalence (about 10%) (11). 
Data from a variety of clinical trials with FGFR inhibitors confirmed a high objective 
response rate (ORR > 30%) in urothelial carcinoma patients having a tumor with genetic 
(DNA) alterations in FGFR3-encoding gene (12, 13). However, clinical benefits from FGFR 
inhibitor treatment have also been reported in a urothelial carcinoma patient with high FGFR1 
mRNA expression levels (14) and in a patient with high FGFR2 protein expression (15), 
although FGFR1 and FGFR2-positive UC tumors are more rare compared to FGFR3-positive 
tumors. In the Phase 1 Study 16443 (see Section 3.2.2), out of the > 120 tumor biopsies 
evaluated, 43 % were found to be positive for at least one FGFR isoform (FGFR1, or FGFR2 
or FGFR3). Out of the FGFR-positive UC samples, prevalence of FGFR3 and FGFR1 
mRNA-positivity was 92.4 % and 5.7 %, respectively, whereas isolated FGFR2-positivity 
could not be observed. It should be noted that this does not preclude future development of a 
test which is also able to identify the FGFR2 isoform, e.g. for different indication or to 
generate further data in urothelial carcinoma patients. However, as FGFR2 expression is 
considerably low in urothelial carcinoma patients, patient selection for Study 17403 will be 
based on FGFR1 and FGFR3 expression only. For the test device, FGFR1 and FGFR3 will be 
tested in parallel in one kit.
3.2.2
Clinical experience with rogaratinib
Details of the clinical experience with rogaratinib can be found in the latest available version 
of the investigator's brochure (IB) for rogaratinib, which contains comprehensive information 
on the study drug. The IB in its most current version is available in the study file.
Key risks of rogaratinib
Based on the cumulative evidence from the Phase 1 studies 16443 and 16958, the following 
clinical concepts are considered key risks of rogaratinib:


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Retinal disorders
Retinal detachment was observed in association with the treatment with some tyrosine kinase 
inhibitors including AZD4547–a compound with pan-FGFR inhibitory activity. Therefore, 
ophthalmological examination was implemented at the baseline and during the course of the 
Phase 1 trial (Study 16443) to assess the potential effects of the compound on the retinal 
structure and function.
Details of retinal disorders that have occurred so far can be found in the latest available 
version of the IB for rogaratinib. Patients should be closely monitored for the risk of retinal 
disorders during the clinical trials.
Hyperphosphatemia and soft-tissue mineralization
Hyperphosphatemia is a pharmacodynamic effect of rogaratinib, driven by the inhibition of 
FGFR1 in the kidney and therefore is expected to occur in any patient treated with rogaratinib. 
Hyperphosphatemia is pathophysiologically linked to soft-tissue mineralization. Although no 
signs suggestive for soft-tissue mineralization were observed in patients treated with 
rogaratinib, soft-tissue mineralization is regarded to represent a potential risk of rogaratinib.
Therefore, serum phosphate levels of patients treated with rogaratinib must be monitored to 
avoid a long-lasting hyperphosphatemia beyond the critical level defined as phosphate level 
≥7 mg/dL (study-specific measures are described in Section 9.6.3.1). Elevation of serum 
phosphate level starts within few days after initiation of treatment with rogaratinib and may 
reach a critical level within 1 or 2 weeks. 
Nail toxicity 
Nail toxicity manifesting as nail dystrophy, onychomadesis, paronychia, and onycholysis 
were observed in patients treated with rogaratinib. Based on the currently available 
information the clinical course of nail toxicity can be summarized as follows:
The initial nail changes manifest as painless yellowish/brownish discoloration of the distal 
part of the nail, within 2-3 months after the start of the therapy with rogaratinib (800 mg 
b.i.d.). The nail changes progress and affect the structure and surface of the whole nail 
resulting in a symmetric (all fingers similarly affected) onychodystrophy. Painless 
onycholysis may follow on some fingers or toes. Nail bed, matrix and the tissue of finger/last 
phalanx do not seem to be affected. Nail bed inflammation or nail bed infection is regarded to 
be secondary to onychodystrophy and onycholysis. No SAEs related to nail disorders have 
been observed.
Please also refer to the latest available version of the investigator’s brochure (IB) for 
rogaratinib.
3.3
Chemotherapy
Docetaxel
For docetaxel, the most common adverse reactions across all indications are infections, 
neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, 


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dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, 
nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, and myalgia. The most serious 
reactions include toxic deaths, hepatotoxicity, neutropenia, hypersensitivity, fluid retention, 
acute myeloid leukemia, cutaneous reactions, neurologic reactions, eye disorders, asthenia, 
alcohol intoxication (16). Additional information can be found in the SmPC.
Paclitaxel
Very common side effects for paclitaxel are neutropenia, anemia, leukopenia, peripheral 
neuropathy, nausea, diarrhea, vomiting, mucositis, alopecia, arthralgia, myalgia and 
hypersensitivity reaction (17). Additional information can be found in the SmPC.
Vinflunine
For vinflunine, the most common treatment-related adverse reactions reported in patients with 
transitional cell carcinoma of the urothelium were hematological disorders, mainly 
neutropenia and anemia; gastrointestinal disorders, especially constipation, anorexia, nausea, 
stomatitis/mucositis, vomiting, abdominal pain and diarrhea, and general disorders such as 
asthenia/fatigue (18). Additional information can be found in the SmPC.
3.4
Rationale of the study
The preliminary ORR of 24% as well as the toxicity profile observed for rogaratinib in Study 
16443 in the urothelial carcinoma are considered favorable compared with other treatment 
options. 
Single-agent taxanes and pemetrexed achieved response rates between 6% and 13% (reviewed 
in (19)). A Phase 3 trial comparing vinflunine to best supportive care (BSC) reported an ORR 
of 9% in the vinflunine treatment arm with a median PFS of 3 months for vinflunine (5).
More recently, the PD-L1-blocking antibody atezolizumab has shown an ORR of 15% in the 
total patient population regardless of PD-L1 expression with a median PFS of 
2.7 months (20). Pembrolizumab, a PD-1 inhibitor, reached an ORR of 21% and a PFS of 
2.1 months (21). 
Additional PD-1 and PD-L1 inhibitors including nivolumab, durvalumab and avelumab have 
shown similar ORR results as atezolizumab and have recently been approved by the FDA for 
patients with locally advanced or metastatic urothelial carcinoma (mUC). 
The encouraging results of Study 16443 support the continuation of the development of 
rogaratinib in urothelial carcinoma.
To this end, Study 17403 forms part of the sponsor’s clinical development program for 
rogaratinib. It is intended to generate the pivotal data in support of rogaratinib’s registration 
for the urothelial carcinoma indication in FGFR positive patients.
3.5
Benefit-risk assessment
The pre-clinical information on rogaratinib provides a sound rationale for its clinical activity 
in several tumor types including urothelial carcinoma. This is confirmed by preliminary 


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efficacy data from the Phase 1 Study 16443 indicating promising single agent anti-cancer 
activity of rogaratinib (ORR 24.0%) in patients with urothelial bladder cancer progressing 
after standard anti-cancer therapy, which is in line with the published data for other selective 
pan-FGFR inhibitors. The ORR is higher (30.6%) in patients with UC tumors without gain-
of-function mutations in phosphatidylinositol-3-kinase catalytic subunit alpha gene (PIK3CA) 
or without gain-of-function mutations in genes coding for rat sarcoma (RAS) protein family. 
This data indicates that gain-of-function mutations in PIK3CA and RAS protein family may 
be responsible for resistance of UC tumors to treatment with pan-FGFR receptor inhibitors.
Available data in this subgroup of patients is limited and it cannot be concluded that there is 
no treatment benefit with rogaratinib. The relevance of these mutations to the activity of 
standard chemotherapy is also unknown. Beyond UC, a promising anti-tumor efficacy was 
observed in patients with FGFR-positive head and neck cancer, sqNSCLC and adenoid cystic 
carcinoma.
The overall safety and tolerability profile of rogaratinib is manageable with risk monitoring 
and minimization activities reflected in the clinical trial protocols and the recommendations 
given in the current investigator’s brochure. In addition, the results of the full review and 
analysis of FORT-1 data (cut-off date of 14 June 19) were also consistent with the known
safety profile of rogaratinib.
Most frequent toxicities of rogaratinib such as blood phosphorus increased, diarrhea, nail 
toxicity and alopecia as well as frequent treatment emergent adverse events such as dry mouth, 
decreased appetite, fatigue, dysgeusia, dry skin, nausea, mucositis and arthralgia can be 
managed with supportive care in oncology. 
The key risks associated with the use of rogaratinib are retinal disorders and soft tissue 
mineralization. 
Retinal disorders consistent with retinal pigment epithelial detachment / central serous 
retinopathy (RPED/CSR) were observed in patients treated with rogaratinib. Mainly 
asymptomatic course and mild intensity (Grade 1, 2) of the rogaratinib associated RPED/CSR 
is in line with known benign nature of RPED/CSR. The risk of irreversible retinal damage is 
low and can be reduced by rogaratinib treatment withdrawal in case of symptomatic persistent 
or progressive retinal detachment. Regular ophthalmologic visits will be performed in patients 
participating in this trial.
Soft tissue mineralization was observed in toxicological studies with rogaratinib and other 
pan-FGFR inhibitors manifesting as ectopic calcification lesions in kidney, stomach, heart 
and blood vessels. During the course of the clinical testing of rogaratinib no events consistent 
with “soft tissue mineralization” were observed. The risk can be predicted and prevented by 
monitoring and control of phosphate levels in serum.
Risk monitoring and minimization activities reflected in the planned examinations are part of 
general medical practice and do not expose study participants to an undue risk or burden. 
The randomized, controlled study design which includes single-agent chemotherapy, a 
standard of care treatment option used after failure of platinum-containing chemotherapy, 
ensures that patients in the control arm receive an active treatment. 


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Overall, the non-clinical and clinical data collected cumulatively for rogaratinib are 
considered to support a favorable benefit-risk profile of rogaratinib for use in this study for 
the planned patient population.
4.
Study objectives
The original objectives of the study are provided below:
Primary objective:

To demonstrate the superiority of rogaratinib over chemotherapy in terms of 
prolonging overall survival of urothelial carcinoma patients with FGFR positive 
tumors. 
Secondary objectives:

To evaluate additional efficacy including the following variables
o progression-free survival (PFS)
o objective response rate (ORR)
o disease control rate (DCR)
o duration of response (DOR)

To evaluate the safety of rogaratinib (adverse events) 
Tertiary objectives:

Patient-reported outcome (PRO) 

Evaluate biomarkers to investigate the drug (i.e. mode-of-action-related effect and/or 
safety) and/or the pathomechanism of the disease 

Pharmacokinetics
The objective for the Phase 2 part of the study is to demonstrate the efficacy of rogaratinib 
over chemotherapy in terms of objective response rate of urothelial carcinoma patients with 
FGFR positive tumors (see Section 10.5). The Phase 3 part of the study will no longer be 
conducted, therefore OS will be considered an exploratory efficacy variable for Phase 2.
The procedures and variables used to address the objectives are specified in Section 9.
5.
Study design
5.1
Design overview
This is a randomized, open-label, multicenter Phase 2/3 study to evaluate the efficacy and 
safety of rogaratinib (BAY 1163877) compared to chemotherapy in patients with FGFR-
positive locally advanced or metastatic urothelial carcinoma who have received prior 
platinum-containing chemotherapy. 
The primary objective of this entire study 17403 is to compare rogaratinib (BAY 1163877) 
with chemotherapy (docetaxel, paclitaxel or vinflunine) in terms of prolonging the overall 


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survival (OS) of patients with FGFR positive urothelial carcinoma. The objective for the 
Phase 2 part of the study is to demonstrate the efficacy of rogaratinib over chemotherapy in 
terms of objective response rate (ORR) of urothelial carcinoma patients with FGFR positive 
tumors. For all study objectives, see Section 4.
At randomization, patients will have locally advanced or metastatic urothelial carcinoma and 
have received at least one prior platinum-containing chemotherapy regimen. Only patients 
with FGFR1 or 3 positive tumors can be randomized into the study. Archival tumor tissue is 
adequate for testing of FGFR1 and 3 mRNA expression, which will be determined centrally
using an RNA in situ hybridization (RNA-ISH) test (see Section 9.7.1).
The study will comprise the following periods: 
1) Pre-treatment period, including FGFR testing and screening,
2) Treatment period, and
3) Follow-up period, including active follow-up and long-term follow-up. 
Patients will be considered “on study” during the pre-treatment, treatment and active follow-
up periods. During the long-term follow-up period the patients will be considered “off study”
(i.e. no study-related procedures with the patient). An overview of the study design is 
presented in Figure 5–1.


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Figure 5–1: Study 17403 – Design overview
Informed 
consent for
FGFR testing
Randomization 
1:1
1st dosing of 
study treatment
Last protocol-
stipulated 
procedure
Discontinuation of
study treatment 
(End of Treatment)
Treatment
Active follow-up c
On study
Long term follow-up
Pre-treatment
Off study
Rogaratinib (600 mg p.o. b.i.d. – continuously)
Taxane or vinflunine (i.v. every 3 weeks)
Informed 
consent for
study treatment 
eligibility
FGFR testing a
Screening b
Follow-up
b.i.d. = Twice daily, bis in die; FGFR = Fibroblast growth factor receptor; i.v. = intravenously; mg = Milligram; PIK3CA = 
Phosphoinositide 3-kinase, catalytic subunit alpha isoform; p.o. = Orally, per os; RAS = Rat sarcoma; mRNA = Messenger 
ribonucleic acid.
a: During FGFR testing period, patients will be tested for FGFR1 and 3 mRNA expression levels and, after a 
positive FGFR test result was obtained, these patients are also tested for presence or absence of potential 
FGFR inhibitor resistance mutations, PIK3CA and/or RAS. PIK3CA and/or RAS mutation status will not affect 
patient eligibility, but will be used for patient stratification.
b: Only FGFR-positive patients (high expression of at least FGFR1 or 3) can enter screening.
c: Safety information is collected for all discontinued patients for at least 30 (up to +7) days after the last 
administration of study treatment, and both safety and efficacy information is collected for patients who 
discontinue study treatment without disease progression.
Phase 2/3 design
This study was originally designed to follow a Phase 2/3 design with interim analysis, 
meaning the patients recruited to the Phase 2 part of the study will automatically continue to 
the Phase 3 part without interruption if futility is not demonstrated at the 1st interim ORR 
analysis (see below and Section 10.5). An overview of the Ph2/3 study design is presented in 
Figure 5–2 below. The Phase 2 and 3 parts of the study follow the same screening, treatment 
and follow-up assessment schedule (Figure 5–1). The Phase 2 part will end at the time of the 
cut-off for the 1st interim ORR analysis. To help structure the protocol flow, we present this 
Phase 2/3 study as one study protocol with two interim analyses, while the first interim 
indicates the end of the Phase 2 part, and the second and final analyses are considered the 
Phase 3 part including Phase 2 patients in the analyses.


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Figure 5–2: Overview of the original Phase 2/3 design
Study start
Phase 2
Phase 3
Study end
1st interim analysis 
for futility (ORR)
after first approx. 116 
confirmed FGFR positive 
patients with WT PIK3CA 
and RAS biomarkers have 
completed 4.5 months of 
treatment
2nd interim analysis 
for futility (OS) 
after 195 PIK3CA and RAS 
WT patients have died
Final analysis (OS) 
after 390 PIK3CA and 
RAS WT patients have 
died
FGFR = Fibroblast growth factor receptor; ORR = Objective response rate; OS = Overall survival; PIK3CA = 
Phosphoinositide 3-kinase, catalytic subunit alpha isoform; RAS = Rat sarcoma; WT = Wild type.
Based on a current assumption that roughly 75% of all study population are PIK3CA and 
RAS WT patients, at the time when 450 WT patients are randomized, approximately a total of 
600 patients (450 WT + 150 mutant patients) will be randomized in the all study population. 
The study will focus on randomizing 450 PIK3CA and RAS WT patients while leaving the 
number of PIK3CA and/or RAS mutant patients open to reflect the distributions in the study 
population.
The Phase 2 part of the study ends when the first approx. 116 confirmed FGFR positive 
patients with wild-type PIK3CA and RAS biomarkers have completed 4.5 months of 
treatment, at which time the analysis of Phase 2 part will be triggered. A DMC meeting will 
be scheduled to review the Phase 2 data. Decisions on trial termination, amendment or 
cessation of patient recruitment based on risk benefit assessments will be made after 
recommendations from the DMC have been assessed by the sponsor. In the meantime, the 
study will continue its routine recruitment until trial termination or recruitment cessation 
decisions are announced.
If the decision is made to continue the study at the end of Phase 2 period, the study moves on 
to Phase 3 part of the study. Randomization and treatment will continue the same as in the 
Phase 2 part of the study until 390 deaths are seen in the PIK3CA and RAS WT patients.
Before achieving the criteria for the first interim analysis, the study recruitment was put on 
hold after a recommendation of the study DMC. The sponsor decided to perform a full 
analysis and review of all study data and stop the recruitment permanently.
Due to the stop of enrollment and full data analysis, the study will not move forward to its 
Phase 3 and will remain as Phase 2. The study will remain open until the survival data is 
considered adequate for analysis by the sponsor.


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5.2
Study periods
5.2.1
Pre-treatment period
FGFR testing
Before testing for FGFR1 and 3 mRNA expression levels, patients must sign a patient 
information/informed consent form (PI/ICF) (see Section 13.4.1), and meet all eligibility 
criteria for FGFR testing (see Section 6.1). Mandatory FGFR testing will be performed prior 
to start of screening (signing of informed consent for study treatment eligibility). The timing 
of the FGFR test is at the discretion of the investigator.
See more about FGFR testing in Section 9.7.1.
Only patients with FGFR-positive tumors (high expression of at least FGFR1 or 3) will be 
eligible to continue to the screening.
During the FGFR testing period, and after a positive FGFR test result was obtained, these 
samples are also tested for presence or absence of potential FGFR inhibitor resistance 
mutations, phosphoinositide 3-kinase catalytic subunit alpha isoform (PIK3CA) and/or in the 
human orthologues of rat sarcoma (RAS). PIK3CA and RAS testing is done in tumor DNA 
derived from archival biopsy specimen. The outcome of the mutation testing will not affect 
the study eligibility, it will be used for patient stratification. For more background information 
on the potential FGFR inhibitor resistance mutations, please refer to Section 5.4.
Screening
The screening period will start after the patient has signed the PI/ICF for study treatment 
eligibility (see Section 13.4.2). The screening for treatment eligibility will be scheduled 
within 28 days before randomization. Please refer to Table 9–1 for the detailed schedule for 
screening assessments.
5.2.2
Treatment period
All patients who meet the eligibility criteria will be randomized 1:1 into two treatment arms
using an Interactive Voice/Web Response System (IxRS):

Rogaratinib administered as oral (p.o.) 600 mg (3 x 200 mg) tablets twice daily (b.i.d.)
continuously, or

Chemotherapy as taxane (docetaxel or paclitaxel) or vinflunine administered through 
intravenous (i.v.) infusion every 3 weeks (on Day 1 of the cycle).
Randomization will be stratified by:

PIK3CA and/or RAS activating mutations (presence vs. absence)
o
In cases when PIK3CA and/or RAS genetic testing results are not available 
before randomization, those patients with unknown mutation status prior to 
randomization will be grouped into the mutation “presence” strata in the 
randomization process.

Prior immunotherapy (yes vs. no)


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
Modified 4-factor Bellmunt risk score (high vs. low) (22)
The first administration of study drug should take place within 3 days of randomization. 
The start of the treatment period is defined by the first administration of study treatment.
The planned length of a treatment cycle is 3 weeks (21 days) (see Sections 7.4.3.1 and 7.4.3.2
respectively for rogaratinib and chemotherapy dose modifications, which may lead to 
prolongation of the duration of a cycle).
Patients may continue on study treatment until any of the following events occur:

Radiological disease progression according to RECIST v.1.1. At the investigator’s 
discretion, study treatment may continue beyond radiological progression as defined 
by RECIST v.1.1 if the clinical condition of the patient is stable or the patient is 
improving symptomatically, and the investigator expects continued clinical benefit for 
the patient

Clinical progression

Unacceptable toxicity

Death

Withdrawal of consent

Withdrawal from the study (see Section 6.4.1).
After discontinuation from study treatment, patients should be treated according to local 
practice. Please refer to Section 8.2 for post-study therapy.
The end-of-treatment (EOT) visit will be performed for all patients within 14 days after 
permanent discontinuation of study treatment.
5.2.3
Follow-up periods
5.2.3.1
Active follow-up
Safety information is collected for all discontinued patients for at least 30 (up to +7) days 
after the last administration of study treatment, and both safety and efficacy information is 
collected for patients who discontinue study treatment without disease progression. Follow-up 
tumor evaluations will be performed (by CT or MRI) until progression of malignancy and/or 
start of subsequent systemic anti-cancer treatment, whichever comes first, or any other 
criterion for withdrawal is met. During the active follow-up period, CT/MRI evaluations will 
be performed at the same intervals as during study treatment (every 6 weeks up to week 18, 
and thereafter, every 9 weeks) (see Table 9–1). Study drug-related toxicity/AE assessment 
will be followed up and patients will also be contacted for monthly survival assessment.
5.2.3.2
Long-term follow-up
Following completion of the active follow-up, patients will be contacted (telephone contact is 
sufficient) every month (±7 days) to determine survival status and obtain information on 
subsequent systemic anti-cancer treatment until either data maturation for the final planned 
OS analysis is reached, death of the patient or any other criterion for withdrawal is met. If a 


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patient is lost to follow-up, the site will try to contact the patient, the patient’s relatives, or 
another doctor treating the patient, unless prohibited by local requirements. An additional 
contact attempt should be made at the time of each survival sweep. 
Patients are considered “off-study” (i.e. no study-related procedures with the patient) while in 
long-term follow-up.
5.3
Primary variable
The primary efficacy variable of the Phase 3 of this study was overall survival. Due to the 
stop of enrollment and full data analysis, the study will not move forward to its Phase 3 and 
will remain as Phase 2. The study will remain open until the survival data is considered 
adequate for analysis by the sponsor.
The primary efficacy variable of Phase 2 is ORR, and will be analyzed based on central 
review assessment. OS will be considered an exploratory efficacy variable for the Phase 2 
part. 
See Section 9.4 for the full definition. See Section 10.3.1.1 for the planned statistical analyses 
of the primary variable.
For secondary efficacy variables, see Section 9.4. 
Further variables are specified in Section 9.6 (safety variables), Section 9.5 (PK variables) 
and Section 9.7 (biomarker and PRO variables).
5.4
Justification of the design
Level of blinding: Due to the different dosing schedule, administration route and safety 
profile with the control drugs, an open-label study design is deemed justified. In addition, 
overall survival is the primary endpoint, an endpoint that is reliable and easy to measure, 
documented by date of death, thus bias is not a factor in this endpoint measurement.
Justification of rogaratinib dosage: in the Phase 1 Study 16443, no dose limiting toxicities 
(DLTs) were observed at doses ranging from 50 mg b.i.d. to 800 mg b.i.d. continuously in 
3-week cycles. The highest evaluated dose of 800 mg b.i.d. was initially chosen as the 
recommended dose regimen for rogaratinib trials. Per DMC data review of 17403 study, the 
dose of 600 mg b.i.d., was recommended as the maximum starting dose of rogaratinib 
treatment. This dose regimen was accepted based on the following considerations:

In the first-in-human study 16443 evaluating rogaratinib in the dose range from 50 mg 
b.i.d. to 800 mg b.i.d., exploratory rogaratinib plasma exposure to selected adverse 
events (fatigue, diarrhea and nausea) analysis did not show clear correlation. 
Additionally, exploratory rogaratinib plasma exposure-clinical response analysis also 
did not show clear correlation. Based on PK data in small number of patients treated at 
600 mg BID (n=4) in Study 16443, a small difference of approximately 10% to 15% 
in rogaratinib plasma exposures was observed between 600mg b.i.d. and 800 mg b.i.d. 
dose levels. The range of rogaratinib plasma exposures after 600 mg b.i.d. and 800 mg 
b.i.d. are expected to largely overlap, although slightly lower at 600 mg b.i.d.


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
Dose dependent changes in plasma phosphate concentration confirmed the mechanism 
of action related to inhibition of renal FGFR activity

Clinical responses were observed in patients with urothelial bladder cancer and other 
tumor types with reduced dose regimen schedules.
In conclusion, the new dose schedule of rogaratinib 600 mg b.i.d is considered to be able to 
provide adequate exposure to the drug with favorable benefit-risk profile.
Choice of comparator: After relapse of first line chemotherapy, no standard of care treatment 
exists for patients with locally advanced or metastatic urothelial carcinoma. Most of the data 
are derived from uncontrolled trials and are variable depending on patient selection. Potential 
treatment options after failure of platinum containing chemotherapy include single agent 
chemotherapy (docetaxel, paclitaxel or vinflunine) (5-7). Gemcitabine has also shown good 
response rates, but most patients already receive this drug as part of their first line therapy (8). 
For selected patients combination chemotherapy can be considered. Recently immune 
checkpoint inhibitors targeting PD-L1 or PD-1, including atezolizumab, pembrolizumab, 
nivolumab, durvalumab and avelumab, have shown activity in relapsed urothelial carcinoma
patients and have been approved by the FDA (20, 23).
Based on the current treatment paradigm and recommendations from US and European 
guidelines, single agent chemotherapy of either a taxane or vinflunine is chosen as the 
comparator for the proposed Phase 3 study. This ensures that study participants in the control 
arm will receive an active treatment. The doses are in line with current practice in the majority 
of the countries worldwide. To ensure suitable patients are given the opportunity of treatment 
with immune checkpoint inhibitors, where available, prior treatment with these agents will be 
allowed, but is not mandatory.
Patient selection: The FGFR1&3 RNA-ISH assay will be used to aid in the selection of cancer 
patients who may benefit from the pan-FGFR inhibitor (rogaratinib) therapy. In pre-clinical 
studies, only xenograft models with high expression levels of either FGFR1 or FGFR2 or 
FGFR3 demonstrated significant (> 50%) anti-tumor efficacy upon rogaratinib treatment. 
Preliminary data from Phase 1 Study 16443 confirms that a treatment benefit of having either 
a partial response or a long-lasting stable disease (SD) is observed in patients that have a high 
FGFR expression level. Therefore, having at least one FGFR isoform with a high FGFR 
expression level was selected as inclusion criterion for FGFR-positivity for this Study 17403. 
In Study 16443, out of > 120 UC biopsies, no single biopsy was found to be positive for 
FGFR2 only; 83 % were found positive for FGFR3 only, and 5.7 % were found positive for 
FGFR1 only. Instead, 11.3 % of samples were found to be positive for more than one FGFR 
isoform (FGFR1/2, FGFR1/3 and FGFR2/3). As either FGFR1 or FGFR3 was detected in all 
double-positive samples, the use of a FGFR2-specific probe would not lead to the 
identification of additional patients. 
Randomization: Randomization will be stratified to ensure balance of the treatment groups 
with respect to the following important factors and to avoid any bias that may be associated 
with an imbalance. 


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Stratification factors are:

PIK3CA and/or RAS activating mutations (presence vs. absence)
Rationale: It has been recently published that activating mutations in PIK3CA and 
RAS genes (NRAS/KRAS/HRAS) are a resistance factor to FGFR inhibitors (24-26). 
Retrospective mutation analysis of urothelial carcinoma patients enrolled on 
rogaratinib in Study 16443 revealed that none of the 12 patients presenting with a 
partial response (PR) as best response according to RECIST v1.1, had an activating 
mutation in the aforementioned genes. In contrast, 7 out of 14 patients presenting with 
progressive disease (PD) as best response by rogaratinib-treatment, had an activating 
mutation in either PIK3CA and/or RAS-encoding genes. It is therefore planned to 
detect PIK3CA and RAS mutational status in tumor DNA after the FGFR testing in 
archival tumor biopsy specimen for stratification at randomization to ensure balance of 
the treatment groups with respect to these mutations. See additional details in 
Section 9.7.1.

Prior immunotherapy (yes vs. no),
Rationale: To ensure suitable patients are given the opportunity of prior treatment with 
the recently approved immune checkpoint inhibitors, stratification regarding use of 
prior immunotherapy is part of the study.

Modified 4-factor Bellmunt risk score (high vs. low) (see Section 9.3.3)
Rationale: Prognostic factors have been identified for both first and second line 
treatment of patients with urothelial carcinoma. For second line, the modified 4-factor 
Bellmunt risk score defines ECOG performance status, hemoglobin level, liver 
metastases and time from last systemic anti-cancer therapy dose as main prognostic 
factors for overall survival. Presence of liver metastases, ECOG PS ≥1, hemoglobin 
< 10 g/dL and time from last systemic anti-cancer therapy dose < 90 days are 
recognized as prognostic factors for predicting shorter overall survival (22).
For justification of the sample size, please refer to Section 10.4.
For justification of study procedures and measurements, see Section 9.8.
For strategies to limit the amount and impact of missing data, see Section 11.4.
5.5
End of study
For each participating EU country, the end of the study according to the EU Clinical Trial 
Directive will be reached when the last visit of the last patient for all centers in the respective 
country has occurred.
The end of the study as a whole will be reached when the last visit of the last patient has been 
achieved in all participating centers (EU and non-EU), or the primary completion event has 
been reached, whichever comes later.
LPLV is defined as the last patient’s last active follow-up visit.


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However, the LPLV date can also be reached based on the last patient stopping study 
treatment, switching to a roll-over study, a post-trial access program, or being switched 
to commercial drug supply with no cost to the patient. 
If the trial is stopped but benefits are observed for patients, further treatment options may be 
discussed and agreed between the investigator, sponsor and the patients.
See also Sections 7.2 and 8.2 for further details on the roll-over study.
5.6
Primary completion
In the Phase 3 part, the primary completion for this study (i.e. corresponding to the final OS 
analysis) was planned when approximately 390 patients have died in the PIK3CA and RAS 
WT patient population.
Due to the stop of enrollment and full data analysis, the study will not move forward to its 
Phase 3 and will remain as Phase 2. The study will remain open until the survival data is 
considered adequate for analysis by the sponsor.
The primary completion date for this study according to the FDA Amendment Act is specified 
in a separate document (not part of this study protocol).
For post-study therapy, refer to Section 8.2.
6.
Study population
Patient eligibility will be checked at two sequential time points:
1. At FGFR testing:

Mandatory FGFR testing of urothelial carcinoma patients will be performed prior to 
start of screening (signing of informed consent for study treatment eligibility). The 
timing of the FGFR test is at the discretion of the investigator.

Besides the basic criteria for FGFR testing specified below, any criterion as outlined 
under inclusion and exclusion criteria for screening already known to prohibit the 
patient’s participation in the study should be considered. For “FGFR testing failure”
see Section 6.4.1.1.
2. At screening:
FGFR1 or 3-positive patients will be checked for study treatment eligibility using all 
further selection criteria specified below. For “screening failure” see Section 6.4.1.1.


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6.1
Inclusion criteria
The following inclusion criteria must be met before randomization unless otherwise specified:
Inclusion criteria
to be checked at
FGFR 
testing
Screening 
1. Ability to understand and signing of the written patient 
information/informed consent form (PI/ICF) for FGFR testing

2. Existence of archival or fresh biopsy for FGFR testing. 
Mandatory FGFR testing of patients will be performed prior to 
start of screening (signing of informed consent for study 
treatment eligibility). The timing of the FGFR test is at the 
discretion of the investigator. Investigators should ensure all 
patients will be eligible in terms of disease status and lines of 
treatment.

3. Male or female patients ≥ 18 years of age (at least age of legal 
maturity)

4. Documented urothelial carcinoma (transitional cell carcinoma) 
including urinary bladder, renal pelvis, ureters, urethra, meeting 
all of the following criteria 
o
Histologically confirmed 

Patients with mixed histologies are required to 
have a dominant transitional cell pattern. 
o
Locally advanced (T4, any N; or any T, N 2−3) or 
metastatic disease (any T, any N and M1).
Locally advanced bladder cancer must be unresectable 
i.e. invading the pelvic or abdominal wall (stage T4b) or 
presenting with bulky nodal disease (N2-3).

5. ECOG Performance Status of 0 or 1


6. Disease progression during or following treatment with at least 
one platinum-containing regimen (patients should have been 
treated for at least 2 cycles). In patients who received prior 
adjuvant/neoadjuvant platinum-containing chemotherapy, 
progression had to occur within 12 months of treatment.



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Inclusion criteria
to be checked at
FGFR 
testing
Screening 
7. High FGFR1 or 3 mRNA expression levels in archival or fresh 
tumor biopsy specimen quantified as outlined in the lab manual.

8. Ability to understand and signing of the written PI/ICF for study 
treatment eligibility. Signed informed consent form must be 
available before any study-specific procedure for the respective 
study parts may begin.

9. At least 1 measurable lesion according to Response Evaluation 
Criteria in Solid Tumors (RECIST v.1.1) in contrast enhanced 
(unless contraindicated) CT or MRI

10. Adequate laboratory and organ function: 
o
Absolute neutrophil count (ANC) ≥ 1,500/mm3
o
Platelet count ≥ 100,000/mm3
o
Hemoglobin ≥ 9.0 g/dL (without transfusion or 
erythropoietin within 4 weeks before randomization)
o
Total bilirubin ≤ 1.5 times the upper limit of normal 
(ULN). Known Gilbert syndrome is allowed if total 
bilirubin is ≤ 3 x ULN. 
o
Alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN for 
patients with liver involvement of their cancer) 
o
Alkaline phosphatase limit ≤ 2.5 x ULN (≤ 5 x ULN for 
patients with liver and bone involvement of their cancer) 
o
Lipase < 2 x ULN 
o
Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m2
according to Modification of Diet in Renal Disease 
(MDRD) abbreviated formula.
o
International normalized ratio (INR) ≤1.5 ULN, and 
partial thromboplastin time (PTT) or activated PTT 
(aPTT) ≤1.5 ULN. Patients being treated with 
anticoagulant, e.g. warfarin or heparin, will be allowed 
to participate provided no prior evidence of an 
underlying abnormality in these parameters exists. Close 
monitoring of at least weekly evaluations will be 
performed until INR is stable based on a pre-dose 
measurement as defined by the local standard of care.

11. Women of childbearing potential (WOCBP) and fertile men 
must agree to use adequate contraception when sexually active 



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Inclusion criteria
to be checked at
FGFR 
testing
Screening 
from signing of the ICF for study treatment eligibility until at 
least 12 weeks after the last study drug administration of 
rogaratinib or vinflunine and until at least 6 months for 
docetaxel or paclitaxel. The investigator or a designated 
associate is requested to advise the patient how to achieve 
highly effective birth control. Highly effective (failure rate of 
less than 1% per year) contraception methods include:
o
Combined (estrogen and progesterone containing: oral, 
intravaginal, transdermal) and progesterone-only (oral, 
injectable, implantable) hormonal contraception 
associated with inhibition of ovulation.
o
Intrauterine device (IUD) or intrauterine hormone-
releasing system (IUS).
o
Bilateral tubal occlusion or vasectomized partner 
(provided that partner is the sole sexual partner and has 
received medical assessment of the surgical success).
o
Sexual abstinence (reliability to be evaluated in relation 
to the duration of the clinical trial and the preferred and 
usual lifestyle of the patient). 

Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, or postovulation methods) and 
withdrawal are not acceptable methods of 
contraception.
Male patients with a female partner of childbearing potential 
must use a condom and ensure that an additional form of 
contraception is also used during treatment and until 12 weeks 
after last study drug administration.
Genetic consultation is recommended if the patient wishes to 
have children after ending the treatment with chemotherapy or 
rogaratinib. These treatments could affect male fertility; 
therefore fertility preservation (sperm conservation) should be 
considered before starting treatment with the study drug.
Note: a woman is considered WOCBP, i.e. fertile, following 
menarche and until becoming postmenopausal unless 
permanently sterile. Permanent sterilization methods include but 
are not limited to hysterectomy, bilateral salpingectomy and 
bilateral oophorectomy. A postmenopausal state is defined as no 
menses for 12 months without an alternative medical cause. A 
high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a 


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Inclusion criteria
to be checked at
FGFR 
testing
Screening 
postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy. A man is 
considered fertile after puberty unless permanently sterile by 
bilateral orchiectomy.
12. Negative serum pregnancy test in women of childbearing 
potential (performed within 7 days before randomization). 
Negative results must be available prior to study drug 
administration.

6.2
Exclusion criteria
The following exclusion criteria must be met before randomization unless otherwise 
specified:
Exclusion criteria
to be 
checked at
Screening
1. Previous or concurrent cancer except 
o
cervical carcinoma in situ
o
treated basal-cell or squamous cell skin carcinoma
o
any cancer curatively treated > 3 years before 
randomization
o
curatively treated incidental prostate cancer (T1/T2a)



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Exclusion criteria
to be 
checked at
Screening
2. Active symptomatic or untreated brain metastases as determined 
by CT or MRI evaluation during screening and prior 
radiographic assessment. Patients with treated asymptomatic 
CNS metastases are eligible, provided they meet all of the 
following criteria: 
o
evaluable or measurable disease outside the CNS
o
no metastases to midbrain, pons, medulla, cerebellum, or 
within 10 mm of the optic apparatus (optic nerves and 
chiasm)
o
no history of intracranial or spinal cord hemorrhage
o
no evidence of significant vasogenic edema
o
anticonvulsants at stable dose are allowed
o
no stereotactic radiation, whole-brain radiation or 
neurosurgical resection within 12 weeks before the first 
study drug administration
o
radiographic demonstration of interim stability (i.e. no 
progression) between the completion of CNS-directed 
therapy and the screening radiographic study
o
screening CNS radiographic study ≥ 4 weeks since 
completion of radiotherapy or surgical resection.
Also the patient must not be undergoing acute steroid therapy or 
taper (chronic steroid therapy is acceptable provided that the 
dose is stable for one month prior to and following screening 
radiographic studies).

3. Known human immunodeficiency virus (HIV) infection

4. Renal dialysis

5. Any malabsorption condition

6. Breast-feeding

7. Ongoing or previous treatment with anti-FGFR directed 
therapies (e.g. receptor tyrosine kinase inhibitors including 
rogaratinib or FGFR-specific antibodies) or with taxanes or 
vinflunine



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Exclusion criteria
to be 
checked at
Screening
8. More than two prior lines of systemic anti-cancer therapy for 
urothelial carcinoma given for advanced unresectable/metastatic 
disease

9. Ongoing or previous anti-cancer treatment within 4 weeks 
before randomization. 
o
Patients who have received prior treatment with anti-
CTLA-4 may be enrolled provided at least 5 half-lives 
(approximately 75 days) have elapsed before 
randomization.
o
Prior cancer vaccines and cellular immunotherapy are 
permitted.
o
Previous radiotherapy is acceptable under the following 
conditions: 

Therapeutic radiotherapy ≥ 3 weeks before the 
baseline tumor scan.

Palliative radiotherapy for bone metastases or soft 
tissue lesions is allowed and should be completed 
>7 days prior to baseline tumor scan.

Lesions at the site of previous radiotherapy should 
have evidence of progressive disease if this is the 
only site of disease.
Anti-cancer therapy is defined as any agent or combination of 
agents with clinically proven anti-tumor activity, including 
immunotherapy administered by any route with the purpose of 
affecting the malignancy, either directly or indirectly, including 
palliative and therapeutic endpoints.

10. Use of strong inhibitors and inducers of CYP3A4 (see 
Appendix 16.1) should have been stopped 2 weeks before 
randomization.

11. Concomitant therapies that are known to increase serum 
calcium or phosphate levels and cannot be discontinued or 
switched to a different medication before randomization

12. Substance abuse, medical, psychological or social conditions 
that may interfere with the patient’s participation in the study or 
evaluation of the study results

13. Major surgery, or significant trauma within 4 weeks before 
randomization (central line surgery is not considered major 
surgery)



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Exclusion criteria
to be 
checked at
Screening
14. Unresolved toxicity higher than National Cancer Institute’s 
Common Terminology Criteria for Adverse Events, version 
4.03 (CTCAE v.4.03) Grade 1 attributed to any prior 
therapy/procedure excluding alopecia, anemia and/or 
hypothyroidism

15. History or current condition of an uncontrolled cardiovascular 
disease including any of the following conditions:
o
Congestive heart failure (CHF) NYHA > Class 2
o
Unstable angina (symptoms of angina at rest) or new-onset 
angina (within last 3 months before randomization) 
o
Myocardial infarction (MI) within past 6 months before 
randomization 
o
Unstable cardiac arrhythmias requiring anti-arrhythmic 
therapy. Patients with arrhythmia under control with anti-
arrhythmic therapy such as beta-blockers or digoxin are 
eligible

16. Arterial or venous thrombotic events or embolic events such as 
cerebrovascular accident (including transient ischemic attacks), 
deep vein thrombosis or pulmonary embolism within 3 months 
before randomization

17. Current evidence of endocrine alteration of calcium phosphate 
homeostasis (e.g. parathyroid disorder, history of 
parathyroidectomy, tumor lysis, tumoral calcinosis, 
paraneoplastic hypercalcemia)

18. Current diagnosis of any retinal detachment, retinal pigment 
epithelial detachment (RPED), serous retinopathy or retinal vein 
occlusion 

19. Active infection with hepatitis B or C, requiring treatment
Note: prophylactic antiviral treatment against reactivation of 
chronic hepatitis B (e.g. entecavir) is allowed

20. Active infections (≥ CTCAE v.4.03 Grade 3)

21. Evidence or history of bleeding diathesis or coagulopathy

22. Any hemorrhage / bleeding event ≥ CTCAE v.4.03 Grade 3 
within 4 weeks before randomization

23. Seizure disorder requiring therapy

24. Serious, non-healing wound, ulcer or bone fracture



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Exclusion criteria
to be 
checked at
Screening
25. Any condition that is unstable or could jeopardize the safety of 
the patient and his/her compliance in the study

26. Inability to swallow oral medications

27. Known hypersensitivity to any of the study drugs, study drug 
classes, or excipients in the formulation

28. Previous assignment to study treatment during this study

29. Investigational drug treatment outside of this study during or 
within 4 weeks before randomization.

30. Close affiliation with the investigational site; e.g. a close 
relative of the investigator, dependent person (e.g. employee or 
student of the investigational site)

6.3
Justification of selection criteria
The selection criteria are chosen to ensure that patients with specific risks for administration 
of the study drugs and/or patients with conditions which may have an impact on the aims of 
the study are excluded.
6.4
Withdrawal of patients from study
6.4.1
Withdrawal
6.4.1.1
Screening failure
Depending on the time point of withdrawal before randomization, a withdrawn patient is 
referred to as either “FGFR testing failure” or “screening failure” as specified below:
FGFR testing failure (pre-screening failures)
A patient with low FGFR 1 or 3 mRNA expression levels, quantified as outlined in the lab 
manual, must not be screened for study treatment eligibility but needs to be withdrawn 
from the study and is regarded as a “FGFR testing failure”. The “FGFR testing failure” will 
be registered in IxRS. 
For data to be collected for FGFR testing failures, refer to Section 11.1 (data recorded during 
FGFR testing period)
Screening failure
Patients who have signed the pre-screening informed consent and have not completed the 
FGFR test and FGFR-positive patients who, for any reason (e.g. failure to meet the selection 


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criteria), terminate the study before randomization, are regarded as “screening failures”. The 
“screening failure” will be registered in IxRS.
For data to be collected for screening failures, refer to Section 11.1 (data recorded during 
screening).
6.4.1.2
Re-screening
Patients who have signed the pre-screening informed consent and have not completed the 
FGFR test could have the FGFR test done. Re-testing for FGFR expression level after 
obtaining an initial negative result is not allowed.
Re-starting the defined set of screening procedures to enable the “screening failure” patient’s 
participation at a later time point is not allowed.
Re-screening might be possible considering the following examples:
The patient had successfully passed the screening procedures, but could not start 
subsequent treatment on schedule.
Initial screening occurred too early to complete the required washout period after prior 
therapy.
The in- / exclusion criteria preventing the patient’s initial attempt to participate have 
been changed (via protocol amendment).
Re-screening of patients is only allowed once after discussion with the sponsor’s designated 
medical representative and after approval by the sponsor. Sponsor’s approval of re-screening 
for a patient must be documented.
In any case, the investigator has to ensure that the repeated screening procedures do not 
expose the patient to an unjustifiable health risk. Also, for re-screening, the patient has to re-
sign the informed consent form, even if it was not changed after the patient’s previous 
screening.
The screening failure will be registered in IxRS to close the patient identification number 
(PID), and re-screening will start again by signing a new informed consent form and being 
assigned a new PID via IxRS. 
6.4.1.3
Withdrawal criteria
Withdrawal from study treatment 
Patients must be withdrawn from the study treatment if any of the following occurs:

Unacceptable toxicity.
Any adverse reaction deemed sufficiently serious to warrant discontinuation of 
treatment by the investigator or his/her designated associate(s). Use of illicit drugs or 
other substances that may, in the opinion of the investigator or his/her designated 
associate(s), have a reasonable chance of contributing to toxicity or otherwise 
confound the results. For further details of toxicities leading to treatment 
discontinuation, please refer to Section 7.4.3 (dose modifications).


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
Any grade of recurrent symptomatic pancreatitis. 

Grade 4 non-hematological toxicities in patients treated with rogaratinib.
o For non-hematological toxicities in patients treated with chemotherapy, refer to 
the respective SmPC; the decision of dose modification or withdrawal is at the 
investigator’s discretion.

Grade 3 liver toxicity at the 2nd re-appearance, or grade 3 liver toxicity with AST or 
ALT > 8x ULN and concomitant rise in bilirubin (in case of negative risk-benefit 
assessment). 

Clinical progression and/or decline in ECOG PS that can be attributed to disease 
progression. 
o Symptomatic deterioration (i.e. uncontrollable pain secondary to disease or 
unmanageable ascites, etc.) attributed to disease progression as determined by 
the investigator after integrated assessment of radiographic data and clinical 
status.

At their own request or at the request of their legally acceptable representative. At any 
time during the study and without giving reasons, a patient may decline to participate 
further. The patient will not suffer any disadvantage as a result. 

If, in the investigator's opinion, continuation of the study would be harmful to the 
patient's well-being. 

Start of a new anti-cancer regimen. 

Development of a malignancy other than urothelial carcinoma or excised non-
melanoma skin cancer. 

Any decrease in visual acuity, ocular pain or discomfort, or symptomatic retinal 
disorders including retinal detachment / retinal pigment epithelial detachment / serous 
retinopathy / retinal vein occlusion classified analog to CTCAE v.4.03 as Grade 2 or 
higher. Based on the individual benefit risk assessment and after discussion with the 
sponsor, patient may interrupt treatment until recovery to at least Grade 1 and then 
treatment may be resumed at one dose level below. Patients with low visual acuity at 
baseline (best corrected visual acuity worse than 20/40 and up to 20/200) have to 
undergo individual clinical evaluation to determine the maintenance in the study, 
according to investigator’s judgment and based on the individual benefit risk 
assessment.

Newly diagnosed soft-tissue mineralization suspected to be caused by rogaratinib. 

Severe allergic reaction to study drugs (such as exfoliative erythroderma or Grade 3 or 
4 hypersensitivity reaction). 

Substantial non-compliance with the requirements of the study. 

Interruption/delay in the administration of study treatment for > 24 days (due to 
toxicity) or for > 31 days (due to other reasons) from the next intended dose. 


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
Patients with a positive ß-human chorionic gonadotropin (HCG) test or any other sign 
consistent with pregnancy. Pregnancy will be reported via the Pregnancy Monitoring 
Form. 

Patient lost to follow-up. 
Patients may be withdrawn from the study treatment if any of the following occurs:

Documented radiological progression (according to RECIST 1.1 criteria) of urothelial 
carcinoma (local and/or central assessment), unless the patient may benefit from post-
progression treatment according to the investigator’s judgment. In case radiological 
progression is suspected by the investigator it is strongly recommended to wait for the 
confirmation of progressive disease by central review. The full responsibility for 
patient treatment will nevertheless always be with the treating physician.
In the event of radiological progression as determined by RECIST (version 1.1) 
patients may continue to receive study treatment if identified as having continued 
clinical benefit. For example, a patient with radiological PD per RECIST as assessed 
by local assessment but improved clinical symptoms (clinical benefit defined as the 
absence of deterioration of ECOG performance status [e.g. ECOG should not 
deteriorate from baseline status: 0 to 2 or higher, from 1 to 3 or higher]) may be a 
patient identified as having continued clinical benefit from study treatment. Decisions 
about continuing study treatment will be made at the discretion of the investigator, 
based on the investigator’s judgment about the patient’s clinical status, and the 
sponsor should be informed. The reason for continuing treatment past progression 
needs to be recorded in patient file.

At the specific request of the sponsor and in agreement with the investigator (e.g. 
obvious non-compliance, safety concerns). 

Development of any intercurrent illness or situation which, in the judgment of the 
investigator, may affect assessments of clinical status and study endpoints to a
relevant degree.
For patients who withdraw consent to study, no further study-related procedures will be 
allowed. The patient will not suffer any disadvantage as a result. Any patient removed from 
the study will remain under medical supervision until discharge or transfer is medically 
acceptable. All patients will enter the active follow-up period upon discontinuation of the 
study treatment. Regardless of the reason for discontinuation, all patients will be followed for 
survival until death is documented, except for those who specifically withdraw consent to 
follow-up. 
Withdrawal from active follow-up
Patients must be withdrawn from active follow-up if any of the following occurs:

At their own request or at the request of their legally acceptable representative. At any 
time during the study and without giving reasons, a patient may decline to participate 
further. The patient will not suffer any disadvantage as a result. 


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
Radiologically confirmed PD is observed and/or clinical progression of urothelial 
carcinoma (local and/or central assessment).

Start of subsequent systemic anti-cancer treatment.

Development of a malignancy other than urothelial carcinoma

Substantial non-compliance with the requirements of the study

Withdrawal of consent to active follow-up visits

If, in the investigator's opinion, continuation of the active follow-up visits would be 
harmful to the patient's well-being

Patient lost to follow-up

Death
Withdrawal from long-term follow-up
Patients must be withdrawn from long-term follow-up if any of the following occurs:

Withdrawal of consent to long-term follow-up

Patient lost to follow-up

Death
Patients randomized but not treated
In the event a patient is randomized but never treated, an end-of-treatment electronic case 
report form (eCRF) should be filled out for the patient, stating the date of and reason for not 
treating the patient. Every effort should be made that the patient participates in the efficacy 
assessments of the active follow-up, and the long-term follow-up. No safety assessments are
required.
Patients lost to follow-up
If a patient is lost to follow-up at any stage of the study, the site will try to contact the patient, 
the patient’s relatives, or another doctor treating the patient, unless prohibited by local 
requirements. All attempts to contact the patient or relatives should be documented. 
6.4.1.4
General procedures
In all cases, the reason for withdrawal must be recorded in the eCRF and in the patient’s 
medical records. See Section 11.1 for data recoding.
The patient may object to the generation and processing of post-withdrawal data as specified
in Section 13.4.


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Details for the premature termination of the study as a whole (or components thereof) are 
provided in Section 12 (Premature termination of the study).
6.4.2
Replacement
No replacement of randomized patients will be allowed during this study. 
6.5
Patient identification
After a patient has signed the PI/ICF for FGFR testing, the patient identification number will 
be provided to the investigators through an Interactive Voice / Web Response System (IxRS). 
Patients will be identified by a 9-digit patient identification number consisting of:
Digits 1 to 5 = Unique center number
Digits 6 to 9
= Current patient number within the center
When the patient is found to be eligible for study treatment, a randomization contact to IxRS 
will be performed and the patient will be given a unique randomization number. A patient can 
be randomized only once.
7.
Treatments
7.1
Treatments to be administered
Patients who successfully complete the screening evaluations are eligible and will be 
randomized (using IxRS) to one of the two arms following a 1:1 ratio:

the experimental arm: rogaratinib 
or

the control arm: chemotherapy (docetaxel, paclitaxel or vinflunine)
The chemotherapy will be sourced centrally by the sponsor. The choice of the chemotherapy 
is at the discretion of the investigator taking into consideration the status of the authorization 
or treatment guidelines in the given country.
No other anti-cancer compounds and no placebo will be administered.
7.2
Identity of study treatment
In this study the term “test drug” refers to rogaratinib only. The terms “study drug” or “study 
treatment” refer to any of the two treatment regimens offered in this trial.
All study drugs centrally provided by the sponsor will be labeled according to the 
requirements of local law and legislation. Label text will be approved according to the 
sponsor’s agreed procedures, and a copy of the labels will be made available to the study site 
upon request.
For all study drugs provided, a system of numbering in accordance with all requirements of 
GMP will be used, ensuring that each dose of study drug can be traced back to the respective 


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bulk ware of the ingredients. Lists linking all numbering levels will be maintained by the 
sponsor’s clinical supplies Quality Assurance (QA) group.
A complete record of batch numbers and expiry dates of all study treatment as well as the
labels will be maintained in the sponsor study file.
In case patients are transferred to a roll-over study (ROS) or a post-trial access program, drug 
formulation and / or dosage might change compared to this study depending on the course of 
the clinical development. 
In addition, the supply of commercially available non-Bayer drugs in a roll-over study or a 
post-trial access program will be at the discretion of the sponsor and can potentially change 
from central to local supply by the sponsor, to supply per prescription or any other available 
option.
7.2.1
Rogaratinib (test drug)
Rogaratinib (BAY 1163877) is packaged in a wide-necked, child-proof HDPE plastic bottle 
(90ml) with 56 dark red coated tablets per bottle. Rogaratinib should be stored in the original 
container not above 25ºC (77 ºF).
Details of the test drug rogaratinib are given in Table 7–1.


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Table 7–1: Identity of test drug (IMP): rogaratinib (BAY 1163877)
Generic name / brand name / INN
Rogaratinib
Formulation
Tablet
Substance code number(s)
BAY 1163877 (BAY 1213802, hydrochloride of 
BAY 1163877)
Material
BAY 1163877 hydrochloride coated tablet 200mg
Galenical form / formulation / vehicle and 
reconstitution
IR (immediate release) tablets 
Composition
Active ingredients:
BAY 1163877 as hydrochloride
Other ingredients: 
Cellulose microcrystalline (filler)
Lactose monohydrate (filler)
Crospovidone (disintegrant) 
Copovidone (binder)
Magnesium stearate (lubricant)
Silica colloidal anhydrous (glidant)
Lacquer red (coating material)a
a(contains hypromellose, macrogol, titanium
    dioxide, ferric oxide red)
Strength (amount of drug per unit) or 
concentration
200 mg BAY 1163877 per tablet
Type of packaging and content
HDPE bottles with screw cap closure
sealable to PP (4345 / 0202)
Marketing Authorization Holder
Not applicable 
HDPE = High-density polyethylene; IMP = Investigational medicinal product; INN = International Nonproprietary 
Name; IR = Immediate release; mg = Milligram; PP = Polypropylene.
7.2.2
Chemotherapy (comparator drugs)
This study includes single-agent chemotherapy as a comparator.
The selection of the chemotherapy for the individual patient, either taxane (docetaxel or 
paclitaxel) or vinflunine, is at the discretion of the investigator taking into consideration the 
status of the authorization or treatment guidelines in the given country. The investigator’s 
choice for the individual patient will be determined at the screening visit and recorded in IxRS.
The chemotherapy will be sourced centrally by the sponsor.
Docetaxel, paclitaxel or vinflunine will be prepared at the study centers in accordance with 
the product information and/or local standards and administered per local standards. The 
participating investigators are required to consult the SmPC/desk reference, which contains 
details regarding drug properties, formulation, handling, reconstitution, contraindications, 
precautions and administration. Additional considerations for the use of taxanes (docetaxel, 
paclitaxel) and vinflunine according to local guidelines should be followed.


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7.3
Treatment assignment
The investigator or delegate will contact the IxRS to confirm whether patients have passed or 
failed the screening evaluations at the end of the screening period. Patients who successfully 
complete the screening evaluations are eligible and will be randomized following a 1:1 ratio 
to either the experimental arm (rogaratinib) or the control arm (chemotherapy; docetaxel, 
paclitaxel or vinflunine) using the IxRS.
The choice of the chemotherapy is at the discretion of the investigator taking into 
consideration the status of the authorization or treatment guidelines in the given country, and 
will be recorded in IxRS. The chemotherapy will be provided centrally by the sponsor.
Randomization will be stratified according to 

PIK3CA and/or RAS activating mutations (presence vs. absence)

prior immunotherapy (yes vs. no)

modified 4-factor Bellmunt risk score (high vs. low) (see Section 9.3.3)
The first administration of study drug should take place within 3 days of randomization.
To ensure random assignment, a computer-generated randomization list will be prepared by 
the sponsor and provided to an IxRS. Patients will be randomized using permuted-block 
randomization. The IxRS will assign each eligible patient to a treatment arm based on the 
randomization list and will assign a randomization number to the patient. 
Confirmation of adequate level of FGFR overexpression will be obtained from the central lab.
Confirmation of other inclusion and exclusion requirements will be obtained from the 
investigator. After confirmation of patient eligibility in IxRS, a patient may be randomized.
The IxRS procedure is described in detail in a separate IxRS instruction manual that will be 
maintained in the electronic trial master file (eTMF) and in each center’s investigator site file.
7.4
Dosage and administration
7.4.1
Doses, dosing schedule and route of administration
Rogaratinib 
Following randomization, rogaratinib (BAY 1163877) 600 mg (consisting of 3 tablets à 
200 mg) will be taken orally (p.o.) twice a day (b.i.d.), on every day during a 21-day treatment 
cycle. It is important to take the tablets at the same times each day approximately 12 hours 
apart.


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Special considerations/instructions for rogaratinib dosing:
Rogaratinib tablets should be taken with a glass of water (approximately 200 mL / 7 ounces). 
Tablets should be swallowed intact and not chewed. Rogaratinib tablets can be taken with or 
without food. 
If a dose of rogaratinib is missed, the prescribed dose should be taken as soon as the patient 
remembers and up to 3 hours after the usual time. If this is not possible, missed doses should 
not be replaced and the patient should continue with the next dose as planned.
Chemotherapy
Following randomization, the assigned chemotherapy (monotherapy) will be given as 
intravenous (i.v.) infusion once every three weeks (on day 1 of a 21-day cycle). The cycle 
ends with the next infusion. 
The most current version of the SmPC will be made available to the investigator and should 
be considered whenever necessary. In the comparator arm, patients should receive standard 
premedication for chemotherapy as per local standard-of-care and SmPC.
Docetaxel
The starting dose for docetaxel to be used is 75 mg/m² given as i.v. infusion. 
All patients should be premedicated prior docetaxel administration in order to prevent severe 
hypersensitivity reactions (such as severe hypotension, bronchospasm general rash/erythema
and fluid retention). Such premedication may consist of an oral corticosteroid, such as 
dexamethasone 16 mg per day for three days, starting 1 day prior to docetaxel administration, 
unless contraindicated. The appropriate premedication regimen may be determined by the 
investigator. Patients who have developed severe hypersensitivity reactions (such as severe 
hypotension, bronchospasm or generalized rash/erythema which require immediate 
discontinuation of docetaxel and appropriate therapy) should not be re-challenged with 
docetaxel.
See Section 7.4.3.2 for dose modification guidance.
Paclitaxel
The starting dose for paclitaxel to be used is 175 mg/m² given as i.v. infusion.
All patients should be premedicated prior to paclitaxel administration in order to prevent 
severe hypersensitivity reactions (characterized by dyspnea and hypotension requirement 
treatment, angioedema and generalized urticaria). Such premedication may consist of 
dexamethasone 20 mg p.o. administered approximately 12 and 6 hours before paclitaxel, or 
for i.v. administration: 30 to 60 minutes before paclitaxel, diphenhydramine (or its equivalent) 
50 mg i.v. 30 to 60 minutes prior to paclitaxel, and cimetidine (300 mg) or ranitidine (50 mg) 
i.v. 30 to 60 minutes before paclitaxel. The appropriate premedication regimen may be 
determined by the investigator. Patients who have developed severe hypersensitivity reactions
(such as hypotension requiring therapy, angioedema, respiratory distress requiring 
bronchodilator therapy, or generalized urticaria) should not be re-challenged with paclitaxel.


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See Section 7.4.3.2 for dose modification guidance.
Vinflunine
The starting dose for vinflunine to be used is 320 mg/m² given as i.v. infusion.
In case of ‘ECOG performance status (PS) of 1’ or ‘PS of 0 and prior pelvic irradiation’, the 
treatment should be started at a dose of 280 mg/m². In the absence of any hematological 
toxicity during the first cycle causing treatment delay or dose reduction, the dose will be 
increased to 320 mg/m² every 3 weeks for the subsequent cycles.
Dose recommendation in elderly patients:
In patients of at least 75 years and less than 80 years, dose of vinflunine to be given is 
280 mg/m2 every 3 weeks; in patients 80 years old and above, dose of vinflunine to be given 
is 250 mg/m2 every 3 weeks.
Dose recommendation in patients with renal impairment:
Patients with moderate renal impairment (CrCl 40ml/min - <60 ml/min) the recommended 
dose of vinflunine is 280 mg/m2 every 3 weeks. In patients with severe renal impairment 
(CrCl < 40 ml/min) the recommended dose of vinflunine is 250 mg/m2 every 3 weeks.
Dose recommendation in patients with hepatic impairment:
The recommended dose of vinflunine is 250 mg/m² given once every 3 weeks in patients with 
mild liver impairment (Child-Pugh grade A) or in patients with a prothrombin time 
≥60% ULN and 1.5xULN < bilirubin ≤3xULN and presenting at least one of the following 
criteria: transaminases > ULN and/or GGT > 5xULN.
7.4.2
Justification of selected doses
Please refer to Section 5.4.
7.4.3
Dose modifications
7.4.3.1
Dose modifications of rogaratinib
Doses of rogaratinib may be interrupted/delayed or reduced in case of clinically significant 
hematologic or other toxicities that are possibly, probably or definitely related to rogaratinib. 
Toxicities will be graded using CTCAE v.4.03. Dose modifications will follow pre-defined 
dose levels as indicated below.
Dose levels of rogaratinib are defined in Table 7–2. 
Table 7–2: Dose levels of rogaratinib (BAY 1163877)
Level
Dose
0
600 mg b.i.d.
-1
400 mg b.i.d.
b.i.d = Twice daily, bis in die; mg = Milligram.


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Dose modifications will be based on the highest grade of AE since last contact. If a patient
experiences multiple toxicities, dose modification should be according to the toxicity with the 
highest grade.

In case of multiple toxicities of the same grade, investigator should modify the dose
using the most conservative approach, i.e. the lowest recommended dose.

Patients in whom doses are interrupted due to toxicities should be followed up within 
7 to 10 days to re-assess toxicities, if not specified otherwise.

Patients requiring dose reduction of rogaratinib may have the dose re-escalated by one 
dose level, if they have been on a stable dose for 3 weeks or more without further 
toxicities requiring dose modification with the exception of dose reduction due to liver 
toxicities.

Patients requiring a continuous dose interruption of rogaratinib due to toxicity 
> 24 days from the next intended dose or due to other reasons for > 31 days from the 
next intended dose will be withdrawn from the study treatment.

If further dose reductions below level -1 are needed, per investigator´s risk benefit 
assessment, patients may continue at a 200 mg b.i.d. dose regimen after the approval 
of the sponsor, otherwise, patients will be discontinued from the study treatment.

If a dose of rogaratinib is missed, the prescribed dose should be taken as soon as the 
patient remembers and up to 3 hours after the usual time. If this is not possible, missed 
doses should not be replaced and the patient should continue with the next dose as 
planned.
The cycle duration will consist of 21 days (delays will prolong the duration of a cycle). 
Guidance for dose modifications of rogaratinib is presented in Table 7–3. 
Table 7–3: Criteria for dose modification of rogaratinib due to toxicity (excluding 
hyperphosphatemia, liver toxicity, retinal disorders)
Grade a
Dose interruption/delay
Dose change
1 – 2
Treat as scheduled
No change
3
Interrupt/delay b until recovery to Grade 2
Decrease by 1 dose level
4
Discontinue study drug permanently
Discontinue study drug permanently
a: Excludes alopecia, nausea/vomiting and diarrhea if adequately controlled by antiemetic or antidiarrheal treatments, 
respectively. 
b: If not recovered within 24 days, the test drug must be permanently discontinued.
7.4.3.1.1
Hyperphosphatemia
Dose modifications of rogaratinib for elevated serum phosphate levels (≥ 7 mg/dL) and 
management guidance for hyperphosphatemia are presented in Table 7–4. 


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Table 7–4:
Dose modifications of rogaratinib and management for hyperphosphatemia
Serum phosphate
Countermeasures
Initial phosphate value is
abnormally high, but less than 7 mg/dL
Continue rogaratinib at the same dose.
Consider low phosphate diet a and / or initiate phosphate 
chelators.
≥ 7 mg/dL for two weeks despite 
phosphate lowering treatment
Hold rogaratinib and increase dose of phosphate chelators until 
recovery below 7 mg/dL. 
Re-start rogaratinib at the same dose level and continue 
phosphate chelators.
≥ 7 mg/dL despite optimal phosphate 
lowering treatments and two rogaratinib 
treatment interruptions on the same dose 
within four weeks
Hold rogaratinib and continue phosphate chelators until recovery 
below 7 mg/dL. 
Re-start rogaratinib, but at one dose level lower and continue 
phosphate chelators.
≥ 7 mg/dL despite optimal phosphate 
lowering treatments and two rogaratinib 
treatment interruptions within four weeks 
at 400 mg b.i.d.
Hold rogaratinib and continue phosphate chelators until recovery 
below 7 mg/dL. 
Re-start rogaratinib at 400 mg b.i.d. and continue phosphate 
chelators.
b.i.d. = Twice daily, bis in die.
a: Low phosphate diet can be considered if the patient’s nutritional status is not affected.
In case phosphate binders are not tolerated, phosphate low diet should be considered.
For patients with elevated serum phosphate levels ≥ 7 mg/dL, serum phosphate level and 
standard single 12-lead ECG has to be checked weekly for ≥ 4 weeks until resolution (serum 
phosphate < 7 mg/dL).
In patients with hypocalcemia of CTCAE Grade ≥ 2, an additional 12-lead ECG has to be 
obtained on day of detection of hypocalcemia and should be repeated as clinically indicated.
7.4.3.1.2
Liver toxicity
Dose modifications of rogaratinib for liver toxicity are presented in Table 7–5. Liver toxicity 
refers to ALT and/or AST and/or bilirubin increases and/or hepatic failure considered 
possibly related to rogaratinib, and graded according to CTCAE v.4.03. Liver tests will be 
monitored throughout study treatment.


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Table 7–5: Dose modifications of rogaratinib for liver toxicity
Toxicity
Modification schedule
Grade 1-2
No modifications. Treat as scheduled and check AST, ALT 
and bilirubin weekly for at least 4 weeks.
Grade 3
(except Grade 3 with ALT or AST > 8x ULN 
and a concomitant rise in bilirubin or hepatic 
failure)
Interrupt rogaratinib until recovery to ≤Grade 2 or baseline, 
then reduce 1 dose level and check AST, ALT and bilirubin 
weekly for at least 4 weeks a.
1st reappearance
Interrupt rogaratinib until recovery to ≤Grade 2 or baseline,
then reduce 1 dose level and check AST, ALT and bilirubin 
weekly for at least 4 weeks a,d.
2nd reappearance
Withdraw patient from study treatment permanently b
Grade 3 with ALT or AST > 8x ULN 
and a concomitant rise in bilirubin 
(of any degree compared to previous bilirubin 
level) 
or hepatic failure (of any degree)
In case of a negative risk-benefit assessment, consider 
permanent discontinuation at the first occurrence b,c
OR
Interrupt rogaratinib until recovery to ≤Grade 2 or baseline,
then reduce 1 dose level and check AST, ALT and bilirubin 
weekly for at least 4 weeks a.
1st reappearance
Withdraw patient from study treatment permanently b
AST/ALT > 3x ULN with concomitant bilirubin 
> 2x ULN (absence of another reason)
Withdraw patient from study treatment permanently b
Grade 4 b
Withdraw patient from study treatment permanently b
ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; ULN = Upper limit of normal.
a: Dose will not be re-escalated to original dose after dose reduction for liver toxicity. 
b: In case of discontinuation, check AST, ALT, and bilirubin weekly until recovery to baseline or stabilization.
c: Patients with Gilbert’s syndrome who develop elevated transaminases should be managed as per the above outlined 
recommendations for the respective observed elevation of ALT and / or AST.
d: If further dose reductions below level -1 are needed, per investigator´s risk benefit assessment, patients may continue at a 
200 mg b.i.d. dose regimen after the approval of the sponsor, otherwise, patients will be discontinued from the study 
treatment.
Permanent discontinuation also applies to patients with ‘AST/ALT > 8x ULN’ or ‘AST/ALT 
> 5x ULN for > 2 weeks’ if no other reason is found for these elevations.
7.4.3.1.3
Retinal disorders
Patients who experience any decrease in visual acuity, ocular pain or discomfort, or any 
retinal disorders including retinal detachment / retinal pigment epithelial detachment / serous 
retinopathy / retinal vein occlusion have to undergo ophthalmologic examinations on Day 1 of 
every cycle.
Patients that experience any decrease in visual acuity, ocular pain or discomfort, or 
symptomatic retinal disorders including retinal detachment / retinal pigment epithelial 
detachment / serous retinopathy / retinal vein occlusion classified analog to CTCAE v.4.03 as 
Grade 2 or higher have to be permanently discontinued from study treatment. Based on the 
individual benefit risk assessment and after discussion with the sponsor, patient may interrupt 
treatment until recovery to at least Grade 1 and then treatment may be resumed at one dose 
level below. Patients with low visual acuity at baseline (best corrected visual acuity worse 


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than 20/40 and up to 20/200) have to undergo individual clinical evaluation to determine the 
maintenance in the study, according to investigator’s judgment and based on the individual 
benefit risk assessment.
Monthly ophthalmological monitoring of the treatment associated retinal abnormality is 
recommended to be continued until resolution of the abnormality and to be documented in the 
source data for patients whose treatment was permanently discontinued.
7.4.3.2
Dose modifications of chemotherapy (comparator drugs)
Before each single administration of the chemotherapy the patient will be assessed for signs 
of hematologic and non-hematologic toxicity by clinical and laboratory investigations (see
Section 9.1).
Findings will be graded according to CTCAE v.4.03 and it will be determined if the 
chemotherapy needs to be delayed or if the dose has to be modified. This decision will be 
clearly documented in the patient’s records and the eCRF. Decision for dose delay and dose 
reduction will be based on local standard-of-care and/or SmPC.
Patients in whom doses are delayed due to toxicities should be followed up within 7 to 10 
days to re-assess toxicities, if not specified otherwise.
Paclitaxel, docetaxel or vinflunine dose will be reduced for toxicities attributed to these drugs. 
Once dose reductions are made, re-escalation of doses is not permitted since dose reductions 
are permanent. Patients requiring a dose delay due to toxicity of > 24 days (or less if required 
in the dose modification section) from the next intended dose or due to other reasons for 
> 31 days from the next intended dose will be withdrawn from the study treatment.
The cycle duration will consist of 21 days, however any delay will prolong the duration of a 
cycle. The cycle ends with the next dose administration.
Specific dose modification guidance for paclitaxel, docetaxel or vinflunine is found in the 
subsections below. Additional considerations for the toxicity management including other 
measurement and dose modification according to local label and/or local guidelines should be 
followed by the investigators.
Specific dose modifications for vinflunine
In case of ’ECOG performance status (PS) of ≥1’ or ‘PS of 0 and prior pelvic irradiation’,
vinflunine treatment should be started at the dose of 280 mg/m2. In the absence of any
hematological toxicity during the first cycle causing treatment delay or dose reduction, the
dose will be increased to 320 mg/m2 every 3 weeks for the subsequent cycles.
The recommended dose of vinflunine is 250 mg/m2 given once every 3 weeks in patients with 
mild liver impairment (Child-Pugh grade A) or in patients with a Prothrombin time
≥60% ULN and 1.5xULN < bilirubin ≤3xULN and presenting at least one of the following
criteria: transaminases > ULN and/or GGT > 5xULN.
In patients who initiate vinflunine at 280 mg/m2 and who experience an AE requiring dose
modification, the dose should be reduced to 250 mg/m2 following the 1st occurrence and
resolution, and discontinued following a 2nd occurrence. In patients who initiate vinflunine at 


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250 mg/m2 and who experience an AE requiring dose modification, vinflunine should be
discontinued.
Cases of posterior reversible encephalopathy syndrome (PRES) have been observed after
administration of vinflunine. The typical clinical symptoms are, with various degrees:
neurological (headache, confusion, seizure, visual disorders), systemic (hypertension), and
gastrointestinal (nausea, vomiting). Radiological signs are white matter abnormalities in the
posterior regions of the brain. Vinflunine should be discontinued in patients who develop 
neurological signs of PRES.
Guidance for dose delay of vinflunine due to toxicity is given in Table 7–6.
Table 7–6: Dose delay for subsequent cycles of vinflunine due to toxicity
Toxicity
Day 1 treatment administration
Neutropenia (ANC < 1,000/mm3) or 
Thrombocytopenia (platelets 
< 100,000/mm3)
-
Delay until recovery (ANC ≥1,000/mm3 and platelets 
≥100,000/mm3) and adjust the dose if necessary 
(see Table 7–7) 
-
Discontinuation if recovery has not occurred within 2 weeks
Organ toxicity: moderate, severe or life-
threatening
-
Delay until recovery to mild toxicity or none, or to initial 
baseline status and adjust the dose if necessary 
(see Table 7–7)
-
Discontinuation if recovery has not occurred within 2 weeks
Cardiac ischemia in patients with prior 
history of myocardial infarction or angina 
pectoris
-
Discontinuation
ANC = Absolute neutrophil count; mm3 = Cubic millimeter.
Source: (18)
Specific dose adjustments for vinflunine due to toxicity are detailed below in Table 7–7.


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Table 7–7: Vinflunine dose adjustments due to toxicity
Toxicity
Dose adjustment
Initial dose:
vinflunine 320 mg/m2
Initial dose:
vinflunine 280 mg/m2 c
Initial dose:
vinflunine 250 mg/m2 d
1st
event
2nd
consecutive 
event
3rd
consecutive 
event
1st
event
2nd
consecutive 
event
1st
event
2nd
consecutive 
event
Neutropenia Grade 4 
(ANC < 500/mm3)       
> 7 days
280
mg/m2
250
mg/m2
Permanent 
treatment 
discontinua-
tion
250
mg/m2
Permanent 
treatment 
discontinua-
tion
225
mg/m2 d
Permanent 
treatment 
discontinua-
tion
Febrile neutropenia 
(ANC < 1.000/mm3
and fever ≥38.5°C)
Mucositis or 
constipation Grade 2 
≥5 days or Grade ≥3 
any durationa
Any other toxicity 
Grade ≥ 3 (severe or 
life-threatening) 
(except Grade 3 
vomiting or nauseab)
ANC = Absolute neutrophil count; °C = Degree(s) Celsius; CrCl = Creatinine clearance; CTCAE = Common Toxicity Criteria 
for Adverse Events; mg/m2 = Milligrams per square meter; ml/min = Milliliters per minute.
a: CTCAE Grade 2 constipation is defined as requiring laxatives, Grade 3 as an obstipation requiring manual evacuation or 
enema, Grade 4 as an obstruction or toxic megacolon. Mucositis Grade 2 is defined as “moderate”, Grade 3 as “severe” 
and Grade 4 as “life-threatening”. 
b: CTCAE Grade 3 nausea is defined as no significant intake, requiring intravenous fluids. Grade 3 vomiting as ≥ 6 episodes 
in 24 hours over pretreatment; or need for intravenous fluids.
c:  Starting dose of 280 mg/m2 for patients with moderate renal impairment (40 ml/min ≤CrCl ≤60 ml/min) and for elderly 
patients between ≥75 and < 80 years.
d: Starting dose of 250 mg/m2 for patients with severe renal impairment (20 mL/min ≤ CrCl > 40 mL/min) and for elderly 
patients ≥80 years. Dose reduction to 225 mg/m2 is allowed only in elderly patients ≥80 years and in patients with 
severe renal impairment because of a higher bioavailability of vinflunine in these patients.
Source: (18)
In patients with moderate renal impairment (40 ml/min ≤CrCl ≤60 ml/min), the 
recommended dose of vinflunine is 280 mg/m² given once every 3 weeks. In patients with 
severe renal impairment (20 ml/min ≤CrCl <40 ml/min), the recommended dose is 
250 mg/m² given once every 3 weeks. For further cycles, the dose should be adjusted in the 
event of toxicities, as shown in Table 7–8.
The doses recommended in patients ≥75 years old are as follows:

in patients at least 75 years old but less than 80 years, the dose of vinflunine to be 
given is 280 mg/m² every 3 weeks.

in patients 80 years old and beyond, the dose of vinflunine to be given is 250 mg/m² 
every 3 weeks.
For further cycles, the dose should be adjusted in the event of toxicities, as shown in Table 7–
8.


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Table 7–8: Vinflunine dose adjustments due to toxicity in renal impaired or elderly patients
Toxicity
Dose adjustment
Initial dose: 
vinflunine 280 mg/m2
Initial dose: 
vinflunine 250 mg/m2
1st event
2nd consecutive 
event
1st event
2nd consecutive 
event
Neutropenia Grade 4 
(ANC < 500/mm3) 
> 7 days
250 mg/m2
Permanent 
treatment 
discontinuation
225 mg/m2 c
Permanent 
treatment 
discontinuation
Febrile neutropenia 
(ANC < 1.000/mm3 and 
fever ≥ 38.5°C)
Mucositis or 
constipation Grade 2 
≥5 days or Grade ≥3 
any duration a
Any other toxicity 
Grade ≥ 3 (severe or 
life-threatening) (except 
Grade 3 vomiting or 
nausea b)
ANC = Absolute neutrophil count; °C = Degree(s) Celsius; CTCAE = Common Toxicity Criteria for Adverse Events; SmPC = 
Summary of Product Characteristics; mg/m2 = Milligrams per square meter; ml/min = Milliliters per minute.
a: CTCAE Grade 2 constipation is defined as requiring laxatives, Grade 3 as an obstipation requiring manual evacuation or 
enema, Grade 4 as an obstruction or toxic megacolon. Mucositis Grade 2 is defined as “moderate”, Grade 3 as “severe” 
and Grade 4 as “life-threatening”. 
b: CTCAE Grade 3 nausea is defined as no significant intake, requiring intravenous fluids. Grade 3 vomiting as ≥ 6 episodes 
in 24 hours over pretreatment; or need for intravenous fluids.
c: Dose reduction to 225 mg/m2 is allowed only in elderly patients and patients with renal impairment due to higher 
bioavailability of vinflunine as per SmPC.
Source: (18)
For further details refer to most current SmPC.
Specific dose modifications for paclitaxel
Paclitaxel should not be administered to patients with baseline neutrophil counts of less than
1500 cells/mm3. Patients should not be re-treated with subsequent cycles of paclitaxel until
neutrophils recover to a level ≥1500 cells/mm3 and the platelet count is ≥100,000 /mm³. 
Patients who experience severe neutropenia (neutrophil count < 500 /mm³ [corresponding to 
CTCAE Grade 4] for ≥7 days) or severe peripheral neuropathy (CTCAE Grade ≥3) should 
receive a dose reduction of 20 % for subsequent cycles. If further dose reduction is needed, 
treatment with paclitaxel should be discontinued.
Severe cardiac conduction abnormalities have been reported rarely with single agent 
paclitaxel. If patients develop significant conduction abnormalities during paclitaxel 
administration, appropriate therapy should be administered and continuous cardiac monitoring 
should be performed during subsequent therapy with paclitaxel. A dose reduction or 
withdrawal from treatment is at the discretion of the investigator after individually assessing 
the safety of each patient. Hypotension, hypertension, and bradycardia have been observed 


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during paclitaxel administration; patients are usually asymptomatic and generally do not 
require treatment.
Patients with hepatic impairment may be at increased risk of toxicity, particularly Grade 3-4 
myelosuppression. There is no evidence that the toxicity of paclitaxel is increased when given 
as a 3-hour infusion to patients with mildly abnormal liver function. Patients with severe 
hepatic impairment should not be treated with paclitaxel.
For further details refer to most current SmPC.
Specific dose modifications for docetaxel
In general, docetaxel should not be administered unless the neutrophil count is 
≥1,500 cells/mm3.
In patients who experience either febrile neutropenia, neutrophil count < 500 cells/mm3
(CTCAE Grade 4)for more than one week, severe or cumulative cutaneous reactions or 
severe peripheral neuropathy (CTCAE Grade ≥3) during docetaxel therapy, the dose of 
docetaxel should be reduced from 75 mg/m2 to 60 mg/m2. If the patient continues to 
experience these reactions at 60 mg/m², the treatment should be discontinued.
Patients with hypersensitivity reactions:
If hypersensitivity reactions occur, minor symptoms such as flushing or localized cutaneous 
reactions do not require interruption of therapy. However, severe reactions, such as severe 
hypotension, bronchospasm or generalized rash/erythema require immediate discontinuation 
of docetaxel and appropriate therapy. Patients who have developed severe hypersensitivity 
reactions should not be re-challenged with docetaxel.
Patients with hepatic impairment:
For patients with the following conditions, no dose reduction can be recommended as per 
SmPC and docetaxel should not be used unless strictly indicated: 

serum bilirubin > ULN and alkaline phosphatase > 6 x ULN

serum bilirubin > ULN and ALT and AST > 3.5 x ULN and alkaline phosphatase 
> 6 x ULN

ALT and AST > 3.5 x ULN and alkaline phosphatase > 6 x ULN
For further details refer to most current SmPC.
7.4.4
Treatment duration
Treatment with assigned study drug continues until any of the following events:

Radiological disease progression according to RECIST v.1.1 as assessed by 
independent central radiology review. 
o
At the investigator’s discretion, study treatment may continue beyond centrally 
confirmed radiological progression as defined by RECIST v.1.1 if the clinical 


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condition of the patient is stable or the patient is improving symptomatically, 
and the investigator expects continued clinical benefit for the patient.

Clinical progression

Unacceptable toxicity

Death

Withdrawal of consent

Withdrawal from the study treatment at the discretion of the investigator or designated 
associate(s)
For full list of withdrawal criteria refer to Section 6.4.1.3.
7.5
Blinding
Not applicable; this is an open-label study.
7.6
Drug logistics and accountability
All study drugs will be stored at the investigational site in accordance with GCP and GMP 
requirements and the instructions given by the clinical supplies department of the sponsor (or 
its affiliate/CRO), and will be inaccessible to unauthorized personnel. Special storage 
conditions and a complete record of batch numbers and expiry dates can be found in the 
sponsor’s electronic trial master file (eTMF); the site-relevant elements of this information 
will be available in the investigator site file. On the day of receipt, the responsible site 
personnel will confirm receipt of study drug via IxRS. The personnel will use the study drug 
only within the framework of this clinical study and in accordance with this protocol. Receipt, 
distribution, return and destruction (if any) of the study drug must be properly documented 
according to the sponsor’s agreed and specified procedures.
Written instructions on medication destruction will be made available to affected parties as 
applicable.
The number of rogaratinib tablets dispensed and returned by the patients will be recorded on 
the eCRF and on the appropriated drug dispensing form. Reason(s) for dose interruption, 
reduction or omission will also be recorded on the eCRF.
For the chemotherapy (docetaxel, paclitaxel or vinflunine) the number of vials used will be 
recorded on the appropriate treatment dispensing form. Reasons for dose delay, reduction, or 
omission will be recorded in the source documents and on the eCRF.
All study drugs supplied by the sponsor will have a 2-panel standard label or booklet label 
affixed. One panel will be permanently attached to the smallest shippable unit (SSU), while 
the other panel will be a tear-off section that will be appended to the dispensing 
documentation.
Drug accountability on patient level must be done at every cycle on Day 1 visit, starting on 
Day 1 of Cycle 1. The monitor will review overall drug accountability and destruction per the 
site documentation.


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7.7
Treatment compliance
Patient compliance with the treatment and protocol includes willingness to comply with all 
aspects of the protocol, and to have blood collected for all safety evaluations. Patients may be 
discontinued from the study treatment for non-compliance with follow-up visits or study 
treatment, at the discretion of the principal investigator or sponsor.
All reasons for non-compliance should be clearly documented in the patients’ records and the 
eCRF.
Any discrepancies between actual and expected amount of returned study drug (rogaratinib) 
must be discussed with the patient at the time of the visit, and any explanation must be 
documented in the source records.
The preparation and administration of the chemotherapy (docetaxel, paclitaxel or vinflunine) 
will be performed by appropriately trained personnel (e.g. site or pharmacy staff) that will 
ascertain and document that the patient receives all treatments as planned.
Each administration of the study drug must be recorded in the source documentation and the 
eCRF including every interruption/delay or reduction of the study treatment, regardless of the 
duration as well as reasons for dose interruption/delay, reduction, re-escalation (rogaratinib 
only) or omission. 
Reasons for dose interruption / delay, reduction, re-escalation or omission will also be 
recorded in the source documents and in the eCRF.
An adequate record of receipt, distribution, and return/destruction of all study drugs must be 
kept in the form of a Drug Accountability Form.
8.
Non-study therapy
8.1
Prior and concomitant therapy
Any medication which is considered necessary for the patient’s welfare, and which is not 
expected to interfere with the evaluation of the study treatment, may be given at the discretion 
of the investigator. In general, patients should be closely monitored for side effects of all 
concomitant medications regardless of elimination path, especially those with narrow 
therapeutic indices, such as warfarin and digoxin. 
Guidance on recording of prior and concomitant medications can be found in Section 11.1.
Excluded prior therapies are listed in Section 6.2 (Exclusion criteria).
Prohibited concomitant therapy
Both treatment arms
Systemic anti-cancer therapy including cytotoxic therapy, signal transduction inhibitors, 
immunotherapy and hormonal therapy 


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Bisphophonates and denosumab as supportive treatment started prior start of study 
treatment can be continued during the course of study, but newly start of treatment with 
denosumab or bisphophonates during the course of study drug treatment will not be 
allowed.
Bone marrow transplant or stem cell rescue.
Radiotherapy, except:
o
Concomitant palliative radiation therapy is allowed if the target lesion(s) are 
not included within the radiation field and no more than 10% of the bone 
marrow is irradiated.
o
A short course of radiotherapy during study treatment due to a pathological 
fracture will be allowed after consultation with the sponsor, if the underlying 
bone lesion is not considered as a target lesion.
Biotin-containing supplements (alternative names in over-the-counter drugs might be 
used, e.g. vitamin B7, vitamin H, coenzyme R) containing more than 30 µg daily dose 
should not be taken because of potential interference with laboratory tests (27).
Rogaratinib treatment arm only
Rogaratinib is mainly metabolized by CYP3A4 and to a lesser extent by CYP2C9.
Therefore,
o
Use of strong inhibitors and strong inducers of CYP3A4 (see Appendix 16.1) is not 
permitted for 2 weeks before the start of study treatment or during the study. 
Concomitant use of moderate and weak CYP3A4 inducers should be avoided as 
clinically significant decrease in plasma concentrations of rogaratinib cannot be ruled 
out. 
o
Concomitant use of herbal preparations containing CYP3A4 inducers (e.g. St John’s 
wort) are not permitted for 2 weeks before the start of study treatment or during the 
study.
o
Grapefruit and grapefruit juice (CYP3A4 inhibitor) consumption is not permitted 
during the study.
Therapies that are known to increase serum calcium or phosphate levels (i.e. antacids, 
phosphate-containing laxatives oral/rectal, potassium phosphate) are prohibited.
Chemotherapy arm only
Drugs prohibited according to locally approved package inserts of paclitaxel, docetaxel 
and vinflunine are not permitted. The following information should be considered as a 
guidance based on package insert / summary of product characteristics:
o
The metabolism of paclitaxel is catalyzed by cytochrome P450 isoenzymes CYP2C8 
and CYP3A4. Caution should be exercised when administering paclitaxel 
concomitantly with known substrates or inhibitors of the cytochrome P450 
isoenzymes CYP2C8 and CYP3A4. Caution should be exercised when paclitaxel is 


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concomitantly administered with known substrates (e.g., midazolam, buspirone, 
felodipine, lovastatin, eletriptan, sildenafil, simvastatin, and triazolam), inhibitors 
(e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, 
nelfinavir, ritonavir, saquinavir, and telithromycin), and inducers (e.g., rifampin and 
carbamazepine) of CYP3A4. Caution should also be exercised when paclitaxel is 
concomitantly administered with known substrates (e.g., repaglinide and 
rosiglitazone), inhibitors (e.g., gemfibrozil), and inducers (e.g., rifampin) of CYP2C8.
Concomitant therapies that should be avoided
Rogaratinib treatment arm only

Fluconazole is considered a moderate to strong inhibitor of CYP2C9 and should be 
avoided, if possible.

Narrow therapeutic index drugs that are CYP3A4, P-gp and BCRP substrates
(e.g. alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, 
quinidine, sirolimus, and tacrolimus) should be avoided, because drug interactions caused 
by irreversible inhibition of CYP3A4, P-gp and BCRP by rogaratinib cannot be ruled out.
Chemotherapy arm only

Docetaxel is a CYP3A4 substrate. In vitro studies have shown that the metabolism of 
docetaxel may be modified by the concomitant administration of compounds that induce, 
inhibit, or are metabolized by cytochrome P450 3A4. Concomitant use of docetaxel and 
drugs that inhibit CYP3A4 may increase exposure to docetaxel and should be avoided. In 
patients receiving treatment with docetaxel, close monitoring for toxicity and docetaxel 
dose reduction could be considered if systemic administration of a potent CYP3A4 
inhibitor cannot be avoided.

The concomitant use of vinflunine and potent CYP3A4 inhibitors (such as ritonavir, 
ketoconazole, itraconazole and grapefruit juice) or inducers (such as rifampicin and 
Hypericum perforatum (St John’s wort) should be avoided since they may increase or 
decrease vinflunine and metabolite of vinflunine concentrations.
8.2
Post-study therapy
At the end of study treatment for the individual patient, further therapy is at the discretion of 
the investigator.
At the conclusion of the study, patients who demonstrate clinical benefit may be eligible to 
continue to receive study treatment. They may receive further treatment, assessments and/or 
be followed either via a post-trial access program, a roll-over study - subject to approval by 
the competent health authority and ethics committee - or through any other mechanism in 
accordance with local legal and compliance rules. This applies to patients on study treatment 
and in follow-up.


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In the event a roll-over study is established, the present study will end when all patients have 
transitioned into the roll-over study or discontinued from this study for another reason (e.g. 
consent withdrawn, lost to follow-up, death). Until the transition to the roll-over study, 
patients will continue to follow all the procedures and visits required in the current version of 
the protocol.
9.
Procedures and variables
9.1
Tabular schedule of evaluations
Tabular schedule of evaluations is presented in Table 9–1.


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Table 9–1: Tabular schedule of evaluations
Trial Periods
Pre-treatment
Treatment
EOT
Follow-up
Visit Name
FGFR testing
Screening
Cycle 1
Cycle 2
Cycle 
≥ 3
EOT
Active FU
Long-term 
FU
Visit Dayhh
Day 
1
Day 
8
Day 
15
Day 
1
Day 
15
Day 1
At least 30 days after 
last dose
for safety 
assessmentsii
Every 
month
Time Window (Days)
Within 28 days 
before 
randomization
Within 7 days 
before 
randomization
+/- 3
+/- 3
+/- 3
+/- 3
+/- 3
Within 14 
days*
up to +7
+/- 7
Screening and enrollment
Informed consent for 
FGFR testinga
X
Informed consent for 
study treatment eligibilitya
X
Contact IxRSb
X
X
X
X
X
X
Archival or fresh tissue 
for FGFR test and 
PIK3CA and RAS 
mutation testc
X
Demographic data
X
Documentation of 
urothelial carcinoma 
diagnosis
X
Previous therapy for 
urothelial carcinomad
X
X
Medical historyd
X
Inclusion / exclusion 
criteria checke
X
X
X
Xx
ECOG 
X
X
X
X
X
X
X
Smoking history
X
Bellmunt risk score
X


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Trial Periods
Pre-treatment
Treatment
EOT
Follow-up
Visit Name
FGFR testing
Screening
Cycle 1
Cycle 2
Cycle 
≥ 3
EOT
Active FU
Long-term 
FU
Visit Dayhh
Day 
1
Day 
8
Day 
15
Day 
1
Day 
15
Day 1
At least 30 days after 
last dose
for safety 
assessmentsii
Every 
month
Time Window (Days)
Within 28 days 
before 
randomization
Within 7 days 
before 
randomization
+/- 3
+/- 3
+/- 3
+/- 3
+/- 3
Within 14 
days*
up to +7
+/- 7
Medication
Randomization
Xy
Rogaratinib 
administration
continuously
Chemotherapy 
administration 
X
X
X
Efficacy
Tumor assessment (CT 
or MRI)f
Xg
Every 6 weeks up to week 18 and thereafter 
every 9 weeksz
Xcc
Xdd
applies only to patients 
who discontinued without 
progressive disease
Brain (CT or MRI) and 
bone scan 
Xh
Survival assessment
Monthlyee
applies only to patients 
who discontinued without 
progressive disease
Monthlyee
Safety
Physical examinationi
X
X
X
X
X
X
Ophthalmologic 
examinationj
X
Xbb
Xbb
X
Vital signs (BP, heart 
rate, body temperature), 
including weightn and 
heighto
X
X
X
X
X
X
X
X
X
Hematologyp
X
X
X
X
X
X
X
X
X
Coagulation panelq
X
X
X
X
X
X
Biochemistry Fullr, s
X
X
X
X
X
X


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Trial Periods
Pre-treatment
Treatment
EOT
Follow-up
Visit Name
FGFR testing
Screening
Cycle 1
Cycle 2
Cycle 
≥ 3
EOT
Active FU
Long-term 
FU
Visit Dayhh
Day 
1
Day 
8
Day 
15
Day 
1
Day 
15
Day 1
At least 30 days after 
last dose
for safety 
assessmentsii
Every 
month
Time Window (Days)
Within 28 days 
before 
randomization
Within 7 days 
before 
randomization
+/- 3
+/- 3
+/- 3
+/- 3
+/- 3
Within 14 
days*
up to +7
+/- 7
Biochemistry Limitedr, t
X
X
X
Hormone panel (TSH, 
free T3, free T4)
X
X
X
X
X
X
Urinalysisu
X
X
X
X
X
eGFR (MDRD 
abbreviated formula)
X
X
X
X
X
Pregnancy test (if 
applicable)v
X
12-lead ECGk
X
X
X
X
X
Toxicity / AE assessmentl
continuously
Concomitant 
medicationsff
continuously
Subsequent systemic 
anti-cancer treatment
X
X
X
Other
Healthcare resource 
utilizationgg
continuously
PRO questionnaires 
(EORTC QLQ-C30 and 
EQ-5D-3L)m
X
X
X
X
X
X
Pharmacokinetic 
samplingaa
X
X
Xaa
Blood sampling for 
plasma-based biomarker 
analysesw
X
X
X
X
X
AE = Adverse event; ALP = Alkaline phosphatase; ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; BP = Blood pressure; BUN = Blood urea nitrogen; CT = 
Computed tomography; CTCAE = Common Terminology Criteria Adverse Event; ECG = Electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = Electronic 
case report form; eGFR = Estimated glomerular filtration rate; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer 30 item Quality of Life 


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Questionnaire; EOT = End of treatment; EQ-5D-3L = EuroQol Group’s five dimensions questionnaire; FGFR = Fibroblast growth factor receptor; FU = Follow-up; ICF = Informed 
consent form; INR = International normalized ratio; IxRS = Interactive Voice / Web Response System (IVRS/IWRS); LDH = Lactic dehydrogenase; MDRD = Modification of Diet 
in Renal Disease; MRI = Magnetic resonance imaging; PI/ICF = Patient information/informed consent form; PIK3CA = Phosphoinositide 3-kinase, catalytic subunit alpha isoform; 
PK = Pharmacokinetic(s); PRO = Patient-reported outcome; PT = Prothrombin time; PTT = Partial thromboplastin time; QTc = Corrected QT interval; RAS = Rat sarcoma;
RECIST = Response Evaluation Criteria in Solid Tumors; RBC = Red blood cell count; SAE = Serious adverse event; T3 = Triiodothyronine; T4 = Thyroxine; TSH = Thyroid-
stimulating hormone; WBC = White blood cell count.
a.
Routine procedures performed before informed consent can be used as screening data.
b.
Contact IxRS (IVRS/IWRS) to record the following:  - to register the patient who has signed the ICF for FGFR testing (a unique patient identifier will be assigned), - ICF for 
study treatment eligibility has been signed, - the patient is a FGFR test failure or screening failure (e.g. failed to meet the criteria during FGFR testing or the screening 
period), - for randomization, - on Day 1 of every treatment cycle so that the specific patient drug bottle/vial can be provided for dispensing purposes and also in case the 
patient has discontinued the study treatment (EOT) for any reason. 
c.
Archival tumor tissue should be used, fresh tissue should only be obtained when no archival tissue is available and when there is no additional risk for the patient in the 
investigator’s judgment. Tissue will be used for central FGFR testing in all patients, and in addition for PIK3CA and RAS mutation testing in all FGFR-positive patients and 
for exploratory tumor-based biomarker analyses in randomized patients.
d.
At FGFR testing, study disease characteristics are collected and prior therapies for the study indication including outcome are reviewed. 
At screening, study disease characteristics are updated if applicable; prior therapies for the study indication including outcome, medical history and non-study-indication-
related medications are collected. 
e.
Limited inclusion criteria will be checked in patients before FGFR testing (see Section 6.1).
f.
The radiological evaluation must include computed tomography (CT) or magnetic resonance imaging (MRI) of the chest, abdomen and pelvis with contrast media. Chest 
CT is strongly recommended and preferred versus chest MRI. MRI shall be performed instead of CT when local regulations do not permit the use of CT as requested per 
protocol schedule. Note: all images need to be submitted continuously for independent central imaging review in digital format.
g.
Pre-study contrast-enhanced CT/MRI (chest/abdomen/pelvis, and other areas of disease if applicable) may be acceptable as a baseline scan if done within 28 days before 
the first dose of study treatment and if evaluable by RECIST version 1.1.
h.
A contrast enhanced (unless contraindicated) CT scan or MRI of the brain is required at screening to rule out brain metastases. Acquisition of both contrast enhanced 
(unless contraindicated) and unenhanced scans of the brain at baseline is strongly recommended. Further CT scan or MRI of the brain only need to be repeated if 
metastases or symptoms are present. Bone scan (Technetium-99m) must be performed at screening. All suspected sites of disease should be imaged. If bone metastases 
are present at screening and cannot be seen on CT or MRI scans, or if clinically indicated, Technetium-99m bone scans should be repeated when complete response is 
identified in target disease or when progression in bone is suspected.
i.
Full physical examination is done at screening and at the EOT visit. Brief physical examinations are mandatory on Day 1 of each cycle and at the safety assessment visit of 
the active follow-up. 
j.
Ophthalmologic examinations comprise previous eye history (at screening only), any ophthalmic symptoms, best corrected visual acuity, dilated indirect ophthalmoscopy 
with macular involvement assessment and optical coherence tomography including measurement of central retinal thickness. Examinations during treatment are to be 
conducted on Day 1 of every 2nd cycle, starting at Cycle 2 and at the EOT visit. Additionally, the investigator will ask the patient for changes in vision at each site visit. If 
change in vision is reported, an ophthalmological examination must be performed. In case of any findings, please refer to Section 9.6.3.6. 
k.
In each patient,12-lead ECG (supine position) is to be performed at screening, on Day 1 of Cycle 1, 2, 3, 4 and 5 at pre-dose (before supervised dose administration), and 
between 0.5 and 1.5 hours post-dose (for patients on the rogaratinib treatment arm, the ECGs can be performed together with required PK blood sampling). Beyond Cycle 
5, 12-lead ECG is to be performed on Day 1 of every 3rd cycle (pre-dose) and at EOT (if not performed within 4 weeks). Triple 12-lead ECG (supine position) is to be 


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performed (pre-dose and post-dose) in case of QTc prolongation under treatment. Weekly 12-lead ECGs have to be performed in patients with an elevated phosphate level 
(≥7mg/dL) until resolution (phosphate level <7mg/dL). In patients with hypocalcemia (CTCAE Grade ≥2), an additional 12-lead ECG has to be obtained on day of 
detection of hypocalcemia and should be repeated as clinically indicated. See also Section 9.6.3.3.
l.
All AEs identified after the patient has signed the PI/ICF for FGFR testing and until the patient ends the study (up to at least 30 days after the last administration of study 
treatment or end of active follow-up) must be fully documented in the source data. During FGFR testing period: AEs/SAEs related to the procedure of taking a fresh biopsy 
for FGFR testing corresponding AE/ SAE must be recorded. After the patient has signed the informed consent for study treatment eligibility any new finding or worsening of 
any ongoing medical history condition must be recorded as an AE/SAE up to at least 30 days after the last administration of study treatment. Thereafter, only AEs related 
to the study drugs have to be recorded until the end of active follow-up. However, at the investigator’s discretion, SAEs may be reported if considered potentially relevant. 
In such cases, the SAEs will be processed by the sponsor according to all applicable regulations. 
m.
To be completed before the patient meets with a clinician and before any examination or test is performed on that day. Questionnaires are to be completed at screening, 
on Day 1 of every cycle, at the EOT visit and at the safety assessment visit of the active follow-up.
n.
Weight is to be measured at screening (within 7 days before randomization) and on Day 1 of each cycle. 
o.
Height is to be measured only at screening (within 7 days before randomization). 
p.
Hematology panel: Hemoglobin, hematocrit, platelet count, red blood cell count (RBC), white blood cell count (WBC). WBC must include differential including neutrophil, 
lymphocyte, monocyte, basophil, and eosinophil counts. 
q.
Coagulation panel: PTT or activated PTT and PT-INR. 
r.
Including weekly evaluations of phosphate levels in patients with an elevated phosphate level ≥7 mg/dL. 
s.
Full biochemistry panel: sodium, potassium, chloride, magnesium, calcium (total or ionized), phosphate, glucose (fasting or non-fasting), AST, ALT, bilirubin (total and 
direct), ALP, total protein, albumin, lipase, lactic dehydrogenase (LDH), blood urea nitrogen (BUN) or urea, and creatinine.
t.
Limited biochemistry panel: sodium, potassium, chloride, magnesium, calcium (total or ionized), phosphate, blood urea nitrogen (BUN) or urea, and creatinine. 
u.
Urine chemistry test is done at screening, on Cycle 1 Day 1 and Day 8, on Cycle 2 Day 1 and at the EOT. Microscopic examinations will be performed if clinically indicated. 
v.
Pregnancy test is to be repeated as frequently as required by local regulations. 
w.
The blood samples are intended for isolation of plasma to study tumor markers (genetic and non-genetic) circulating in blood. During the treatment cycles, plasma samples 
are to be collected before administration of study drugs. 
x.
Prior to randomization. 
y.
The first administration of study drug should take place within 3 days of randomization.
z.
Tumor assessments (CT or MRI) are to be done according to RECIST v.1.1 (see Section 9.4.1) every 6 weeks (± 7 days) starting from Cycle 1 Day 1 up to week 18, and 
thereafter, every 9 weeks (± 7 days). A minimum of at least 6 weeks from start of treatment is mandatory for the 1st “on treatment” tumor assessment. 
aa.
PK sampling in all rogaratinib-treated patients to be collected on Day 1 of Cycle 1, 2, 3, 4 and 5 at pre-dose (before supervised dose administration) and between 0.5 and 
1.5 hours post-dose. 
bb.
During treatment (on Day 1 of every second cycle starting at Cycle 2) a time window of -7 days is allowed. 
cc.
Radiological tumor evaluation (within 14 days after last study treatment) (CT/MRI of chest, abdomen, and pelvis) using RECIST version 1.1. This is not necessary if the 
previous tumor evaluation was performed within 4 weeks (up to week 18) or within 7 weeks (beyond week 18). 


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dd.
For patients who discontinue study treatment without disease progression, follow-up tumor evaluations will be performed (by CT or MRI) until progression of malignancy 
and/or start of subsequent systemic anti-cancer treatment, whichever comes first, or any other criterion for withdrawal is met. During the active follow-up period, CT/MRI 
evaluations will be performed at the same intervals as during study treatment period (every 6 weeks up to week 18, and thereafter, every 9 weeks). 
ee.
Survival sweeps (e.g. telephone calls to collect survival status information) are to be implemented for all ongoing patients to occur in the 2-week period after the data cut-
off date is determined for the formal interim and primary completion analyses for overall survival. 
ff.
From signing of PI/ICF for study treatment eligibility up to 30 days after the last administration of study treatment, all concomitant medications (including start/stop dates, 
dose, frequency, route of administration and indication) must be recorded in the patient’s source documentation, as well as on the appropriate pages of the eCRF.
gg.
Healthcare resource utilization information will be recorded once a patient has a hospitalization/healthcare visit, during the course of the study. Information on the start 
date, end date, ongoing status, location, scheduling status, main diagnosis at discharge, and number of working days missed must be recorded. Data will be analyzed on 
an ad hoc basis. See Section 9.7.3.
hh.
It may be necessary to perform the procedures at unscheduled time points if deemed clinically necessary by the investigator.
ii.
If the study treatment was permanently discontinued after dose interruption/delay of more than 30 days, the active follow-up visit should occur within 14 days of 
discontinuation. If the EOT and active follow-up visits will be scheduled at the same time, the visits can be combined.
* EOT visit will be performed within 14 days after permanent discontinuation of study treatment.


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9.2
Visit description
9.2.1
Pre-treatment period
Routine procedures performed before informed consent can be used as screening data
provided that they fall into the protocol-specified time window. Archival tissue obtained from 
the patients at any time during the course of their disease may also be used prior to the 
informed consent date and time, if performed as part of the standard of practice. 
9.2.1.1
FGFR testing
Mandatory FGFR testing of patients will be performed prior to start of screening (signing of 
informed consent for study treatment eligibility). The timing of the FGFR test is at the 
discretion of the investigator.
The following procedures will be performed prior to FGFR testing:

Signed PI/ICF for FGFR testing (see Section 13.4.1).

Contact IxRS to register patient (a unique patient identifier will be assigned).

Check inclusion criteria for FGFR testing (see Section 6.1).
o
If a patient does not meet the selection criteria for FGFR testing, contact IxRS and 
confirm that the patient is a ‘FGFR testing failure’ and additionally provide the 
reason, if applicable in the eCRF.

Documentation of demographics data, including year of birth, age, gender, race (as 
allowed by local regulation) and ethnicity (as allowed by local regulation).

Obtain archival or fresh tumor tissue.
o
Only if no archival tumor tissue sample is available which has been handled and 
processed as described in the lab manual: perform a biopsy to obtain fresh tumor 
material. See more details in Section 9.7.1.
o
Tissue will be used for central FGFR testing in all patients, and in addition for 
PIK3CA and RAS mutation testing in all FGFR-positive patients, and for 
exploratory tumor-based biomarker analyses in randomized patients (see Section 
9.7.1).

Document study disease characteristics and review previous therapy for urothelial 
carcinoma including outcome (see Section 9.3.3).

Check Eastern Cooperative Oncology Group performance status (ECOG PS) (see Section 
9.6.3.5).

Toxicity/AE assessment: during the FGFR testing period: AEs/SAEs related to the 
procedure of taking a fresh biopsy for FGFR testing (in case archival tumor tissue is not 
available) the corresponding AE and SAE have to be reported and must be fully 
documented in the source data. For all other events, these have to be fully documented in 
the source data and will be reported in the medical history only for those patients who 
have signed the PI/ICF for study treatment eligibility.


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The following procedure will be performed after FGFR testing:

For patients not meeting the eligibility criteria “high FGFR expression level” following
confirmation by the central lab: record the patient in IxRS as a ‘FGFR testing failure’.
9.2.1.2
Screening
After confirmation of high FGFR1 or 3 mRNA expression level has been received from 
central lab, the patient may enter the screening. Screening examinations for FGFR-positive 
patients will only be performed after having received the patient’s written ICF for study
treatment eligibility (see Section 13.4.2).
Note: Healthcare resource utilization information must be recorded once a patient has a 
hospitalization/healthcare visit (see Section 9.7.2).
The following screening procedures will be performed within 28 days before
randomization:

Signed PI/ICF for study treatment eligibility (see Section 13.4.2).

Contact IxRS to confirm PI/ICF for study treatment eligibility has been signed and that 
the patient has started screening; select investigator’s choice for the chemotherapy.

PRO questionnaires (EORTC QLQ-C30 and EQ-5D-3L) (see Section 9.7.2).
o
Questionnaires are to be completed before the patient meets with a clinician and 
before any examination or test is performed on that day.

Check the inclusion and exclusion criteria for study treatment eligibility (see Section 6.1
for inclusion criteria and Section 6.2 for exclusion criteria). 

Update study disease characteristics (if applicable) and document previous therapy for 
urothelial carcinoma including outcome (see Section 9.3.3).

Document relevant medical history (see Section 9.3.2) and non-study-indication-related 
medications (see Section 9.3.3).

Document smoking history (see Section 9.3.3).

Tumor assessment (CT or MRI) according to RECIST v.1.1 (see Section 9.4.1).
o
Pre-study contrast-enhanced CT/MRI (chest/abdomen/pelvis and other areas of 
disease if applicable) may be acceptable as a baseline scan if done within 28 days 
before the first dose of study treatment and if evaluable by RECIST version 1.1.
o
A contrast enhanced (unless contraindicated) CT scan or MRI of the brain is 
required at screening to rule out brain metastases. Acquisition of both contrast 
enhanced (unless contraindicated) and unenhanced scans of the brain at baseline is 
strongly recommended. Further CT scan or MRI of the brain only need to be 
repeated if metastases or symptoms are present.


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o
Bone scan (Technetium-99m) must be performed at screening. If bone metastases 
are present at screening and cannot be seen on CT or MRI scans, or if clinically 
indicated, Technetium-99m bone scans should be repeated when complete 
response is identified in target disease or when progression in bone is suspected.
o
Note: all images need to be submitted for independent central image review in 
digital format (for details see Section 9.4.1).

Perform full physical examination (see Section 9.6.3.2).
o
Complete review of all organ systems, and full physical examination of (including 
but not limited to) general appearance, skin, head and neck, eyes, ears, nose, throat, 
heart, lungs, abdomen, musculoskeletal system, lymph nodes, genitourinary 
system, neurological system.

Send patient for ophthalmological examination (see Section 9.6.3.6).
o
Ophthalmologic examinations comprise previous eye history (at screening only), 
any ophthalmic symptoms, best corrected visual acuity, dilated indirect 
ophthalmoscopy with macular involvement assessment and optical coherence 
tomography including measurement of central retinal thickness. 
o
In case of any findings, please refer to Section 9.6.3.6.

12-lead ECG (see Section 9.6.3.3).

Toxicity/AE assessment
o
Following signing of the PI/ICF for study treatment eligibility, any new finding or 
worsening of any ongoing medical history condition must be recorded as an AE 
and fully documented in both SOURCE DATA and eCRF (see Section 9.6.1.3)

Record concomitant medication (see Section 8.1).
The following screening procedures will be performed within 7 days before randomization:

Check the inclusion and exclusion criteria for study treatment eligibility (see Section 6.1
for inclusion criteria and Section 6.2 for exclusion criteria). 

ECOG PS (see Section 9.6.3.5).

Measure vital signs, including blood pressure, heart rate and body temperature. Height and 
body weight will be measured and body surface area (BSA) will be derived (see 
Section 9.6.3.4).

Hematology panel: hemoglobin, hematocrit, platelet count, red blood cell count (RBC), 
white blood cell count (WBC). WBC must include differential including neutrophil, 
lymphocyte, monocyte, basophil, and eosinophil counts. See Section 9.6.3.1.

Coagulation panel: PTT or activated PTT and PT-INR (see Section 9.6.3.1).


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
Full biochemistry panel: sodium, potassium, chloride, magnesium, calcium (total or 
ionized), phosphate, glucose (fasting or non-fasting), AST, ALT, bilirubin (total and 
direct), ALP, total protein, albumin, lipase, lactic dehydrogenase (LDH), blood urea 
nitrogen (BUN) or urea, and creatinine. (See Section 9.6.3.1).

Hormone panel: thyroid function testing (thyroid-stimulating hormone [TSH], free T3, 
free T4) for all patients (see Section 9.6.3.1).

Urinalysis test (See Section 9.6.3.1), and if clinically indicated, microscopic examinations.

Calculate eGFR according to MDRD abbreviated formula (see Appendix 16.4).

Serum pregnancy test in women of childbearing potential. Negative serum pregnancy test 
must be documented before start of study treatment. Postmenopausal women who have 
not had periods for more than 1 year or surgically sterilized women will not be required to 
undergo a pregnancy test (this information should be recorded under medical history on 
the eCRF). See Sections 9.6.2 and 9.6.3.1. 
o
Note: Pregnancy test to be repeated as frequently as required by local regulations.

Blood sampling for plasma-based biomarker analyses. 
o
Note: the blood samples are intended for isolation of plasma to study tumor 
markers (genetic and non-genetic) circulating in blood (see Section 9.7.1). 

Toxicity/AE assessment
o
Following signing of the PI/ICF for study treatment eligibility, any new finding or 
worsening of any ongoing medical history condition must be recorded as an AE 
and fully documented in both SOURCE DATA and eCRF (see Section 9.6.1.3).

Review concomitant medications (see Section 8.1).

Calculate and record Bellmunt risk score (high vs. low) (see Section 9.3.3 for guidance to 
calculate the score).

Contact IxRS, if a patient does not meet study treatment eligibility criteria, and confirm 
that the patient is a ‘screening failure’ and additionally provide the reason, if applicable, in 
the eCRF.
9.2.2
Treatment period
After all screening assessments have been completed and the patient’s eligibility has been
confirmed and documented, the patient will be randomly assigned to one of the following 
treatment arms: rogaratinib or chemotherapy, using IxRS. Rogaratinib will be administered 
continuously twice daily, and chemotherapy will be administered intravenously on Day 1 of 
each cycle, see Section 7.4.1 for dosing schedule. 
For tumor assessments to be performed during the treatment period, see Section 9.2.2.7.
Healthcare resource utilization information must be recorded once a patient has a 
hospitalization/healthcare visit (see Section 9.7.2).


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9.2.2.1
Day 1 of Cycle 1
The following procedures will be performed on C1D1 before receiving study treatment
unless otherwise specified. Procedures that have been performed at screening within 3 days 
prior to start of study drug treatment do not need to be repeated on Cycle 1 Day 1 (with the 
exception of blood pressure, heart rate and body temperature). Eligibility must be confirmed 
and documented prior to randomizing the patient in IxRS.

Contact IxRS to randomize the patient (see Section 7.3) and to dispense (rogaratinib) 
or apply (chemotherapy) medication based on derived BSA entered into IxRS, as 
applicable.
The first administration of study drug should take place within 3 days of 
randomization. In case the study treatment will not start at the day of randomization, 
the date of the first dose needs to be entered into IxRS.

PRO questionnaires (EORTC QLQ-C30 and EQ-5D-3L) (see Section 9.7.2).
o
Questionnaires are to be completed before the patient meets with a clinician 
and before any examination or test is performed on that day.

Review the inclusion and exclusion criteria for study treatment eligibility (see Section 
6.1 for inclusion criteria and Section 6.2 for exclusion criteria). 
o
If a patient does not meet criteria for study treatment eligibility and is not
eligible for randomization then the patient must be registered as a ‘screening 
failure’ in IxRS and additionally provide the reason, if applicable, in the eCRF.

AE/toxicity assessments (see Section 9.6.1.3).

Ask the patient for changes in vision. If change in vision is reported, an 
ophthalmological examination must be performed.
o
In case of any findings, please refer to Section 9.6.3.6.

Review of concomitant medications (see Section 8.1).

ECOG PS (see Section 9.6.3.5).

Perform brief physical examination (see Section 9.6.3.2).
o
Brief physical examination includes, but is not limited to, review of organ 
systems and physical areas of symptomatic concern or investigator’s degree of 
suspicion for any abnormality.

Vital signs, including blood pressure, heart rate and body temperature. Body weight 
will be measured and BSA will be derived (see Section 9.6.3.4).

Hematology panel: hemoglobin, hematocrit, platelet count, red blood cell count (RBC), 
white blood cell count (WBC). WBC must include differential including neutrophil, 
lymphocyte, monocyte, basophil, and eosinophil counts. See Section 9.6.3.1.

Coagulation panel: PTT or activated PTT and PT-INR (see Section 9.6.3.1).


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
Full biochemistry panel: sodium, potassium, chloride, magnesium, calcium (total or 
ionized), phosphate, glucose (fasting or non-fasting), AST, ALT, bilirubin (total and 
direct), ALP, total protein, albumin, lipase, lactic dehydrogenase (LDH), blood urea 
nitrogen (BUN) or urea, and creatinine. (See Section 9.6.3.1).
o
Note: weekly evaluations of phosphate levels should be done in patients with 
an elevated phosphate level (≥7 mg/dL) until resolution (phosphate level < 7 
mg/dL).

Hormone panel: thyroid function testing (thyroid-stimulating hormone [TSH], free T3, 
free T4) for all patients (see Section 9.6.3.1).

Urinalysis test (See Section 9.6.3.1), and if clinically indicated, microscopic 
examinations.

Calculate eGFR according to MDRD abbreviated formula (see Appendix 16.4).

12-lead ECG (see Section 9.6.3.3)
o
12-lead ECG (supine position) is to be performed at pre-dose (before 
supervised dose administration) and between 0.5 and 1.5 hours post-dose (for 
patients on the rogaratinib treatment arm, the ECGs can be performed together 
with required PK blood sampling).
o
Note: Triple 12-lead ECG (supine position) is to be performed (pre-dose and 
post-dose) in case of QTc prolongation under treatment.
o
Note: weekly 12-lead ECGs to be performed for patients with an elevated
phosphate level (≥7mg/dL) until resolution (phosphate level < 7 mg/dL). In 
patients with hypocalcemia (CTCAE Grade ≥ 2), an additional 12-lead ECG 
has to be obtained on day of detection of hypocalcemia and should be repeated 
as clinically indicated.

PK sampling (pre- and post-dose) (see Section 9.5).
o
Note: sampling in all rogaratinib-treated patients to be collected on Day 1 of 
Cycle 1 at pre-dose (before supervised dose administration) and between 0.5 
and 1.5 hours post-dose.

Blood sampling (pre-dose) for plasma-based biomarker analyses. 
o
Note: the blood samples are intended for isolation of plasma to study tumor 
markers (genetic and non-genetic) circulating in blood (see Section 9.7.1). 
During the treatment cycles, plasma samples are to be collected before 
administration of study drugs.

Administration of chemotherapy (applicable to comparator arm only) (see 
Section 7.4).


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9.2.2.2
Day 8 of Cycle 1
The following visit will be performed on C1D8 (± 3 days), laboratory procedures are allowed 
to be performed within 3 days prior to the visit unless otherwise specified:

AE/toxicity assessments (see Section 9.6.1.3).

Ask the patient for changes in vision. If change in vision is reported, an 
ophthalmological examination must be performed.
o
In case of any findings, please refer to Section 9.6.3.6.

Review of concomitant medications (see Section 8.1).

Vital signs, including blood pressure, heart rate and body temperature.

Hematology panel: hemoglobin, hematocrit, platelet count, red blood cell count 
(RBC), white blood cell count (WBC). WBC must include differential including 
neutrophil, lymphocyte, monocyte, basophil, and eosinophil counts. See Section 
9.6.3.1.

Limited biochemistry panel: sodium, potassium, chloride, magnesium, calcium (total 
or ionized), phosphate, blood urea nitrogen (BUN) or urea, and creatinine (see Section 
9.6.3.1).
o
Note: weekly evaluations of phosphate levels and 12-lead ECG should be done 
in patients with an elevated phosphate level (≥7 mg/dL) until resolution 
(phosphate level < 7 mg/dL).

Urinalysis test (See Section 9.6.3.1), and if clinically indicated, microscopic 
examinations.
For patients on the rogaratinib treatment arm, the procedures should be performed before 
receiving study treatment.
9.2.2.3
Day 15 of Cycle 1
The following visit will be performed on C1D15 (± 3 days), laboratory procedures are 
allowed to be performed within 3 days prior to the visit unless otherwise specified:

AE/toxicity assessments (see Section 9.6.1.3).

Ask the patient for changes in vision. If change in vision is reported, an 
ophthalmological examination must be performed.
o
In case of any findings, please refer to Section 9.6.3.6.

Review of concomitant medications (see Section 8.1).

Vital signs, including blood pressure, heart rate and body temperature (see 
Section 9.6.3.4).


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
Hematology panel: hemoglobin, hematocrit, platelet count, red blood cell count (RBC), 
white blood cell count (WBC). WBC must include differential including neutrophil, 
lymphocyte, monocyte, basophil, and eosinophil counts. See Section 9.6.3.1.

Limited biochemistry panel: sodium, potassium, chloride, magnesium, calcium (total 
or ionized), phosphate, blood urea nitrogen (BUN) or urea, and creatinine (see Section 
9.6.3.1).
o
Note: weekly evaluations of phosphate levels and 12-lead ECG should be done
in patients with an elevated phosphate level (≥7 mg/dL) until resolution 
(phosphate level < 7 mg/dL).
For patients on the rogaratinib treatment arm, the procedures should be performed before 
receiving study treatment.
9.2.2.4
Day 1 of Cycle 2
The following visit will be performed on Day 1 (± 3 days) of Cycle 2, laboratory procedures 
are allowed to be performed within 3 days prior to the visit before receiving study treatment
unless otherwise specified:

PRO questionnaires (EORTC QLQ-C30 and EQ-5D-3L) (see Section 9.7.2).
o
Questionnaires are to be completed before the patient meets with a clinician 
and before any examination or test is performed on that day.
o
PRO questionnaires are to be completed on Day 1 of each cycle.

AE/toxicity assessments (see Section 9.6.1.3).

Review of concomitant medications (see Section 8.1).

ECOG PS (see Section 9.6.3.5).

Perform brief physical examination (see Section 9.6.3.2).
o
Brief physical examination includes, but is not limited to, review of organ 
systems and physical areas of symptomatic concern or investigator’s degree of 
suspicion for any abnormality.

Send patient for ophthalmological examination (see Section 9.6.3.6). Note: A time 
window of -7 days is allowed.
o
Ophthalmologic examinations comprise any ophthalmic symptoms, best 
corrected visual acuity, dilated indirect ophthalmoscopy with macular 
involvement assessment and optical coherence tomography including
measurement of central retinal thickness. 
o
Examinations during treatment are to be conducted on Day 1 (-7 days) of every 
2nd cycle, starting at Cycle 2.
o
In case of any findings, please refer to Section 9.6.3.6.


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
Vital signs, including blood pressure, heart rate and body temperature. Body weight 
will be measured and BSA will be derived (see Section 9.6.3.4).

Hematology panel: hemoglobin, hematocrit, platelet count, red blood cell count (RBC), 
white blood cell count (WBC). WBC must include differential including neutrophil, 
lymphocyte, monocyte, basophil, and eosinophil counts. See Section 9.6.3.1.

Coagulation panel: PTT or activated PTT and PT-INR (see Section 9.6.3.1).

Full biochemistry panel: sodium, potassium, chloride, magnesium, calcium (total or 
ionized), phosphate, glucose (fasting or non-fasting), AST, ALT, bilirubin (total and 
direct), ALP, total protein, albumin, lipase, lactic dehydrogenase (LDH), blood urea 
nitrogen (BUN) or urea, and creatinine. (See Section 9.6.3.1).
o
Note: weekly evaluations of phosphate levels and 12-lead ECG should be done
in patients with an elevated phosphate level (≥7 mg/dL) until resolution 
(phosphate level < 7 mg/dL).

Hormone panel: thyroid function testing (thyroid-stimulating hormone [TSH], free T3, 
free T4) for all patients (see Section 9.6.3.1).

Urinalysis test (See Section 9.6.3.1), and if clinically indicated, microscopic 
examinations.
o
Note: from C2D1 onwards, urinalysis should be done only if clinically 
indicated.

Calculate eGFR according to MDRD abbreviated formula (see Appendix 16.4).

12-lead ECG (see Section 9.6.3.3)
o
12-lead ECG (supine position) is to be performed at pre-dose (before 
supervised dose administration) and between 0.5 and 1.5 hours post-dose (for 
patients on the rogaratinib treatment arm, the ECGs can be performed together 
with required PK blood sampling).
o
Note: Triple 12-lead ECG (supine position) is to be performed (pre-dose and 
post-dose) in case of QTc prolongation under treatment.
o
Note: weekly 12-lead ECGs to be performed for patients with an elevated 
phosphate level (≥7 mg/dL) until resolution (phosphate level < 7 mg/dL). In 
patients with hypocalcemia (CTCAE Grade ≥ 2), an additional 12-lead ECG 
has to be obtained on day of detection of hypocalcemia and should be repeated 
as clinically indicated.

Contact IxRS on Day 1 of every treatment cycle to register the corresponding 
treatment cycle so that the specific patient drug bottle/vial can be provided for 
dispensing/applying purposes and also in case the patient has discontinued the study
treatment for any reason.

PK sampling (pre- and post-dose) (see Section 9.5).


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o
Note: sampling in all rogaratinib-treated patients to be collected on Day 1 of 
Cycle 2, 3, 4 and 5 at pre-dose (before supervised dose administration) and 
between 0.5 and 1.5 hours post-dose. 

Blood sampling (pre-dose) for plasma-based biomarker analyses. 
o
Note: the blood samples are intended for isolation of plasma to study tumor 
markers (genetic and non-genetic) circulating in blood (see Section 9.7.1). 
During the treatment cycles, plasma samples are to be collected before 
administration of study drugs.

Study drug accountability.

Administration of chemotherapy (applicable to comparator arm only) (see 
Section 7.4).
9.2.2.5
Day 15 of Cycle 2
The following visit will be performed on Day 15 (± 3 days) of Cycle 2, laboratory procedures 
are allowed to be performed within 3 days prior to the visit unless otherwise specified:

AE/toxicity assessments (see Section 9.6.1.3).

Ask the patient for changes in vision. If change in vision is reported, an 
ophthalmological examination must be performed.
o
In case of any findings, please refer to Section 9.6.3.6.

Review of concomitant medications (see Section 8.1).

Vital signs, including blood pressure, heart rate and body temperature (see 
Section 9.6.3.4).

Hematology panel: hemoglobin, hematocrit, platelet count, red blood cell count (RBC), 
white blood cell count (WBC). WBC must include differential including neutrophil, 
lymphocyte, monocyte, basophil, and eosinophil counts. See Section 9.6.3.1.

Limited biochemistry panel: sodium, potassium, chloride, magnesium, calcium (total 
or ionized), phosphate, blood urea nitrogen (BUN) or urea, and creatinine (see Section 
9.6.3.1).
o
Note: weekly evaluations of phosphate levels and 12-lead ECG should be done
in patients with an elevated phosphate level (≥7 mg/dL) until resolution 
(phosphate level < 7 mg/dL).
For patients on the rogaratinib treatment arm, the procedures should be performed before 
receiving study treatment.
9.2.2.6
Day 1 of Cycle ≥ 3
The following visit will be performed on Day 1 (± 3 days), laboratory procedures are allowed 
to be performed within 3 days prior to the visit of all subsequent cycles starting from Cycle 3 
before receiving study treatment unless otherwise specified. From Cycle 3 onwards, visits 
are scheduled only for Day 1 of the treatment cycle.


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
PRO questionnaires (EORTC QLQ-C30 and EQ-5D-3L) (see Section 9.7.2).
o
Questionnaires are to be completed before the patient meets with a clinician 
and before any examination or test is performed on that day.
o
PRO questionnaires are to be completed on Day 1 of each cycle.

AE/toxicity assessments (see Section 9.6.1.3).

Every 2nd cycle (Cycle 4, 6, 8…): Send patient for ophthalmological examination (see 
Section 9.6.3.6). Note: A time window of -7 days is allowed.
o
Ophthalmologic examinations comprise any ophthalmic symptoms, best 
corrected visual acuity, dilated indirect ophthalmoscopy with macular 
involvement assessment and optical coherence tomography including 
measurement of central retinal thickness. 
o
In case of any findings, please refer to Section 9.6.3.6.

Ask the patient for changes in vision. If change in vision is reported, an 
ophthalmological examination must be performed.
o
In case of any findings, please refer to Section 9.6.3.6.

Review of concomitant medications (see Section 8.1).

ECOG PS (see Section 9.6.3.5).

Perform brief physical examination (see Section 9.6.3.2).
o
Brief physical examination includes, but is not limited to, review of organ 
systems and physical areas of symptomatic concern or investigator’s degree of 
suspicion for any abnormality.

Vital signs, including blood pressure, heart rate and body temperature. Body weight 
will be measured and BSA will be derived. (See Section 9.6.3.4)

Hematology panel: hemoglobin, hematocrit, platelet count, red blood cell count (RBC), 
white blood cell count (WBC). WBC must include differential including neutrophil, 
lymphocyte, monocyte, basophil, and eosinophil counts. See Section 9.6.3.1.

Coagulation panel: PTT or activated PTT and PT-INR (see Section 9.6.3.1).

Full biochemistry panel: sodium, potassium, chloride, magnesium, calcium (total or 
ionized), phosphate, glucose (fasting or non-fasting), AST, ALT, bilirubin (total and 
direct), ALP, total protein, albumin, lipase, lactic dehydrogenase (LDH), blood urea 
nitrogen (BUN) or urea, and creatinine. (See Section 9.6.3.1).
o
Note: weekly evaluations of phosphates levels and 12-lead ECG should be 
done in patients with an elevated phosphate level (≥7 mg/dL) until resolution 
(phosphate level < 7 mg/dL).

Hormone panel: thyroid function testing (thyroid-stimulating hormone [TSH], free T3, 
free T4) for all patients (see Section 9.6.3.1).


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
Calculate eGFR according to MDRD abbreviated formula (see Appendix 16.4).

12-lead ECG (see Section 9.6.3.3)
o
12-lead ECG (supine position) is to be performed on Day 1 of Cycles 3, 4 and 
5 at pre-dose (before supervised dose administration) and between 0.5 and 
1.5 hours post-dose (for patients on the rogaratinib treatment arm, the ECGs 
can be performed together with required PK blood sampling). Beyond Cycle 5, 
12-lead ECG is to be performed on Day 1 of every 3rd cycle (pre-dose).
o
Note: Triple 12-lead ECG (supine position) is to be performed (pre-dose and 
post-dose) in case of QTc prolongation under treatment.
o
Note: weekly 12-lead ECGs to be performed for patients with an elevated 
phosphate level (≥7 mg/dL) until resolution (phosphate level < 7 mg/dL). In 
patients with hypocalcemia (CTCAE Grade ≥ 2), an additional 12-lead ECG 
has to be obtained on day of detection of hypocalcemia and should be repeated 
as clinically indicated.

Contact IxRS on Day 1 of every treatment cycle to register the corresponding 
treatment cycle so that the specific patient drug bottle/vial can be provided for 
dispensing/applying purposes and also in case the patient has discontinued the study 
treatment for any reason.

PK sampling (pre- and post-dose) (see Section 9.5).
o
Note: sampling in all rogaratinib-treated patients to be collected on Day 1 of 
Cycle 2, 3, 4 and 5 at pre-dose (before supervised dose administration) and 
between 0.5 and 1.5 hours post-dose. 

Blood sampling (pre-dose) for plasma-based biomarker analyses. 
o
Note: the blood samples are intended for isolation of plasma to study tumor 
markers (genetic and non-genetic) circulating in blood (see Section 9.7.1). 
During the treatment cycles, plasma samples are to be collected before 
administration of study drugs.

Study drug accountability.

Administration of chemotherapy (applicable to comparator arm only) (see 
Section 7.4).
9.2.2.7
Tumor assessments during treatment period
Scans (CT or MRI) for tumor assessments according to RECIST v.1.1 (see Section 9.4.1) are 
to be done every 6 weeks (± 7 days) starting from Cycle 1 Day 1 up to week 18, and 
thereafter, every 9 weeks (± 7 days) until the patient has permanently discontinued study 
treatment and has disease progression.
A minimum of at least 6 weeks from start of treatment is mandatory for the 1st “on treatment”
tumor assessment in order to achieve a valid response of stable disease. In exceptional cases, 


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when it is deemed clinically necessary by the investigator due to safety reasons, an imaging 
scan at an earlier time point is allowed.
Note: all images need to be submitted for central image review in digital format (for details 
see Section 9.4.1).
9.2.2.8
End-of-treatment (EOT) visit 
An end-of-treatment (EOT) visit will be performed within 14 days after permanent 
discontinuation of study treatment. 
The following examinations will be done at the EOT visit:

PRO questionnaires (EORTC QLQ-C30 and EQ-5D-3L) (see Section 9.7.2)
o
Questionnaires are to be completed before the patient meets with a clinician 
and before any examination or test is performed on that day.

Contact IxRS to register that the patient has discontinued study treatment for any 
reason.

AE/toxicity assessments (see Section 9.6.1.3).

Review of concomitant medications (see Section 8.1).

Check ECOG PS (see Section 9.6.3.5).

Perform full physical examination (see Section 9.6.3.2).
o
Complete review of all organ systems, and full physical examination of 
(including but not limited to) general appearance, skin, head and neck, eyes, 
ears, nose, throat, heart, lungs, abdomen, musculoskeletal system, lymph 
nodes, and if indicated by patient’s history, the genitourinary system, 
gynecological organs, rectum. 

Send patient for ophthalmological examination (see Section 9.6.3.6). 
o
Ophthalmologic examinations comprise any ophthalmic symptoms, best 
corrected visual acuity, dilated indirect ophthalmoscopy with macular 
involvement assessment and optical coherence tomography including
measurement of central retinal thickness. 
o
In case of any findings, please refer to Section 9.6.3.6.

Vital signs, including blood pressure, heart rate and body temperature (see 
Section 9.6.3.4).

Hematology panel: hemoglobin, hematocrit, platelet count, red blood cell count (RBC), 
white blood cell count (WBC). WBC must include differential including neutrophil, 
lymphocyte, monocyte, basophil, and eosinophil counts. See Section 9.6.3.1.

Coagulation panel: PTT or activated PTT and PT-INR (see Section 9.6.3.1).


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
Full biochemistry panel: sodium, potassium, chloride, magnesium, calcium (total or 
ionized), phosphate, glucose (fasting or non-fasting), AST, ALT, bilirubin (total and 
direct), ALP, total protein, albumin, lipase, lactic dehydrogenase (LDH), blood urea 
nitrogen (BUN) or urea, and creatinine. (See Section 9.6.3.1).
o
Note: weekly evaluations of phosphate levels and 12-lead ECG should be done
in patients with an elevated phosphate level ≥7 mg/dL.

Hormone panel: thyroid function testing (thyroid-stimulating hormone [TSH], free T3, 
free T4) for all patients (see Section 9.6.3.1).

Urinalysis test (See Section 9.6.3.1), and if clinically indicated, microscopic 
examinations.

Blood sampling for plasma-based biomarker analyses. 
o
Note: the blood samples are intended for isolation of plasma to study tumor 
markers (genetic and non-genetic) circulating in blood (see Section 9.7.1).

Calculate eGFR according to MDRD abbreviated formula (see Appendix 16.4)

12-lead ECG (see Section 9.6.3.3)
o
Note: Triple 12-lead ECG (supine position) is to be performed (pre-dose and 
post-dose) in case of QTc prolongation under treatment.
o
Note: weekly 12-lead ECGs to be performed for patients with an elevated 
phosphate level (≥7 mg/dL) until resolution (phosphate level < 7 mg/dL).

Tumor assessment (CT/MRI) according to RECIST v.1.1 (see Section 9.4.1).
o
Note: Radiological tumor evaluation should be done within 14 days after last 
study treatment. This is not necessary if the previous tumor evaluation was 
performed within 4 weeks (up to week 18) or within 7 weeks (beyond 
week 18).
o
Note: all images need to be submitted for central image review in digital 
format (for details see Section 9.4.1).

Document information on subsequent systemic anti-cancer treatment (if applicable).
9.2.3
Follow-up periods
9.2.3.1
Active follow-up
Safety information is collected for all discontinued patients for at least 30 (up to +7) days 
after the last administration of study treatment, and both safety and efficacy information are 
collected for patients who discontinue study treatment without disease progression. If the 
EOT and safety follow-up visits will be scheduled at the same time, the visits can be 
combined.


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The following assessments are to be done for all patients at least 30 (up to +7) days after the 
last administration of study treatment:

PRO questionnaires (EORTC QLQ-C30 and EQ-5D-3L) (see Section 9.7.2).
o
Questionnaires are to be completed before the patient meets with a clinician 
and before any examination or test is performed on that day.

AE/toxicity assessments (see Section 9.6.1.3).
o
All AEs and SAEs identified from the PI/ICF up to at least 30 days after the
last administration of study treatment must be documented in the source and 
reported on the eCRF. Thereafter, AEs related to the study drugs have to be 
reported and must be fully documented in the source data.

Perform brief physical examination (see Section 9.6.3.2).
o
Brief physical examination includes, but is not limited to, review of organ 
systems and physical areas of symptomatic concern or investigator’s degree of 
suspicion for any abnormality.

Ask the patient for changes in vision. If change in vision is reported, an 
ophthalmological examination must be performed.
o
In case of any findings, please refer to Section 9.6.3.6.

Review of concomitant medications (see Section 8.1).

Check ECOG PS (see Section 9.6.3.5).

Vital signs, including blood pressure, heart rate and body temperature (see 
Section 9.6.3.4).

Hematology panel: hemoglobin, hematocrit, platelet count, red blood cell count (RBC), 
white blood cell count (WBC). WBC must include differential including neutrophil, 
lymphocyte, monocyte, basophil, and eosinophil counts. See Section 9.6.3.1.

Coagulation panel: PTT or activated PTT and PT-INR (see Section 9.6.3.1).

Full biochemistry panel: sodium, potassium, chloride, magnesium, calcium (total or 
ionized), phosphate, glucose (fasting or non-fasting), AST, ALT, bilirubin (total and 
direct), ALP, total protein, albumin, lipase, lactic dehydrogenase (LDH), blood urea 
nitrogen (BUN) or urea, and creatinine. (See Section 9.6.3.1).
o
Note: weekly evaluations of phosphate levels should be done in patients with 
an elevated phosphate level (≥7 mg/dL) until resolution (phosphate level < 7 
mg/dL).

Hormone panel: thyroid function testing (thyroid-stimulating hormone [TSH], free T3, 
free T4) for all patients (see Section 9.6.3.1).

Document information on subsequent systemic anti-cancer treatment (if applicable).


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
Healthcare resource utilization information must be recorded once a patient has a 
hospitalization/healthcare visit (see Section 9.7.2).
Additionally, the following assessments are to be done for patients who discontinue study 
treatment for other reasons than disease progression (in case disease progression is not 
confirmed by central review, it strongly recommended, that patients go into active follow-up 
for tumor assessments until central imaging has confirmed disease progression):

Tumor assessment (CT or MRI) according to RECIST v.1.1 (see Section 9.4.1).
o
Note: During the active follow-up period, CT/MRI evaluations will be 
performed at the same intervals as during study treatment (every 6 weeks up to 
week 18, thereafter, every 9 weeks) (see Table 9–1).
o
Note: all images need to be submitted for central image review in digital 
format (for details see Section 9.4.1).

Monthly survival assessment
o
Note: Survival sweeps (e.g. telephone calls to collect survival status 
information) are to be implemented for all ongoing patients to occur in the 
2-week period after the data cut-off date is determined for the formal interim 
and primary completion analyses for overall survival.
9.2.3.2
Long-term follow-up
All patients in the long-term follow-up period will be contacted (telephone contact is 
sufficient) every month (±7 days) to determine survival status and obtain information on
subsequent systemic anti-cancer treatment until either data maturation for the final planned 
OS analysis is reached, death of the patient or any other criterion for withdrawal is met. If a 
patient is lost to follow-up, the site will try to contact the patient, the patient’s relatives, or 
another doctor treating the patient, unless prohibited by local requirements.
The information to be recorded at the long-term follow-up contacts:

Monthly survival assessments
o
Note: Survival sweeps (e.g. telephone calls to collect survival status 
information) are to be implemented for all ongoing patients to occur in the 
2-week period after the data cut-off date is determined for the formal interim 
and primary completion analyses for overall survival.

Document information on subsequent systemic anti-cancer treatment (if applicable).
9.3
Population characteristics
9.3.1
Demographic
The following demographic characteristics will be collected:


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
Year of birth

Age at Informed Consent (derived)

Gender

Race (as allowed by local regulation) and

Ethnicity (as allowed by local regulation)
The demographic data are to be collected prior to FGFR testing.
Routine procedures performed before informed consent can be used as screening data.
9.3.2
Medical history
Medical history findings (i.e. previous diagnoses, diseases or surgeries) meeting all criteria 
listed below will be collected as available to the investigator:

Start before signing of the informed consent for study treatment eligibility

Considered relevant for the patient’s study eligibility.
Detailed instructions on the differentiation between (i) medical history and (ii) adverse events 
can be found in Section 9.6.1.1.
9.3.3
Other baseline characteristics
Baseline study disease characteristics to be collected for all enrolled patients during the 
FGFR test period:

Urothelial carcinoma classification/diagnosis including 
o
date of initial diagnosis 
o
type of assessment
o
date of first progression / relapse 
o
date of the most recent progression / relapse 
o
histology
o
location of primary cancer
o
TNM classification of urothelial carcinoma at initial diagnosis and at study 
entry

At initial diagnosis: TNM classification according to the current AJCC 
edition at that time point 

At study entry: TNM classification according to the AJCC 8th edition
o
grading at initial diagnosis
o
status of primary tumor at study entry
Prior systemic anti-cancer medication including outcome have to be reviewed and must be 
fully documented in the source data.


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Further baseline study disease characteristics to be collected for all FGFR-positive patients
enrolled for screening:

PIK3CA and/or RAS activating mutations (presence vs. absence)

Prior systemic anti-cancer medication including outcome.

Liver metastases (yes / no)

Prior anti-cancer therapy for urothelial carcinoma
o
Any prior medications, significant non-drug therapies and diagnostic 
procedures for the study indication will be collected, including:

Medications (any prior systemic anti-cancer therapy) 

Trade name of medication

Dose of medication

Start date and end date

Surgery

Date of surgery

Type of surgery

Radiotherapy

Regimen

Location

Intent

Start date and end date

Cumulative dose

Local therapy

Diagnostic procedures
o
All non-study-indication-related medications taken within 2 weeks before 
randomization will be documented, including:

Trade name of medication

Reason for medication (indication)

Dose of medication

Start date and end date or if continuing at patient's last visit. 

Smoking history


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Modified 4-factor Bellmunt risk score
Prognostic factors have been identified for both first and second line treatment of patients 
with urothelial carcinoma. For second line the modified 4-factor Bellmunt risk score defines 
ECOG performance status, hemoglobin level, liver metastases and time from last systemic 
anti-cancer therapy dose as main adverse prognostic factors for overall survival (22). 
In this study, the modified 4-factor Bellmunt risk score (high vs. low) is used as one of the 
stratification factors for randomization. 
The Bellmunt risk score for stratification is divided in ‘high’ and ‘low’ as follows:

‘High’ score: 3-4 points

‘Low’ score: 0-2 points.
Modified 4-factor Bellmunt risk score will be calculated based on the following parameters 
collected within 7 days before randomization:

Hemoglobin level < 10 g/dL vs. ≥ 10 g/dL

ECOG performance status 0 vs. 1 (see Section 9.6.3.5)

Liver metastases absent vs. present

Time from last systemic anti-cancer therapy dose (< 90 vs. ≥90 days)
The risk score is calculated by adding up the points for each parameter (0 or 1 for each). 
Guidance for calculating the score is given in Table 9–2.
Table 9–2: Guidance for calculating modified 4-factor Bellmunt risk score
Risk factor
High risk (1 point)
Low risk (0 points)
Hemoglobin level
< 10 g/dL
≥ 10 g/dL
ECOG performance status
1
0
Liver metastases
present
absent
Time from last systemic anti-cancer therapy dose
< 90 days
≥90 days
ECOG = Eastern Cooperative Oncology Group; g/dL = Grams per deciliter.
9.4
Efficacy
The original primary efficacy variable for the Phase 3 part of the study was overall survival.
The primary efficacy variable of Phase 2 is ORR, and will be analyzed based on central 
review assessment. Although OS is the primary variable originally planned for the Phase 3 
part of this study, it is considered an exploratory efficacy variable for the Phase 2 part. The 
analysis will be performed when survival data is considered adequate for analysis by the 
sponsor.
OS is defined as the time (days) from randomization to death due to any cause. Patients alive 
at the date of data cut-off for analysis will be censored at the last date known to be alive. If a 
patient is lost to follow-up before any assessment after randomization, this patient will be 
censored at Day 1.


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Secondary efficacy variables of the study are:

Progression-free survival (PFS) 

Objective response rate (ORR) 

Disease-control rate (DCR) 

Duration of response (DOR) 
The secondary efficacy endpoints (PFS, ORR, DCR, and DOR) will be assessed based on 
central radiological tumor evaluation.
PFS is defined as the time (days) from randomization to date of first observed disease 
progression (radiological or clinical assessment) or death due to any cause, if death occurs 
before progression is documented. The actual date that the tumor scan was performed will be 
used for this calculation. If a tumor assessment is performed over more than one day (e.g. 
scans for chest and abdomen done on different days for a same evaluation), the earliest date 
will be used for the calculation of PFS. For patients without documented radiological or 
clinical progression or death at the time of analysis, PFS will be censored at the last actual 
visit date of tumor evaluation.
For all patients, the best overall tumor response at each assessment will be determined locally 
by the investigator and centrally using the RECIST criteria (v1.1).
ORR is defined as the percentage of patients with complete response (CR) or partial response 
(PR). Patients for whom overall best response is not CR or PR, as well as patients without any 
post-baseline tumor assessment will be considered non-responders.
DCR is defined as the percentage of patients, whose overall best response was not progressive 
disease (i.e. CR, PR, SD or Non CR/Non PD). Tumor assessments with SD as response, that 
is performed prematurely after randomization of the patient (i.e. substantially earlier than the 
first planned radiological tumor assessment at 6 weeks), will not be taken into account.
DOR (for PR and CR) is defined as the time from the first documented objective response of 
PR or CR, whichever is noted earlier, to disease progression or death (if death occurs before 
progression is documented). DOR will be defined for responders only, i.e. patients with a CR 
or PR. The actual dates the tumor scans were performed will be used for this calculation. 
DOR for patients who have not progressed or died at the time of analysis will be censored at 
the date of their last tumor assessment.
9.4.1
Radiological tumor assessments
Tumor response will be measured using CT or MRI scans (with contrast unless 
contraindicated) and evaluated using RECIST v.1.1 (28) (see Appendix 16.2) to determine the 
secondary efficacy variables (progression-free survival [PFS], objective response rate [ORR], 
disease-control rate [DCR] and duration of response [DOR]). Radiological tumor assessments 
will be done locally, and in addition centrally to determine the secondary efficacy variables 
(see details below).
MRI shall be performed instead of CT when local regulations do not permit the use of CT as 
requested per protocol schedule. The first radiological tumor evaluation will be conducted 


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during screening within 28 days before randomization (see flow chart in Table 9–1). Scans
(CT or MRI) for tumor assessments according to RECIST v.1.1 are to be done every 6 weeks 
(± 7 days) starting from Cycle 1 Day 1 up to week 18, and thereafter, every 9 weeks 
(± 7 days). A minimum of at least 6 weeks from start of treatment is mandatory for the 1st “on 
treatment” tumor assessment in order to achieve a valid response of stable disease. In 
exceptional cases, when it is deemed clinically necessary by the investigator due to safety 
reasons, an imaging scan at an earlier time point is allowed.
For patients who discontinue study treatment without disease progression, follow-up tumor 
evaluations will be performed (by CT or MRI) until progression of malignancy and/or start of 
subsequent systemic anti-cancer treatment, whichever comes first, or any other criterion for 
withdrawal is met. During the active follow-up period, CT/MRI evaluations will be performed 
at the same intervals as during study treatment (every 6 weeks up to week 18, thereafter, 
every 9 weeks) (see Table 9–1).
The radiological evaluation at baseline must include CT or MRI of the chest, abdomen and 
pelvis with contrast media (unless contraindicated). At follow-up CT or MRI can be done 
exceptionally without use of contrast media if this is contraindicated (e.g. renal impaired 
patients). Chest CT is strongly recommended and preferred versus chest MRI. The same 
technique (e.g. slice thickness, field of view) and the same image method (CT or MRI) should 
be used within any given patient. All CT/MRI scans must meet the standard of care for 
imaging of lesions in the respective organ system(s). All suspected sites of disease will be 
imaged.
A contrast enhanced (unless contraindicated) CT scan or MRI of the brain is required at 
screening to rule out brain metastases. Acquisition of both contrast enhanced (unless 
contraindicated) and unenhanced scans of the brain at baseline is strongly recommended. An 
MRI scan of the brain is required to confirm or refute the diagnosis of central nervous system 
(CNS) metastasis at baseline in the event of an equivocal scan. Patients with definitely treated 
stable CNS metastases may be eligible for the study. Further CT scan or MRI of the brain is 
only to be repeated if metastases or symptoms are present.
The specific contrast media rules are provided in a separate imaging manual.
If a CT scan for tumor assessment is performed in a positron emission tomography (PET)/CT 
scanner, the CT acquisition must be consistent with the standard for a diagnostic CT scan, i.e. 
adequate radiation dose and i.v. contrast, if intended to be used for target lesion measurements.
Bone scans (Technetium-99m) should be performed at screening. If bone metastases are 
present at screening and cannot be seen on CT or MRI scans, or if clinically indicated, TC-
99m bone scans should be repeated when complete response is identified in target disease or 
when progression in bone is suspected.
New lesions in PET or bone scan should be confirmed by CT or MRI.
All scans should be done with the identical modality (CT or MRI) and the identical technique 
(e.g., slice thickness, field of view) to those obtained at baseline.
Independent central image review


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An ongoing central image review will be conducted for this study in order to determine the 
secondary efficacy variables (see Section 10.3.1.2). The blinded readers/adjudicator will be 
board certified, experienced and independent radiologists with broad expertise in oncology 
radiology and RECIST v.1.1 criteria. They will not have been involved in the clinical part of 
the study. In addition, investigators will determine treatment response according to RECIST 
v.1.1. Further details will be described in the Imaging Review Charter, IRC.
All image sets of the study, i.e. CT, MRI, bone scans and exceptionally FDG-PET (if needed 
for lesion confirmation) must be anonymized by the study sites and provided digitally as 
Digital Imaging and Communications in Medicine (DICOM) format after every imaging time
point. The investigator must assure that all the images are of acceptable diagnostic quality.
Additional specific information on the handling (i.e. collection, shipment, tracking) of the 
images for the central image review will be provided in a separate imaging manual.
9.5
Pharmacokinetics / pharmacodynamics
Plasma samples for measurement of rogaratinib (BAY 1163877) concentrations (and 
metabolite(s) concentrations, if needed) will be collected from all rogaratinib-treated patients 
as follows:

Day 1 of Cycle 1, 2, 3, 4 and 5: 
o
at pre-dose (before supervised dose administration)
o
1 (±0.5h) hour post-dose (between 0.5 and 1.5 after dose administration)
Oral administration of the morning dose of rogaratinib will be done under supervision 
of site staff on rogaratinib PK days.
Deviations from planned sampling time intervals will not be considered protocol deviations. 
The date and clock time of each sample as well as dates and times of the doses will be 
recorded in the eCRF as PK calculations will be based on the sampling times relative to 
dosing times. Missed samples do not need to be collected beyond Cycle 5. Samples may be 
collected irrespective of any dose modifications during the treatment cycle. No detailed 
dosing history is required before the pre-dose sample, but the dose that separates the pre- and 
post-dose sample needs to be taken under supervision and the time recorded. Data from this 
study will be pooled with data from other clinical trials for pharmacometric analysis. 
Plasma concentrations of all analytes will be measured using a validated method. If required, 
other metabolites may be measured. Exploratory measurements of other moieties may be 
performed, if needed.
Details about the collection, processing, storage and shipment of samples will be provided in 
the laboratory manual.
Please refer to Section 10.3.3.1 for the analysis of the PK variables.


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9.6
Safety
9.6.1
Adverse events
Investigators should refer to the Safety Information section of the current investigator’s 
brochure (IB) of rogaratinib for the expected side effects. As with any agent, there is always 
the potential for unexpected AEs, including hypersensitivity reactions. The IB will be updated 
if any new relevant safety data are obtained. 
For the expected side effects of the comparator chemotherapy drugs (docetaxel, paclitaxel or 
vinflunine), please refer to the respective SmPCs.
Therapeutic monitoring should be performed following dose modification of study drugs in a 
manner consistent with the local clinical standard of care. In general, patients should be 
closely monitored for adverse drug reactions of all concomitant medications regardless of the 
path of drug elimination.
All concomitant medications must be recorded in the patient’s source documentation as well 
as on the eCRF.
Patients must be carefully monitored for AEs. This monitoring also includes clinical 
laboratory tests. AEs should be assessed in terms of their seriousness, intensity, and 
relationship to the study drug, or chemotherapy.
9.6.1.1
Definitions
Definition of adverse event (AE)
In a clinical study, an AE is any untoward medical occurrence (i.e. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation patient after providing written informed consent for study treatment 
eligibility. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
A surgical procedure that was planned prior to the start of the study by any physician treating 
the patient should not be recorded as an AE (however, the condition for which the surgery is 
required may be an AE).
New lesions or disease progression per se should not be regarded as AEs. Instead, the 
associated signs and symptoms should be recorded as AEs.
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal e.g. physical examination findings, symptoms, diseases, laboratory, 12-lead 
ECG.

Conditions that started before signing of informed consent for study treatment 
eligibility and for which no symptoms or treatment are present until signing of 
informed consent for study treatment eligibility are recorded as medical history (e.g. 
seasonal allergy without acute complaints).


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
Conditions that started before signing of informed consent for study treatment 
eligibility and for which symptoms or treatment are present after signing of informed 
consent, at unchanged intensity, are recorded as medical history (e.g. allergic 
pollinosis).

Conditions that started or deteriorated after signing of informed consent for study 
treatment eligibility will be documented as adverse events. This includes intercurrent 
illnesses.
Definition of treatment-emergent adverse event (TEAE)
A treatment-emergent event is defined as any event arising or worsening after the start of 
study drug administration until 30 days after the last administration of study treatment.
Definition of serious adverse event (SAE)
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a – f):
a.
Results in death
b. Is life-threatening
The term ‘life-threatening’ in the definition refers to an event in which the patient was 
at risk of death at the time of the event, it does not refer to an event which 
hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization 
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if 
at least one of the following exceptions is met:
- The admission results in a hospital stay of less than 12 hours
- The admission is pre-planned
(e.g. elective or scheduled surgery arranged prior to the start of the study; 
admission is part of the study procedures as described in Section 9.2)
- The admission is not associated with an AE 
(e.g. social hospitalization for purposes of respite care).
However, it should be noted that invasive treatment during any hospitalization may 
fulfill the criterion of ‘medically important’ and as such may be reportable as an SAE 
dependent on clinical judgment. In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedence.
d. Results in persistent or significant disability / incapacity
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions.
e.
Is a congenital anomaly / birth defect
f.
Is another serious or important medical event as judged by the investigator


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All SAEs occurring must be handled via this process. All serious diagnoses, symptom(s), 
sign(s) or finding(s) that have a start date after signing the ICF for study treatment eligibility
must be recorded as SAEs (see also Section 11.1). This also includes all serious events with a 
start date during screening period. A condition that was present before signing the PI/ICF and 
worsens after signing the PI/ICF for study treatment eligibility must also be recorded as an 
SAE if the serious criteria are met.
9.6.1.2 Classifications for adverse event assessment
All AEs will be assessed and documented by the investigator according to the categories 
detailed below.
9.6.1.2.1
Seriousness
For each AE, the seriousness must be determined according to the criteria given in 
Section 9.6.1.1.
9.6.1.2.2
Intensity
The intensity of AEs should be documented using the National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (NCI-CTCAE, version 4.03) (29).
The intensity of AEs is classified according to the following categories for events not listed in 
the CTCAE v.4.03 (e.g. soft-tissue mineralization):

Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.

Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental Activities of Daily Living (ADL; instrumental ADL refer to 
preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc.).

Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL (self-care ADL refer to bathing, dressing and undressing, feeding self, using 
the toilet, taking medications, and not bedridden). 

Grade 4: Life-threatening consequences; urgent intervention indicated.

Grade 5: Death related to AE.
9.6.1.2.3
Causal relationship 
The assessment of the causal relationship between an AE and the administration of treatment 
is a decision to be made by the investigator, who is a qualified physician, based on all 
information available at the time of the completion of the eCRF.
Causality should be assessed separately for each study treatment as detailed in the eCRF. If 
the investigator feels that the event cannot be firmly attributed to one of the study drugs 
(e.g. owing to a suspected underlying interaction), the same assessment will be documented 
for each study treatment.


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The assessment is based on the question whether there was a “reasonable causal relationship” 
to the study treatment in question.
Possible answers are “yes” or “no”
An assessment of “no” would include:
1. The existence of a highly likely alternative explanation, e.g. mechanical bleeding at 
surgical site.
or
2. Non-plausibility, e.g. the patient is struck by an automobile when there is no 
indication that the drug caused disorientation that may have caused the event; cancer 
developing a few days after the first drug administration.
An assessment of “yes” indicates that that the AE is reasonably associated with the use of the 
study treatment.
Important factors to be considered in assessing the relationship of the AE to study treatment 
include:
- The temporal sequence from drug administration: The event should occur after the drug 
is given. The length of time from drug exposure to event should be evaluated in the 
clinical context of the event.
- Recovery on drug discontinuation (de-challenge), recurrence on drug re-introduction 
(re-challenge): Patient’s response after de-challenge or re-challenge should be considered 
in view of the usual clinical course of the event in question.
- Underlying, concomitant, intercurrent diseases:
Each event should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the patient may have.
- Concomitant medication or treatment: 
The other drugs the patient is taking or the treatment the patient receives should be 
examined to determine whether any of them might have caused the event in question.
- Known response pattern for this class of drug: Clinical/preclinical
- Exposure to physical and/or mental stresses: The exposure to stress might induce adverse 
changes in the recipient and provide a logical and better explanation for the event
- The pharmacology and pharmacokinetics of the study treatment: 
The pharmacokinetic properties (absorption, distribution, metabolism and excretion) of 
the study treatment, coupled with the individual patient’s pharmacodynamics should be 
considered.
- The assessment is not possible.


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Causal relationship to protocol-required procedure(s)
The assessment of a possible causal relationship between the AE and protocol-required 
procedure(s) is based on the question whether there was a “reasonable causal relationship” to 
protocol-required procedure(s).
Possible answers are “yes” or “no”.
9.6.1.2.4
Action taken with study treatment 
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below.
The study treatment action should be recorded as detailed in the eCRF.
- Drug withdrawn
- Drug interrupted
- Drug delayed
- Dose reduced
- Dose not changed
- Not applicable
- Unknown
9.6.1.2.5
Other specific treatment(s) of adverse events
- None
- Remedial drug therapy
- Other
9.6.1.2.6
Outcome
The outcome of the AE is to be documented as follows: 
- Recovered/resolved
- Recovering/resolving
- Recovered/resolved with sequelae
- Not recovered/not resolved
- Fatal
- Unknown
9.6.1.3
Assessments and documentation of adverse events
All AEs identified after the patient has signed the PI/ICF for FGFR testing and until the 
patient ends the study (up to at least 30 days after the last administration of study treatment or 
end of active follow-up) must be fully documented in the source data. AEs are obtained by 
observation and as volunteered by the patients.


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The following procedure applies after signing of the PI/ICF for FGFR testing:
For patients with AE or SAE related to the procedure of taking a fresh biopsy for 
FGFR testing the corresponding AE and SAE have to be reported in the eCRF and 
must be fully documented in the source data.
For all other events, these have to be fully documented in the source data and will be 
reported in the medical history only for those patients who have signed the PI/ICF for 
study treatment eligibility.
The following procedure applies after signing of the PI/ICF for study treatment eligibility. 
For screening failures, the investigator must record every SAE (see Section 11.1) and 
AE in the eCRF from the PI/ICF until date of screening failure.
For patients eligible for treatment, all AEs and SAEs identified from the PI/ICF up to 
at least 30 days after the last administration of study treatment must be reported on the 
eCRF. Thereafter, AEs related to the study drugs have to be reported and must be fully 
documented in the source data.
After the end of the active follow-up phase there is no requirement to actively collect AEs 
(deaths will continue to be followed for efficacy purposes). An AE (irrespective of causal 
relationship) not completely resolved at the end of the pre-defined collection period must be 
followed up until resolution (chronicity, baseline grade or complete resolution) or until the 
investigator considers the event will not improve further. The type of information that should 
be assessed and recorded by the investigator for each AE is listed in Section 9.6.1.2.
The investigator is responsible for grading and judging the causal relationship (see Section 
9.6.1.2.3) of the recorded AEs.
AE documentation is event-based: All AEs that were ongoing at the end of treatment should 
be reviewed and updated up to at least 30 days after the last administration of study treatment. 
All new AEs that in the opinion of the investigator could be related to study treatment 
(information may be obtained via phone call), should also be collected and recorded up to at 
least 30 days after the last administration of study treatment. 
All AEs should be followed until resolution or stabilization unless, in the investigator’s 
opinion, the condition is unlikely to resolve due to the patient’s underlying disease. If any 
patient should die within 30 days of treatment discontinuation, the investigator will inform the 
sponsor and record the cause of death in detail within 24 hours of awareness on an SAE form.
Documentation must be supported by an entry in the patient’s file. 
A laboratory test abnormality should only be reported as an AE if considered clinically 
relevant, e.g. causing the patient to withdraw from the study, causing dose modification of the 
study treatment, requiring treatment or causing apparent clinical manifestations, or judged
relevant by the investigator. 
“Death” should not be recorded as an AE on the AE page. Instead, “death” is the outcome of 
underlying AE(s).


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For all serious adverse events (SAEs) the sponsor has to carry out a separate assessment for 
expectedness, seriousness and causal relationship to study drug.
9.6.1.4
Reporting of serious adverse events
The definition of serious adverse events (SAEs) is given in Section 9.6.1.1. Each SAE must 
be followed up until resolution or stabilization by submission of updated reports to the 
designated recipient.
All of the following events are to be reported to the sponsor as SAEs following the reporting 
instructions detailed in this section (a copy of the pathology report should be sent, if 
available):
Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) occurring 
after chemotherapy for cancer.
Any new primary cancers (or malignancy) during the course of the study (including 
skin cancers) regardless of relationship to study treatment.
Once data regarding survival and remission status are no longer required by the 
protocol, only any new primary tumors regarded as related to study treatment should 
be reported.
Recurrent metastatic disease of the study indication should not be reported.
Investigator’s notification of the sponsor
All investigators will be thoroughly instructed and trained on all relevant aspects of the 
investigator’s reporting obligations for SAEs. This information, including all relevant contact 
details, is summarized in the investigator site file. This information will be updated as needed.
The investigator must report immediately (within 24 hours of the investigator’s awareness) all 
SAEs occurring during the observation period defined in Section 9.6.1.3 to the recipient 
detailed in the instructions for SAE reporting included in the Investigator File.
SAEs occurring after the protocol-defined observation period will be processed by the 
sponsor according to all applicable regulations.
Notification of the IECs / IRBs
Notification of the IECs / IRBs about all relevant events (e.g. SAEs, suspected, unexpected, 
serious adverse reactions [SUSARs]) will be performed by the sponsor and/or by the 
investigator according to all applicable regulations.
Notification of the authorities
The processing and reporting of all relevant events (e.g. SAEs, SUSARs) to the authorities 
will be done by the sponsor according to all applicable regulations.
Sponsor’s notification of the investigational site
The sponsor will inform all investigational sites about reported relevant events (e.g. SUSARs) 
according to all applicable regulations.


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9.6.1.5
Expected adverse events
For this study, the applicable reference document is the most current version of the Section 8 
of the investigator’s brochure (IB) for rogaratinib. For chemotherapy (paclitaxel, docetaxel, 
vinflunine), applicable SmPCs will be used.
Overview listings of frequent events that have occurred so far in the clinical development are 
shown in the current IB. If relevant new safety information is identified, the information will
be integrated into an update of the IB and distributed to all participating sites.
The expectedness of AEs will be determined by the sponsor according to the applicable 
reference document and according to all local regulations.
9.6.1.6
Adverse events of special safety interest
Rogaratinib is an investigational drug and current knowledge of the AEs associated with this 
compound is limited. As with any new chemical entity, there is always potential for 
unexpected AEs, including hypersensitivity reactions.
Signs and symptoms suggestive for soft-tissue mineralization, and retinal disorders (classified 
analog to CTCAE v.4.03 as Grade ≥ 2) are defined as AEs of special interest (AESI). AESIs 
should be reported to the sponsor within 24 hours using a safety report form as outlined in 
Section 9.6.1.4 (Reporting of serious adverse events).
Soft-tissue mineralization
Clinical manifestation of soft-tissue mineralization caused by rogaratinib is expected to be 
similar to hyperphosphatemic familial tumoral calcinosis (congenital disease caused by loss-
of function of FGF23-FGFR/Klotho signaling pathway). Therefore, any events consistent 
with ectopic calcification should be reported as AESI (e.g. MedDRA lowest level terms 
[LLTs] tissue calcification, metastatic calcification, calcification of muscles, intestinal 
calcification, cutaneous calcification). 
Any patient with newly diagnosed soft-tissue mineralization suspected to be caused by 
rogaratinib should permanently discontinue the study treatment.
Retinal disorders (CTCAE Grade ≥ 2)
Any symptomatic retinal disorders including retinal detachment / retinal pigment epithelial 
detachment / serous retinopathy / retinal vein occlusion (classified analog to CTCAE v.4.03 
as Grade ≥2) should be reported as AESI. The results of the ophthalmologic examination
(Section 9.6.3.6) including any other abnormal ophthalmological findings should be reported 
in the source data and on a dedicated eCRF page. 
Specific dose modification schemes for retinal disorders are defined in Section 7.4.3.1.3. 
9.6.2
Pregnancies
The investigator must report to the sponsor any pregnancy occurring in a female study patient
during her participation in this study. The outcome of the pregnancy should be followed up 
carefully, and any outcome of the mother and the child at delivery should be reported.


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For a pregnancy in the partner of a male study patient, all efforts will be made to obtain 
similar information on course and outcome, subject to the partner’s consent.
For all reports, the forms provided are to be used. The investigator should submit them within 
the same timelines as an SAE.
Please refer to Section 9.6.3.1 for pregnancy testing.
9.6.3
Further safety
9.6.3.1
Laboratory evaluations
Safety laboratory analyses including urinalysis will be performed locally according to the 
schedule summarized in the tabular schedule of evaluations in Section 9.1.
In the event of implausible results, the laboratory may measure additional parameters to 
assess the quality of the sample (e.g. clotted or hemolyzed) and to verify the results. The 
results from such additional analyses may neither be included in the clinical database of this 
study nor evaluated further. If the results are relevant, the investigator will be informed to 
determine follow-up activities outside of this protocol.
An isolated laboratory abnormality that meets the criteria for a CTCAE Grade 4 classification 
is not reportable as an SAE, unless the investigator assesses that the event meets standard ICH 
criteria for an SAE (see SAE definition in Section 9.6.1.1).
Clinical chemistry
Full clinical chemistry panel includes: sodium, potassium, chloride, magnesium, calcium
(total or ionized), phosphate, glucose (fasting or non-fasting), AST, ALT, bilirubin (total and 
direct), ALP, total protein, albumin, lipase, lactic dehydrogenase (LDH), blood urea nitrogen 
(BUN) or urea, and creatinine.
Limited clinical chemistry includes: sodium, potassium, chloride, magnesium, calcium (total 
or ionized), phosphate, blood urea nitrogen (BUN) or urea, and creatinine.
Phosphate levels should be evaluated weekly in patients with an elevated serum phosphate 
level (≥7 mg/dL) until resolution (serum phosphate < 7 mg/dL).
Hormone panel
The hormone panel includes thyroid function testing (thyroid-stimulating hormone [TSH], 
free T3, free T4) for all patients.
Hematology
Hematology panel includes: Hemoglobin, hematocrit, platelet count, red blood cell count 
(RBC), white blood cell count (WBC). WBC must include differential including neutrophil, 
lymphocyte, monocyte, basophil, and eosinophil counts.
Coagulation panel
Coagulation panel includes: PTT or activated PTT and PT-INR.


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Estimated glomerular filtration rate (eGFR)
eGFR is to be determined during screening for study, on Day 1 of each cycle and at the EOT 
visit (see Table 9–1), and the value should be entered in the eCRF.
In accordance with established nephrology practice and guidelines, renal function at baseline 
and throughout the study will be assessed by means of the estimated Glomerular filtration rate 
(GFR), calculated using the Modification of Diet in Renal Disease (MDRD) study 
abbreviated formula. For the calculation, refer to Appendix 16.4.
Only patients with a baseline eGFR ≥30 mL/min/1.73 m2 are eligible to enter the study (see 
Section 6.1).
Urinalysis
The urine chemistry test includes: WBC, nitrite, pH, glucose, protein, ketones, bilirubin, 
urobilinogen, blood (RBC or hemoglobin).
Microscopic examinations will be performed if clinically indicated.
Pregnancy test
Serum pregnancy test will be performed at screening in women of childbearing potential. 
Negative serum pregnancy test must be documented before start of study treatment. Test to be 
repeated as frequently as required by local regulations. Postmenopausal women who have not 
had periods for more than 1 year or surgically sterilized women will not be required to 
undergo a pregnancy test (this information should be recorded under medical history on the 
eCRF). 
Reporting of medical device failures
In Japanese study centers, the investigator must report immediately all non-approved medical 
device failures which could cause health damage, as well as any health damage that may be 
causally associated with a non-approved medical device failure. For this reporting, the forms 
provided are to be used and sent to the designated recipient.
9.6.3.2
Physical examinations
Physical examinations will be performed according to the schedule of evaluations in Table 9–
1.
Abnormal physical examination findings are recorded either as medical history or as adverse 
events (see Section 9.6.1.1), depending on criteria of relative timing (before or after signing 
the ICF for study treatment eligibility).
Full physical examination
A full physical examination will be done at screening and at the EOT visit.


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Full physical examination includes review of all organ systems and examination of pertinent 
organ systems:

General appearance

Skin

Eyes

Ears, nose and throat

Head and neck

Lungs

Heart

Abdomen

Lymph nodes

Musculoskeletal system (including extremities and spine)

Genitourinary system

Neurological findings
Brief physical examination
Brief physical examination includes, but is not limited to, review of organ systems and 
physical areas of symptomatic concern or investigator’s degree of suspicion for any 
abnormality. Brief physical examinations are mandatory on Day 1 of each cycle and at the 
safety assessment visit of the active follow-up.
9.6.3.3
12-lead ECG
In each patient, 12-lead electrocardiogram (ECG) (supine position) readings will be 
performed at screening, on Day 1 of Cycle 1, 2, 3, 4 and 5 at pre-dose (before supervised dose 
administration) and between 0.5 and 1.5 hours post-dose (for patients on the rogaratinib 
treatment arm, the ECGs can be performed together with required PK blood sampling). 
Beyond Cycle 5, 12-lead ECG is to be performed on Day 1 of every 3rd cycle (pre- dose) and 
at EOT (if not performed within 4 weeks).
Triple 12-lead ECG (supine position) is to be performed (pre-dose and post-dose) in case of 
QTc prolongation under treatment. 12-lead ECG readings will be performed in triplicate (at 
least 1 minute apart with no more than 5 minutes in total for all three ECGs) after resting for 
at least 10 minutes in supine position. QTc prolongation should be followed with triple 
12-lead ECG at the discretion of the investigator as clinically indicated.
Weekly 12-lead ECGs have to be performed in patients with an elevated serum phosphate 
level (≥7 mg/dL) until resolution (serum phosphate < 7 mg/dL).


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In patients with hypocalcemia CTCAE Grade ≥ 2, an additional 12-lead ECG has to be 
obtained on day of detection of hypocalcemia and should be repeated as clinically indicated.
If patients develop significant conduction abnormalities during chemotherapy, appropriate 
therapy should be administered and continuous cardiac monitoring should be performed 
during subsequent therapy with chemotherapy. For details, please refer to the respective 
SmPC.
The overall interpretation of the 12-lead ECG (normal/abnormal, clinical relevance) and the 
12-lead ECG diagnosis and data will be documented in the source documents and on the 
eCRF. This review should be completed by a qualified physician and signed and dated in the 
source at the time of review.
9.6.3.4
Vital signs (including height and body weight)
Vital signs, including systolic and diastolic blood pressure, heart rate and body temperature 
will be collected according to the tabular schedule of evaluations shown in Section 9.1.
Vital signs are to be measured by a member of the investigator’s team. 
Blood pressure has to be measured in a consistent manner throughout the study (preferably 
using a manual cuff at the same arm with the patient sitting for 5 min before the 
measurement). Any clinically relevant measurements or changes are to be reported as AEs 
(e.g. hypertension, tachycardia, bradycardia, etc.).
Height is measured in centimeters (cm) and obtained only at screening.
Body weight will be measured in kilograms (kg), measurement units 0.1 kg, and preferably 
be obtained without shoes. If clinically indicated (e.g. excessive weight loss), it is at the 
investigator’s discretion to perform these measurements more frequently.
Additionally, body surface area (BSA) will be derived.
9.6.3.5
ECOG performance status
Patient’s ability to manage activities of daily living will be appraised utilizing the 
performance status scale by Eastern Cooperative Oncology Group (ECOG). The patient’s 
ECOG performance status (PS) will be estimated according to the schedule summarized in the 
study flow chart in Table 9–1. An ECOG PS score of 0 or 1 is required for study inclusion 
(see Section 6.1). Change of ECOG PS will be measured.
Grading definitions for ECOG performance status are given in Table 9–3 below.


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Table 9–3: Definitions for ECOG PS grading
ECOG Grade
ECOG Status 
0 
Fully active, able to carry on all pre-disease performance without restriction.
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead. 
ECOG PS = Eastern cooperative oncology group performance status.
9.6.3.6
Ophthalmological examination
An ophthalmologic examination will be performed by an ophthalmologist or an equivalent 
specialist at screening, during treatment (Day 1 [-7 days] of every second cycle) starting at 
Cycle 2 and at the EOT visit (see the tabular schedule of evaluations shown in Section 9.1). 
Additionally, the investigator will ask the patient for changes in vision at each site visit. If 
change in vision is reported, an ophthalmological examination must be performed.
As per ICH-GCP, at the principal investigator’s discretion, a chosen optometrist or equivalent 
specialist who is licensed can perform the eye examinations as required by the study protocol.
The exam will include previous eye history (only at screening) and any ophthalmic symptoms, 
best corrected visual acuity, dilated indirect ophthalmoscopy with macular involvement 
assessment and optical coherence tomography (OCT) including measurement of central 
retinal thickness. The examination findings will be described in the source data and on the 
eCRF. Any findings qualifying as an adverse event will be recorded accordingly. 
Patients who experience any retinal disorders including retinal detachment / RPED / serous 
retinopathy / retinal vein occlusion have to undergo ophthalmologic examinations on Day 1 of 
every cycle.
Ophthalmological monitoring of the treatment associated retinal abnormality is recommended 
to be continued until resolution of the abnormality and to be documented in the source data 
for patients whose treatment was permanently discontinued.
For dose modification of rogaratinib due to ophthalmological findings, see Section 7.4.3.1.3.
For reporting of AESI (retinal disorders Grade ≥2), see Section 9.6.1.6.


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9.7
Other procedures and variables
9.7.1
Biomarker investigations
Only urothelial carcinoma patients with high FGFR1 or 3 mRNA expression levels will be 
eligible for study treatment. Therefore patients need to provide written PI/ICF for FGFR 
testing to be enrolled; archival tumor tissue is adequate for testing of FGFR1 and 3 mRNA 
expression.
Additional slides need to be provided for tumor DNA testing of mutations in PIK3CA and 
RAS-encoding genes, which have recently been identified as potential FGFR inhibitor 
resistance factors. Only FGFR positive patients will have the mutational testing as well. The 
outcome of the mutation testing will not affect the study eligibility.
If archival tissue is not available in sufficient quantity or quality for the FGFR1 and 3 RNA-
ISH assay and/or for the PIK3CA and RAS mutation testing to be performed, then a new
biopsy procedure would be necessary if the patient wants to pursue the option of entering the 
trial. This procedure would be performed at the discretion of the investigator and consent 
from the patient. The tumor material should be derived by a biopsy procedure associated with 
a non-significant risk, e.g. ultrasound-guided and will be limited to superficial lymph nodes, 
and other anatomical regions suited for non-invasive biopsy procedures. Fine needle aspirates 
would not be sufficient as a biopsy procedure for biomarker testing. No major organ should 
be biopsied, e.g. biopsy of the brain, lung/mediastinum, pancreas, or endoscopic procedures 
extending beyond the esophagus, stomach or bowel are excluded.
The UC tumor tissue embedded into paraffin will be shipped to a central laboratory to confirm 
high expression levels of fibroblast growth factor receptor (FGFR) mRNA (see Section 6.1: 
Inclusion criteria) in all patients and in addition for testing the absence or presence of 
PIK3CA and/or RAS activating mutations in all FGFR-positive patients who have signed the 
PI/ICF for FGFR testing (see Section 5).
Method applied for patient selection in trial 17403
The FGFR1&3 RNA in situ hybridization (RNA-ISH) test is intended to be used for the 
detection of FGFR1and FGFR3 messenger RNAs (mRNAs) in formalin-fixed, paraffin-
embedded (FFPE) tumor tissue from urothelial carcinoma patients. The FGFR1 and 3 
RNA-ISH test will be used to aid in the selection of cancer patients who may benefit from the 
pan-FGFR inhibitor (rogaratinib) therapy. The RNA-ISH technology allows for the respective 
FGFR probe to bind to the target FGFR mRNA, and in combination with detection chemistry 
results in visualization of the FGFR mRNA signals. The signals are then quantitated by a 
trained pathologist using light microscopy. The final outcome can be used to assess the level 
of FGFR1 and 3 mRNA transcript overexpression. The analysis will be performed centrally.
In pre-clinical studies, only xenograft models with high expression levels of either FGFR1, or 
FGFR2 or FGFR3 demonstrated significant (> 50%) anti-tumor efficacy upon rogaratinib
treatment. Preliminary data from Phase 1 study 16443 confirms that a treatment benefit of 
having either a partial response or a long-lasting stable disease (SD) is observed in patients 


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that have a high FGFR expression level. Therefore, having at least one FGFR isoform with a 
high expression level was selected as inclusion criterion for FGFR-positivity for this Study 
17403.
Details about the collection, processing, storage and shipment of samples will be provided 
separately (laboratory manual).
PIK3CA and RAS mutation testing
The presence or absence of PIK3CA and/or RAS activating mutations is used as one of the 
stratification factors of the study and will be tested only in FGFR-positive patients who have 
signed the PI/ICF for FGFR testing. The detection of activating mutations in PIK3CA and/or 
RAS-encoding genes will be conducted by a central laboratory. Please refer to Section 5.1 for 
justification of the mutation testing.
Exploratory tumor-based biomarker analysis
For all randomized patients exploratory biomarker analyses will be performed from UC tumor 
specimen provided beyond the number of slides needed for FGFR1 and 3 testing and for the 
testing for PIK3CA and RAS mutations. This procedure is covered by the PI/ICF for FGFR 
testing.
These tumor tissue specimens may be used for the following purposes: (1) to evaluate 
mutations, copy numbers or gene rearrangements in FGFR encoding genes and in known 
oncogenes such as p53, PTEN, and cMyc in DNA extracted from tumor tissue specimens; (2) 
to analyze the gene expression of genes that may explain resistance or hyper-responsiveness 
to FGFR inhibitors, such as cMet, cMyc and FGF19 in RNA extracted from tumor tissue 
specimens; (3) to evaluate expression of non-coding tumor relevant RNAs, such as 
microRNAs; (4) to evaluate protein expression of immune markers, such as PD-L1 and CD8A 
in tumor specimen, e.g. by IHC.
Exploratory plasma-based biomarker analysis
All FGFR positive patients will be asked to provide blood samples for biomarker analyses, 
which will be obtained during regular study visits in which blood will be drawn for other 
scheduled but unrelated laboratory tests. The following procedures are covered by the PI/ICF 
for study treatment eligibility.
Genetic biomarkers from plasma:
These samples are intended for isolation of plasma to study tumor markers circulating in 
blood such as circulating tumor DNA (ctDNA) or circulating tumor RNA. Candidates of 
genes for the evaluation from ctDNA are RAS-encoding genes, PIK3CA, and cMet which 
have been described as contributors to acquired FGFR inhibitor resistance but also FGFR 
DNA alterations including but not limited to FGFR3 activating mutations and translocations 
to correlate with the respective FGFR DNA status detected in tumor specimen from the same 
patient. The types of analyses may comprise the identification of mutations or splice variants. 


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Furthermore, these plasma samples will serve as source for non-coding microRNA, as 
possible markers describing treatment response.
Non-genetic biomarkers from plasma:
Plasma samples will also be used to quantify the circulating levels of various proteins of 
interest, to attempt to identify a protein signature that correlates with drug response. 
Plasma samples for the analyses of tumor biomarkers (genetic and non-genetic biomarkers) 
will be prepared from blood samples obtained at the following time points:

At screening visit (within 7 days prior to randomization), 

on Day 1 (pre-dose) of each treatment cycle, and

at the end-of-treatment (EOT) visit.
On treatment days, blood will be drawn for preparation of plasma samples prior to drug 
administration, if possible. In addition to the proteins and genes listed above, other 
biomarkers deemed relevant to this study will be measured if they will be identified as 
possible resistance mechanisms during the course of the study. Data from these additional 
biomarker analyses may also be correlated with measures of clinical efficacy.
9.7.2
Patient-reported outcomes (PRO)
The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life 
Questionnaire Core 30 (QLQ-C30) and the EuroQol Group’s EQ-5D-3L questionnaires will 
be used to collect patient-reported outcomes (PRO). The EORTC QLQ-C30 is a 
multidimensional validated cancer-specific quality of life questionnaire developed by the 
EORTC Study Group on QoL for use in international clinical trial settings. It includes five 
functional scales (physical, role, emotional, social, and cognitive functioning), 3 symptom 
scales (fatigue, pain, and nausea and vomiting), a global health status scale, and a number of 
single items assessing additional symptoms (dyspnea, sleep disturbances, constipation, and 
diarrhea), and perceived financial impact. The EORTC QLQ-C30 will be used to evaluate the 
total score, symptom scales / items and global health status of the patients.
The EQ-5D-3L is a generic, validated quality of life preference-based instrument to measure 
both utility and health status. It contains a descriptive system which measures 5 health 
dimensions: mobility, self-care, usual activity, pain/discomfort, and anxiety/depression. The 
five health dimensions are summarized into a single score, the EQ-5D index score that ranges 
between 0 and 1 (0 representing the worst imaginable health state or death and 1 representing 
perfect health). The EQ-5D also contains a visual analog scale (EQ-visual analog scale 
[VAS]), which records the respondent’s self-rated health status on a vertical graduated visual 
analogue scale ranging from 0 (worst imaginable health state) to 100 (best imaginable health 
state). The EQ-5D-3L will be used to evaluate the index and VAS scores.
Data collection for both instruments would be completed at screening and on Day 1 of each 
cycle, at the EOT visit and at the safety assessment visit of the active follow-up. 


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9.7.3
Healthcare resource utilization
Healthcare resource utilization information will be recorded once a patient has a 
hospitalization/healthcare visit, during the course of the study. Information on the start date, 
end date, ongoing status, location, scheduling status, main diagnosis at discharge, and number 
of working days missed must be recorded. Data will be analyzed on an ad hoc basis. 
9.8
Appropriateness of procedures / measurements
All efficacy and safety parameters, as well as the methods to measure them are standard 
variables / methods in clinical studies and/or clinical practice. They are widely used and 
generally recognized as reliable, accurate, and relevant. To ensure data can be compared 
between the treatment groups, all examinations (except blood sampling for PK analyses) will 
be the same in both treatment arms.
10.
Statistical methods and determination of sample size
10.1
General considerations
Due to the stop of enrollment, the study will not move forward to its Phase 3 and will remain 
as Phase 2. The study will remain open until the survival data is considered adequate for 
analysis by the sponsor. The analysis details of the Phase 3 as well as the transition from 
Phase 2 to Phase 3 are provided in the following sections as a reference to the original design.
Statistical analysis will be performed using SAS; the version used will be specified in the 
statistical analysis plan.
To help structure the section, we present the statistical methods for this Phase 2/3 study as one 
study with two interim analyses, while the first interim indicates the end of the Phase 2 part, 
and the second and final analyses are considered the Phase 3 part including Phase 2 patients in 
the analyses.
Patients will be randomly assigned in a 1:1 ratio to one of the following treatment arms:

Rogaratinib

Chemotherapy (taxane or vinflunine)
More details on the treatments are provided in Section 7.
All patients enrolled to this study are expected to have FGFR positive testing results. Due to 
inter-evaluator variability in the scoring of FGFR test, a confirmation test could be done at the 
discretion of the sponsor to identify the FGFR positive patients which will be referred to as 
confirmed FGFR positive.
Although both PIK3CA and/or RAS mutant and WT patients are recruited, this study is 
powered for the PIK3CA and RAS WT subgroup. Therefore, the recruitment will stop when
450 PIK3CA and RAS WT patients are randomized. In the meanwhile, based on current 
assumption that about 75% of all study population are PIK3CA and RAS WT, roughly 600


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patients in all study population (450 PIK3CA and RAS WT + 150 PIK3CA and/or RAS 
mutant) will be recruited to the study. 
Randomization will be stratified by:

PIK3CA and/or RAS activating mutations (presence vs. absence)

Prior immunotherapy (yes vs. no)

Modified 4-factor Bellmunt risk score (high vs. low) (see Section 9.3.3)
The following rule will be applied for WT and mutant subgroups to potentially remove some 
stratification factors from the subgroups to avoid over-stratification: if the smallest group 
within one stratification factor (other than activating mutation status) is less than 15% of all 
randomized patients in either subgroup (450 patients for WT, and the corresponding number 
of mutant patients for mutant subgroup), and all study population (with the exception of 
always including activating mutation status for all population), then this stratification factor 
will not be introduced into the model for the stratified statistical analysis of efficacy endpoints. 
As the majority of patients are anticipated to be randomized by the time of the planned formal 
interim analysis, this rule will be applied to both the 2nd interim analysis and final analysis of 
OS for consistency.
Data from patients who are transferred to a roll-over study may be pooled and analyzed
together with the data from the study in which the patient was initially included. The results 
from these analyses will be reported separately.
10.2
Analysis sets
Full analysis set (FAS) 
The primary population for the efficacy analysis is the Full analysis set (FAS) population 
(also considered the Intent-to-treat (ITT) analysis set), which is defined as all randomized
patients. Patients will be analyzed as randomized, meaning even if a patient was randomized 
and received no drug or if randomized and received incorrect study drug at any time, these 
patients will still be analyzed for efficacy under FAS, as randomized. The FAS population is 
identical to the ITT population.
Safety analysis set (SAF)
The population for the safety analysis will be comprised of all patients who received at least 
one dose of study treatment (rogaratinib or chemotherapy). Patients will be analyzed as 
treated. Using a conservative approach, patients randomized to the chemotherapy arm will be 
analyzed under the rogaratinib arm if the patient received at least one dose of rogaratinib
treatment, whereas patients randomized to the rogaratinib arm will still be analyzed under the 
rogaratinib arm regardless of receiving any chemotherapy. Only if a patient randomized to the 
rogaratinib arm received chemotherapy treatment only would the patient be analyzed under 
the chemotherapy arm. Note, given the study is designed as open-label and study drug 
between the two arms will be administered differently (i.e. oral versus intravenous) the 
possibility of a patient receiving incorrect treatment is unlikely.


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In addition, in the rare case of early drop out without any post-baseline safety/visit 
information, the patient should be discussed at the Validity Review Meeting where a decision 
on inclusion into SAF set will be made.
10.3
Variables and planned statistical analyses
The formal statistical analyses will be both descriptive and inferential. Summaries will be 
provided for each of the treatment arms, rogaratinib and chemotherapy. In addition, 
descriptive summaries of population characteristics will be provided for the total study 
population. 
Demographic and baseline characteristics, baseline cancer characteristics, medical history, 
prior anti-cancer therapies, concomitant medication, patient disposition will be summarized 
by treatment arm for the FAS population. For continuous measurements, the mean, standard 
deviation, range and median will be computed; for categorical values, the frequency and 
percent will be provided.
See Section 11.4 for handling of missing data.
10.3.1
Efficacy variables
10.3.1.1
Primary efficacy variable
Objective response rate (ORR) is the primary efficacy variable for the Phase 2 part. ORR
will be compared between treatment arms using Fisher’s exact test, based on independent 
central review assessments for both populations. Estimates and 95% confidence intervals will 
be computed for each treatment arm. The differences in ORR between the rogaratinib and 
chemotherapy arms and the corresponding 95% confidence intervals will also be calculated. 
Overall survival was the primary efficacy variable (see Section 9.4 for definition) of the
originally planned Phase 3 part. OS data will be considered mature and the final OS analysis 
(i.e. primary completion) will be performed when approximately a total of 390 PIK3CA and
RAS WT patients have died, in accordance with the power calculations specified for the FAS.
See Section 10.4 for additional details on sample size determination.
Due to the stop of enrollment, the study will not move forward to its Phase 3 and will remain 
as Phase 2. The study will remain open until the survival data is considered adequate for 
analysis by the sponsor. The details below about step-wise hypothesis test and analysis of 
overall survival are provided as a reference to the original design. 
For the primary efficacy variable of overall survival in the Phase 3 part, a stratified log-rank 
test controlling type I error at a level of 0.025 (one-sided) will be conducted for the WT 
population first (step 1). A full alpha of 0.025 (one-sided) will be passed on to OS in all study 
population and some selected secondary endpoints (step 2) if and only if the null hypothesis 
of OS for WT population is rejected. In case of failing to reject null hypothesis of OS for WT 
population, step 2) will not be tested. Details on controlling family-wise type I error within 
step 2) for OS in all study population and selected secondary endpoints will be specified in 
the Statistical Analysis Plan (SAP).


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If the analysis in step 1) based on final OS data in WT population is positive, the efficacy of 
rogaratinib monotherapy in PIK3CA and RAS WT FGFR-positive locally advanced or 
metastatic urothelial bladder patients is considered established; Moreover, if the analysis in 
both step 1) and the OS in all study population part in step 2) are positive based on the testing 
details specified in SAP with the corresponding alpha level allocated for OS in all study 
population, the efficacy of rogaratinib mono therapy in all FGFR-positive locally advanced or 
metastatic urothelial bladder patients is considered established. 
Therefore, to compare OS between the rogaratinib arm and the chemotherapy arm, the 
following hypothesis will be tested for the PIK3CA and RAS WT patients first and then all 
study population:
H0:
hazard ratio (rogaratinib / chemotherapy) ≥ 1
versus
H1:
hazard ratio (rogaratinib / chemotherapy) < 1
The primary efficacy variable of OS in step 1) will be formally compared based on 
approximately 390 death events in the PIK3CA and RAS WT patients for WT population, 
using a stratified log-rank test, stratified by the stratification factors used for randomization, 
with consideration of the rule specified in Section 10.1. 390 death events plus the 
corresponding number of events occurred in the PIK3CA and/or RAS mutant patients during 
the same period of time will be included for the evaluation of the all study population in 
step 2) mentioned above, using the stratified log-rank test applying the same rule.
The primary stratified analysis for OS (and all other efficacy endpoints) will be based on 
stratification information as entered in IxRS for both step 1) and 2).
In addition to the stratified log-rank test, for the PIK3CA and RAS WT patients first and then 
all study population, the hazard ratio (rogaratinib / chemotherapy) for OS and its 95% 
confidence interval will be calculated using the Cox model, stratified by the same factors as 
stated above. Kaplan-Meier (KM) estimates for OS and KM survival curves will also be 
presented for each treatment arm. The KM estimates at time points such as 3 months, 
6 months etc. together with corresponding 95% confidence intervals as well as the differences 
of these estimates will also be calculated between the rogaratinib arm and the chemotherapy 
arm, for both PIK3CA and RAS WT population and all study population (referred to as “both 
populations” below).
The sensitivity analysis will be performed by only including confirmed FGFR positive 
patients for WT population and all study population, respectively.
See Section 10.5 for additional details on the planned interim analysis of OS.
10.3.1.2
Secondary efficacy variables
Secondary efficacy variables including progression-free survival (PFS), disease control rate 
(DCR) and duration of response (DOR) (see Section 9.4 for definitions) will be analyzed 
based on final database.
Further analysis details with respect to PFS, DCR and DOR are summarized below.


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For analyses of PFS, in both populations, the two treatment arms will be compared using a 
log-rank test stratified by three randomization stratification factors based on independent 
central review assessments. The hazard ratio (rogaratinib / chemotherapy) and 95% 
confidence interval will be provided. KM estimates and KM curves will also be presented for 
each treatment arm. The KM estimates at time points such as 2 months, 4 months etc. together 
with corresponding 95% confidence intervals as well as the differences of these estimates 
between the rogaratinib arm and the chemotherapy arm will also be calculated.
DCR will be analyzed similarly to ORR.
For both populations, summary statistics will be displayed for all best response categories: 
CR, PR, SD, Non CR/Non PD, PD by central radiographic imaging, and PD by clinical 
judgment. Frequency counts and percentages with exact 95% confidence intervals will be 
displayed.
Since the responders are not a randomized group, no statistical testing will be performed for 
DOR. Analysis of DOR will be descriptive in nature for both populations based on 
independent central review assessments. KM estimates and KM curves will be displayed for 
each treatment arm.
Analyses based on investigator’s review assessments will also be performed for PFS, DCR 
and DOR as sensitivity analyses.
10.3.1.3
Subgroup analyses
For both populations, subgroup analyses for ORR, PFS and OS will be performed in a 
descriptive fashion if data are warranted. These may include, but may not be limited to, 
subgroups defined by demographics such as sex, race, ethnic group, geographic regions and 
age (calculated at the date of randomization using date of birth), baseline ECOG performance 
status, baseline cancer characteristics and stratification factors at randomization (such as prior 
immunotherapy-treated subgroup etc.). Descriptive statistics and hazard ratio estimates with 
95% CI for OS and PFS will be provided at least within each category of the subgroup, 
provided there are sufficient numbers of events in total for the category within the subgroup 
across the treatment arms.
10.3.2
Safety variables
10.3.2.1
Adverse events (AEs)
Summary of adverse events is considered a secondary objective for this study. All AEs, 
whether considered drug-related or not, will be reported on the eCRF with start / stop dates, 
dates of any grade change, action taken, whether treatment was discontinued, any corrective 
measures taken, and outcome. For all events, the relationship to treatment and the severity of
the event will be determined by the investigator. Adverse events will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA) terms (version 20.0 or later), and graded 
according to National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(NCI CTCAE), version 4.03.


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For both populations, descriptive summary tables (frequency and percentage of patients, not 
of events) will be presented by treatment arm and MedDRA terms and NCI CTCAE v.4.03 
worst grade for the following:

Prevalence of AEs during screening

Incidence rate of all treatment-emergent AEs (TEAEs)

Incidence rate of treatment-emergent drug-related AEs

Incidence rate of treatment-emergent serious AEs (SAEs)

Incidence rate of serious treatment-emergent drug-related AEs

Interval-specific and cumulative event rates for the more common AEs for treatment 
emergent adverse events
A treatment-emergent event is defined as any event arising or worsening after the start of 
study drug administration until 30 days after the last administration of study treatment.
10.3.2.2
Deaths and serious adverse events (SAEs)
The incidence of deaths in the study, and especially deaths up to within 30 days of last dose of 
study drug, will be summarized by treatment arm and cause of death for both populations. All 
deaths up to 30 days of last dose of study drug will be listed by patient with start and stop date 
of study treatment, date of death, and cause of death for both populations. 
In addition to the above mentioned incidence table of all treatment-emergent SAEs, these 
events will be listed by patient with investigator AE term, start and stop date of study drug 
administration, start and stop date of AE, drug relationship, worst NCI CTCAE grade, action 
taken and outcome for both populations.
10.3.2.3
AEs leading to discontinuation of study treatment and/or withdrawal 
from the study and other significant AEs
The incidence of AEs leading to permanent discontinuation of study treatment and / or 
withdrawal from the study will be summarized by treatment arm for both populations, and be 
listed by patient with investigator AE term, start and stop date of study drug administration, 
start and stop date of AE, drug relationship, worst NCI CTCAE grade, action taken and 
outcome. In addition, incidence of AEs that caused dose reduction or interruption will be 
summarized separately by treatment arm for both populations.
10.3.2.4
Clinical laboratory evaluations
Frequency of laboratory abnormalities regarding hematology, clinical chemistry and clinical 
urinalysis will be tabulated by treatment arm for both populations. Worst grades for 
hematological and biochemical toxicities will be calculated according to CTCAE v.4.03 based 
on laboratory measurements, and will be summarized by treatment arm and NCI CTCAE 
v.4.03 category and worst grade for both populations. Frequency tables as well as tables with 
change in worst grade from baseline will be presented.


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10.3.2.5
Other safety measures
For both populations and each treatment arm, vital signs (i.e. blood pressure, heart rate, body 
temperature) will be tabulated and summarized by visit for observed values and changes from 
baseline using descriptive statistics, as appropriate. 12-lead ECG data will also be 
summarized at baseline, by visit and end of treatment for observed values and changes from 
baseline using descriptive statistics, as data are available.
10.3.3
Other variables
All the variables listed in this section are considered tertiary variables.
10.3.3.1
Pharmacokinetic variables
The samples collected on Day 1 of Cycles 1 through 5 at pre-dose and between 0.5 and 
1.5 hours post-dose will document a longitudinal exposure under steady state condition. The 
longitudinal exposure data will be used in exposure-response modelling of adverse events and 
clinical responses. Evaluation of the data described above will be presented in a separate 
report.
The details of the modeling analysis will be described in a separate Modelling and Simulation 
(M&S) Analysis Plan and the results may be reported in a separate M&S Report.
In the clinical study report, only plasma concentration data for all analytes will be listed.
10.3.3.2
Biomarker variables
Patients’ biomarker status at baseline will be correlated with treatment effect in OS, PFS and 
response to explore which biological targets may be particularly important in defining the 
appropriate therapeutic population for the agent. Biomarker analyses and results will be 
provided in a separate report.
10.3.3.3
Patient-reported outcomes (PRO)
PRO data as measured by the EORTC QLQ-C30 and EQ-5D will be analyzed to assess 
differences in health-related Quality of Life (HRQoL) and health utility values between 
treatment arms based on time-adjusted Area Under the Curve (AUC) using all available data.
The scoring of the PRO endpoints and handling of missing data will be detailed in the 
statistical analysis plan. Summary statistics will be presented for each of the PRO endpoints at 
each assessment time point and for change from baseline by treatment group for both 
populations.
Primary Analysis of PROs: If there is sufficient data, an analysis of covariance (ANCOVA) 
model will be used to compare the time-adjusted AUCs between the two treatment groups 
with covariates for baseline HRQoL score and the same stratification factors as used in the 
primary efficacy endpoint at the end of the study for both populations. Least-squares mean 
estimates; standard errors and 95% CIs will be estimated for each treatment group and for the 
treatment group difference for both populations. The treatment by covariate interactions will 
be explored in the ANCOVA models and the consistency of the treatment effect on HRQoL 
across different subsets defined by the covariates in the model will be assessed. In the event 
that the ANCOVA model assumptions (e.g., normality and homogenous variance of the error 


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terms, equality of slopes for different treatment regression lines) are not satisfied, the rank 
analysis of covariance may be used (30, 31).
Secondary Analyses of PROs: Sensitivity analysis using different imputation methods for 
imputing missing assessments may be performed. Additional exploratory analyses may be 
carried out using the linear mixed effect models to explore the effects of treatment, time and 
other covariates on the endpoints, assuming the missing data mechanism is missing at random.
10.4
Determination of sample size
Due to the stop of enrollment and full data analysis, the study will not move forward to its 
Phase 3. As a reference, the following details provide the number of patients originally 
planned for the entire study:
The determination of sample size contains two aspects: Phase 2 and Phase 3 part of the study. 
The sample size for the Phase 2 part of the study (the first interim) is powered on ORR for 
FGFR positive PIK3CA and RAS WT population. The Phase 2 part of the study is designed 
to achieve 90% power to detect the difference in ORR between rogaratinib over 
chemotherapy in FGFR positive WT population with the assumption of 30% response rate in 
rogaratinib and 10% in chemotherapy. Assuming one-sided alpha of 0.1 for the Phase 2 part, 
power of 90%, and a randomization ratio of 1:1 between the rogaratinib and chemotherapy 
arms, a total of approximately 116 confirmed FGFR positive patients with wild-type PIK3CA 
and RAS biomarkers are required for the Phase 2 part, based on Fisher’s exact test. 
The sample size for the Phase 3 part of the study is powered on the primary efficacy variable 
of OS for PIK3CA and RAS WT population. The study is designed to have 90% power to 
detect an approximately 40% increase in median OS (i.e. a hazard ratio [HR] of 0.72, 
rogaratinib over chemotherapy) for the WT population. Assuming one-sided alpha of 0.025
for the Phase 3 part, power of 90%, and a randomization ratio of 1:1 between the rogaratinib
and chemotherapy arms for the WT population, and one futility interim analysis of OS 
(paying a slight alpha penalty of 0.001), a total of 390 death events are required for the final 
OS analysis. If the futility stopping boundary for OS is not met at the interim analysis, the 
study will continue after the second interim for the study and the final OS analysis will be 
performed when approximately 390 death events are observed (see Table 10–1).
It is projected that 390 death events will have accumulated approximately 43 months after the 
start of randomization, assuming approximately 450 PIK3CA and RAS WT patients are 
randomized for two treatment arms combined at a rate of 20 patients per month after an initial 
4-month ramp-up period for a 25-month long enrollment period, a dropout rate of 3%, 
exponentially distributed event times for OS, and 7 and 9.76 month median OS time for the 
chemotherapy and the rogaratinib arms, respectively. With the assumption that 75% of the 
patients in the all study population are PIK3CA and RAS WT, roughly 600 patients in all 
study population will be randomized in the two treatment arms combined. 
East Software version 6.4 was used for determination of the sample size.


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10.5
Planned interim analyses
A Data Monitoring Committee (DMC) will be instituted in order to ensure ongoing safety of 
study patients with respect to a risk/benefit assessment during periodic data review meetings, 
review results from the planned interim analysis and provide a formal recommendation for 
continuation/termination of the study and monitor study conduct to ensure the overall 
integrity of trial in maintained.
Before achieving the criteria for the first interim analysis, the study recruitment was put on 
hold after a recommendation of the study DMC. The sponsor decided to perform a full 
analysis and review of all study data and stopped the recruitment permanently. 
Due to the stop of enrollment and full data analysis, the study will not move forward to its 
Phase 3 and will remain as Phase 2. The study will remain open until the survival data is 
considered adequate for analysis by the sponsor.
The details of the two planned interim analyses are provided below as reference to original 
study design. 
Two futility interim analyses were originally planned for this study. 
The first one will be performed at the end of Phase 2 part when the first approximately 116
confirmed FGFR positive patients with wild-type PIK3CA and RAS biomarkers (58 patients 
each arm) complete 4.5 months of treatment. The study will continue with the Phase 3 part if 
the fisher’s exact test for ORR based on central review assessments for the first approximately 
116 WT patients yields a one-sided p-value less than 0.15. The second interim analysis (Phase 
3 part) is planned when approximately 50% of the planned total number of required death 
events occurred in the WT subgroup (about 195 deaths in WT). The study continues if the 
observed HR for OS in WT subgroup is less than 0.96 (corresponding to greater than 4% 
improvement in OS for rogaratinib comparing to chemo), which is determined using O’Brien 
Fleming type boundary based on 195 death events. The actual stopping boundaries for the 
interim analysis will be calculated based on the actual number of events observed up to the 
database cutoff date used for the interim analysis. 
Please note in both interim analyses, only WT subgroup will be analyzed and tested for 
futility. Analyses in all study population, as well as analyses with additional efficacy 
endpoints (such as DoR, PFS, etc. if data warrants) beyond the ones mentioned above as 
futility rules in both populations (defined earlier) will be performed and provided to DMC as 
supplemental information to assist decision making. 
Recommendation for trial continuation will be guided by the monitoring boundaries at the 
formal interim analysis as well as safety evaluations from all data review meetings according 
to the DMC charter. All analyses to be presented to DMC to aid recommendations for trial 
continuation will be explicated in the DMC charter.
The DMC will be explicitly asked to give recommendations on the continuation or 
termination of the trial. Decisions on trial termination, amendment or cessation of patient
recruitment based on risk benefit assessments will be made after recommendations from the 
DMC have been assessed by the sponsor.


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The DMC is scheduled to receive the interim efficacy and safety data. Data which may 
compromise the integrity of the study (e.g., comparative data) will be analyzed and discussed 
only in the closed session of the DMC meetings. The closed session will be restricted to the 
DMC members and a non-voting and independent facilitator (a biostatistician from an 
independent statistical analysis center). Closed session minutes will be maintained by the 
DMC in confidence and will be provided to the sponsor only at completion of the trial. All 
data provided to the DMC and all deliberations of the DMC will be privileged and 
confidential. DMC members will sign Confidentiality Agreements prior to acceptance of 
participating on the DMC committee.
Table 10–1 summarizes the key elements for interim and final analysis based on the number 
of events assumed. The actual monitoring boundaries will depend on the actual number of 
events observed at the time of the interim analysis. Although we take a small alpha penalty of 
0.001 for the first interim at the end of Phase 2, the nominal alpha for the final analysis 
remains the same, 0.025. East Software version 6.4 was used for determination of the study 
monitoring boundaries.
In case of early termination of the study at either interim due to futility, all the analyses 
specified (as appropriate) in Section 10.3 will be performed for the clinical study report 
including all data available at the time of study termination. 
Table 10–1: Summary of planned interim and final analyses 
No. of patients / events
Endpoints
Go criteria for interim (success 
criteria for final)
Population
1st interim
(Phase 2)
approximately 116
confirmed FGFR positive 
patients with wild-type 
PIK3CA and RAS 
biomarkers
ORR
One-sided p-value less than 0.15 WT only 
2nd interim
(Phase 3)
195 events in WT
OS
Observed HR < 0.96 
(4% improvement)a
WT only 
Final 
(Phase 3)
390 events in WT (and 
correspondent No. of 
events in all study 
population)
OS
One-sided p-value less than 
0.025
Sequential 2 steps: 
WT first then all study 
population
FGFR = Fibroblast growth factor receptor; HR = Hazard ratio; No. = Number; ORR = Objective response rate; OS = Overall 
survival; PIK3CA = Phosphoinositide 3-kinase, catalytic subunit alpha isoform; RAS = Rat sarcoma; WT = Wild type.
a: Just an example based on 116 events in WT patient population at interim. The actual futility boundary will depend on the 
actual number of events observed at the time of the interim.
11.
Data handling and quality assurance
11.1
Data recording
The data collection tool for this study will be a validated electronic data capture system called 
RAVE. Patient data necessary for analysis and reporting will be entered/transmitted into a 
validated database or data system (LSH; SAS).
Data required according to this protocol will be recorded by investigational site personnel via 
data entry into the internet based EDC software system RAVE, which Bayer has licensed 


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from Medidata Solutions Worldwide. RAVE has been validated by Medidata Solutions 
Worldwide and Bayer for use in its clinical studies. RAVE allows for the application of 
software logic to set-up data entry screens and data checks to ensure the completeness and 
accuracy of the data entered by the site personnel. Bayer extensively applies the logic to 
ensure data are complete and reflect the clinical data requirements of the study. Data queries 
resulting from the application of the software logic are resolved by the site personnel. The 
data are stored at a secure host facility maintained by Medidata Solutions Worldwide and 
transferred on a periodic basis to Bayer's internal computer system via a secure Virtual Private 
Network.
All access to the RAVE system is through a password-protected security system that is part of 
the RAVE software. All internal Bayer and external investigator site personnel seeking access 
must go through a thorough RAVE training process before they are granted access to RAVE 
for use in Bayer's clinical studies. Training records are maintained. Study-specific RAVE 
training will be provided at the investigator’s meetings, and a study-specific manual (eCRF 
completion guidelines) will be provided to all sites.
All personnel with access to the RAVE system are supported by a Service Desk staffed with 
trained personnel to answer questions and ensure access is maintained such that data entry can 
proceed in a timely manner.
The RAVE System contains a system-generated audit trail that captures any changes made to 
a data field, including who made the change, why the change was made and the date and time 
it was made. This information is available both at the investigator’s site and at Bayer. Data 
entries made in the RAVE EDC screens are supported by source documents maintained for all 
patients enrolled in this study.
Limited data will be recorded for all patients in the FGFR testing period as described in 
Section 9.1. For patients not being eligible for randomization additional information is 
recorded: the reason for premature discontinuation and date of last visit.
Source documentation
The site must implement processes to ensure availability of all required source 
documentation. A source document checklist (not part of this protocol) will be used at the site 
to identify the source data for key data points collected and the monitor will work with the site 
to complete this.
It is the expectation of the sponsor that all data entered into the eCRF have source 
documentation available at the site. 
Data recorded from FGFR testing failures (pre-screening failures)
At minimum, the following data should be recorded in the eCRF for patients who do not meet 
the eligibility criteria during pre-screening:

Date of informed consent(s) that were signed (PI/ICF for FGFR testing)

Subject (patient) identification 


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
Subject (patient) visit and visit date

Inclusion criteria for FGFR testing met (yes / no)

Demographic information (year of birth / age; sex; if applicable race / ethnicity)

Tissue sampling (archival or fresh biopsy) for FGFR testing and PIK3CA and RAS 
mutation testing

ECOG performance status

Toxicity/AE assessment: during the FGFR testing period: AEs/SAEs related to the 
procedure of taking a fresh biopsy for FGFR testing (in case archival tumor tissue is 
not available) the corresponding AE and SAE have to be reported and must be fully 
documented in the source data

End of FGFR testing period, primary reason for discontinuation

Date of last visit 
Data recorded from main screening failures 
At minimum the following data should be recorded in the eCRF for patients who do not meet 
the eligibility criteria during screening:

Date of informed consent that was signed (PI/ICF for study treatment eligibility)

Inclusion/exclusion criteria for screening met (yes / no)

ECOG PS 

Medical history (see Section 9.3.2)

Reason for discontinuation and date of last visit
These data will be transferred to the respective database.
For patients who signed ICF for FGFR testing and who experienced an SAE related to the 
fresh biopsy procedure for FGFR testing, and for screening failures who had signed consent 
for study treatment eligibility and who experienced SAE, the following data should be 
collected in the eCRF in addition to the data specified above:

All information related to the SAE such as: 
- The SAE itself
- Concomitant medication
- Medical history
- Other information needed for SAE complementary page
- Laboratory results related to SAE, if applicable


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Data recorded of prior and concomitant medication
From signing of PI/ICF for study treatment eligibility up to 30 days after the last 
administration of study treatment, all concomitant medications (including start/stop dates, 
dose, frequency, route of administration and indication) must be recorded in the patient’s 
source documentation, as well as on the appropriate pages of the eCRF. At the EOT visit and 
during active and long term follow-up periods, any new systemic anti-cancer therapy has to be 
reported. With regards to other concomitant medications, only those that are administered to 
treat AEs related to study-specific procedures are mandatory to be reported during active 
follow-up. Administration of contrast media for protocol-specified radiological procedures 
(CT scan or MRI) does not need to be reported on the concomitant medication eCRF page, 
unless there is an AE related to the contrast medium injection (e.g. allergic reaction).
11.2
Monitoring
In accordance with applicable regulations, GCP, and sponsor’s procedures, monitors will 
contact the site prior to the start of the study to review with the site staff the protocol, study 
requirements, and their responsibilities to satisfy regulatory, ethical, and sponsor’s 
requirements. When reviewing data collection procedures, the discussion will also include 
identification and documentation of source data items.
The sponsor/designee will monitor the site activity to verify that the:

Data are authentic, accurate and complete.

Safety and rights of patients are being protected

Study is conducted in accordance with the currently approved protocol 
(including study treatment being used in accordance with the protocol)

Any other study agreements, GCP, and all applicable regulatory requirements are met.

Site completes all the logistic and administration tasks required for efficient study 
conduct in a timely manner.
The monitors will be guided by the study team on expected monitoring visit frequency but
these may increase/decrease dependent on the numbers of patients recruited at the site and
outstanding tasks that need completing at each site.
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents.
11.3
Data processing
Data will be collected as described in Section 11.1. Clinical data management will be 
performed in accordance with applicable sponsor’s standards and data cleaning procedures. 
This is applicable for data recorded on eCRF as well as for data from other sources (e.g. IxRS, 
laboratory [FGFR test results]).
For data coding (e.g. AEs, medication), internationally recognized and accepted dictionaries 
will be used.


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After its initial release for analysis (i.e. locked database), the clinical database is planned to be 
re-opened for the inclusion of additional data e.g. pharmacokinetic data, biomarker data. 
11.4
Missing data 
In order to achieve the goal of a well conducted clinical trial according to Good Clinical 
Practice (GCP), every effort should be made to resolve incomplete or missing dates during the 
course of the study (i.e. edit checks, data cleaning / monitoring etc.). However, in rare 
circumstances, missing parts of either date of last contact or the date of death may occur 
where an imputation algorithm will be defined and stated in the Statistical Analysis Plan
(SAP).
Missing or unevaluable tumor assessments (including a scheduled assessment that was not 
done and an incomplete assessment that does not result in an unambiguous tumor response 
according to RECIST v.1.1) will not be used in the calculation of derived efficacy variables 
related to tumor assessments unless a new lesion occurred or the lesions that were evaluated 
already showed progressive disease. No imputation will be performed for missing lesion 
assessment and tumor response. For example, if a patient misses a scan visit and PD is 
documented at the next available scan visit, the actual visit date of the first documented PD
will be used to calculate PFS.
Further information related to the handling of missing parts of a tumor assessment date or last 
contact / death date for the derivation of efficacy endpoints, such as overall survival and 
progression free survival, will be detailed in the SAP.
For handling of missings in the QoL questionnaires, refer to the EORTC QLQ-C30 Scoring 
Manual (32) and the EuroQol EQ-5D User Guide (33), respectively.
11.5
Audit and inspection
To ensure compliance with GCP and regulatory requirements, a member of the sponsor’s (or a 
designated CRO’s) quality assurance unit may arrange to conduct an audit to assess the 
performance of the study at the study site and of the study documents originating there. The 
investigator/institution will be informed of the audit outcome.
In addition, inspections by regulatory health authority representatives and IEC(s)/IRB(s) are 
possible. The investigator should notify the sponsor immediately of any such inspection.
The investigator/institution agrees to allow the auditor or inspector direct access to all relevant 
documents and allocate his/her time and the time of his/her staff to the auditor/inspector to 
discuss findings and any issues. Audits and inspections may occur at any time during or after 
completion of the study.
11.6
Archiving
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request.
Patient (hospital) files will be archived according to local regulations and in accordance with 
the maximum period of time permitted by the hospital, institution or private practice. Where 


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the archiving procedures do not meet the minimum timelines required by the sponsor, 
alternative arrangements must be made to ensure the availability of the source documents for 
the required period.
The investigator/institution notifies the sponsor if the archival arrangements change 
(e.g. relocation or transfer of ownership).
The investigator site file is not to be destroyed without the sponsor’s approval.
The contract with the investigator/institution will contain all regulations relevant for the study 
center.
12.
Premature termination of the study
The sponsor has the right to close this study (or, if applicable, individual segments thereof 
[e.g. treatment arms; dose steps; centers]) at any time, which may be due but not limited to the 
following reasons: 

If risk-benefit ratio becomes unacceptable owing to, for example,
- Safety findings from this study (e.g. SAEs)
- Results of any interim analysis
- Results of parallel clinical studies
- Results of parallel animal studies 
(on e.g. toxicity, teratogenicity, carcinogenicity or reproduction toxicity).

If the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable time 
frame.

Strategic reasons (e.g. the clinical development of the drug is stopped).
The investigator has the right to close his/her center at any time.
For any of the above closures, the following applies:

Closures should occur only after consultation between involved parties. Final decision 
on the closure must be in writing.

All affected institutions (e.g. IEC(s)/IRB(s); competent authority(ies); study center; 
head of study center) must be informed as applicable according to local law.

All study materials (except documentation that has to remain stored at site) must be 
returned to the sponsor. The investigator will retain all other documents until 
notification is given by the sponsor for destruction.

In the event of a partial study closure, ongoing patients, including those in post study 
follow-up, must be taken care of in an ethical manner.
Details for individual patient's withdrawal can be found in Section 6.4.1.


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13.
Ethical and legal aspects
13.1
Investigator(s) and other study personnel
Sponsor’s Medical Expert
Name:
Address:
Bayer U.S. LLC
100 Bayer Blvd, PO Box 915
Whippany, NJ, 07981 USA
Telephone no.: 
Email:
Coordinating investigators
Name:
Title:
Address:
 USA
Telephone no.:
  and 
Fax no.: 
Name:
Title:
Address:
USA
Telephone no.:
Fax no.: 
All other study personnel not included in this section are identified in a separate personnel list 
(not part of this clinical study protocol) as appropriate. This list will be updated as needed; an 
abbreviated version with personnel relevant for the centers will be available in each center’s 
investigator site file.
Whenever the term ‘investigator’ is noted in the protocol text, it may refer to either the 
principal investigator at the site, or an appropriately qualified, trained and delegated 
individual of the investigational site.
The principal investigator of each center must sign the protocol signature page and must 
receive all required external approvals (e.g. health authority, ethics committee, sponsor) 
before patient recruitment may start at the respective center. Likewise, all amendments to the 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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protocol must be signed by the principal investigator and must have received all required 
external approvals before coming into effect at the respective center.
A complete list of all participating centers and their investigators, as well as all required 
signature documents, will be maintained in the sponsor’s study file.
The global sponsor of this study is identified on the title page of this protocol. If required by 
local law, local co-sponsors will be nominated; they will be identified on the respective 
country-specific signature pages.
External data evaluation bodies
Data Monitoring Committee (DMC)
DMC will be instituted in order to ensure ongoing safety of study patients through a 
risk/benefit assessment during periodic data review meetings and to monitor study conduct to 
ensure that the overall integrity of the trial is maintained.
The DMC will include at least 3 members, including an independent statistician and 
oncologists. The DMC will operate independently of the sponsor and investigators. Data
review meetings will be held periodically as per separate DMC charter. Enrollment to the 
study will continue throughout the scheduled meetings of the DMC. 
The DMC will review the result of the scheduled interim analyses as described in 
Section 10.5, and determine whether to recommend stopping the study for futility per protocol 
criteria.
Decisions on trial termination, amendment, or cessation of patient recruitment based on 
risk/benefit assessment will be made after recommendations from the DMC have been 
assessed by the sponsor.
Steering Committee (SC)
A Steering Committee will support the sponsor during the conduct of the study in all aspects 
of safety and efficacy. 
Central laboratory
PK and biomarker (FGFR expression, PIK3CA and RAS mutation and additional 
blood/tumor-based biomarker) tests will be performed centrally. Further details will be 
provided in the Laboratory Manual.
13.2
Funding and financial disclosure
Funding
This study will be funded by its sponsor.
Financial disclosure 
Each investigator (including principal and/or any sub investigators) who is directly involved 
in the treatment or evaluation of research patients has to provide a financial disclosure 


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according to all applicable legal requirements. All relevant documentation will be filed in the 
trial master file.
13.3
Ethical and legal conduct of the study
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigator abide by 
Good Clinical Practice (GCP) guidelines and the guiding principles detailed in the 
Declaration of Helsinki. The study will also be carried out in keeping with applicable local 
law(s) and regulation(s).
Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating 
centers/countries before start of the study, according to GCP, local laws, regulations and 
organizations. When necessary, an extension, amendment or renewal of the IEC/IRB approval 
must be obtained and also forwarded to the sponsor. The responsible unit (e.g. IEC/IRB, head 
of the study center/medical institution) must supply to the sponsor, upon request, a list of the 
IEC/IRB members involved in the vote and a statement to confirm that the IEC/IRB is 
organized and operates according to GCP and applicable laws and regulations.
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol. 
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties. However, the investigator or the sponsor may 
implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) 
to the trial patients without prior IEC/IRB/sponsor approval/favorable opinion. As soon as 
possible, the implemented deviation or change, the reasons for it and if appropriate the 
proposed protocol amendment should be submitted to the IEC/IRB/head of medical 
institution/sponsor. Any deviations from the protocol must be explained and documented by 
the investigator.
Details on discontinuation of the entire study or parts thereof can be found in Section 12.
13.4
Patient information and consent
13.4.1
PI/ICF for FGFR testing
A patient information and informed consent form (PI/ICF) with brief study information on the 
study will be provided to patients with locally advanced or metastatic urothelial carcinoma
who would like to participate in this study. A sample PI/ICF for the FGFR testing is provided 
as a separate document to this protocol.
The PI/ICF for the FGFR testing includes the general aspects of the study conduct, details on 
the tumor samples required to be taken to perform the FGFR testing in all patients, PIK3CA
and RAS mutation testing in all FGFR-positive patients and exploratory biomarker analyses 
in randomized patients along with information on any trial risks from the fresh biopsy 
sampling (this applies only in case archival tumor sample is not available).


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The patient has the right to ask the investigator to explain the study in detail and has the right 
to refuse his/her participation at any time without giving a reason.
13.4.2
PI/ICF for study treatment eligibility
A PI/ICF for study treatment eligibility will be provided to the patient who is confirmed to 
have FGFR1 or 3 positive urothelial carcinoma and still has interest to participate in this study, 
no longer than 28 days prior to randomization to study treatment.
All relevant information on the study will be summarized in an integrated patient information 
sheet and informed consent form provided by the sponsor or the study center. A sample 
patient information and informed consent form is provided as a document separate to this 
protocol.
Based on this patient information sheet, the investigator or designee will explain all relevant 
aspects of the study to each patient / legal representative or proxy consenter (if the patient is 
under legal protection), prior to his/her entry into the study (i.e. before any examinations and 
procedures associated with the selection for the study are performed or any study-specific data 
is recorded on study-specific forms).
The investigator will also mention that written approval of the IRB/IEC has been obtained.
Each patient / legal representative or proxy consenter will be informed about the following 
aspects of premature withdrawal:

Each patient has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision. 

The patient’s consent covers end-of-study examinations as specified in the visit 
description described in Section 9.2 to be conducted after withdrawal of consent. 

The patient’s data that have been collected until the time of withdrawal will be 
retained and statistically analyzed in accordance with the statistical analysis plan. 

Patient-specific data on the basis of material obtained before withdrawal may be 
generated after withdrawal (e.g. image reading, analysis of biological specimen such 
as blood, urine or tissues); these data would also be retained and statistically analyzed 
in accordance with the statistical analysis plan. The patient has the right to object to 
the generation and processing of this post-withdrawal data. The patient’s oral 
objection may be documented in the patient’s source data.
Each patient / legal representative or proxy consenter will have ample time and opportunity to 
ask questions.
Only if the patient / legal representative or proxy consenter voluntarily agrees to sign the 
informed consent form and has done so, may he/she enter the study. Additionally, the 
investigator / delegate will personally sign and date the form. The patient / legal 
representative or proxy consenter will receive a copy of the signed and dated form.
The signed informed consent statement is to remain in the investigator site file or, if locally 
required, in the patient’s note/file of the medical institution.


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In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or patient’s clinical record must clearly show that informed 
consent was obtained prior to these procedures.
1. If the patient is not capable of providing a signature, a verbal statement of consent can 
also be given in the presence of an impartial witness (independent of the sponsor and 
the investigator). This is to be documented by a signature from the informing 
physician as well as by a signature from the witness.
2. Adults under legal protection, consent shall be given by the legal guardian(s). The 
consent of an adult under legal protection shall also be requested where such a person 
is able to express his/her own will. His/her refusal or the withdrawal of his/her consent 
may not be disregarded.
3. In emergency situations, when prior consent of the patient is not possible, the consent 
of the patient’s legal representative(s) or proxy consenter, if present, should be 
requested. The patient should be informed about the study as soon as possible and 
his/her consent to continue the study should be requested.
The informed consent form and any other written information provided to patients / legal 
representatives or proxy consenters will be revised whenever important new information 
becomes available that may be relevant to the patient’s consent, or there is an amendment to 
the protocol that necessitates a change to the content of the patient information and / or the 
written informed consent form. The investigator will inform the patient / legal representative 
or proxy consenter of changes in a timely manner and will ask the patient to confirm his/her 
participation in the study by signing the revised informed consent form. Any revised written 
informed consent form and written information must receive the IEC/IRB’s approval / 
favorable opinion in advance of use.
13.4.3
PI/ICF for collection of data on pregnancy and birth
A PI/ICF for collection of data on pregnancy and birth will be used for fertile male patients 
whose female partner becomes pregnant. The PI/ICF will be signed by the male study patient 
and their pregnant female partner in case of pregnancy. The consent for the collection of data 
on pregnancy and birth in case a female study patient becomes pregnant is covered in the 
PI/ICF for study treatment eligibility.
13.4.4
PI/ICF on study updates
A PI/ICF on study updates may be used for update information (e.g. if new safety information 
is available) - for patients who are already participating in the study.
13.5
Publication policy and use of data
The sponsor has made the information regarding the study protocol publicly available on the 
internet at www.clinicaltrials.gov. 
The sponsor is interested in the publication of the results of every study it performs.


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All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the sponsor who may utilize them in various ways, such as for 
submission to government regulatory authorities or disclosure to other investigators.
Regarding public disclosure of study results, the sponsor will fulfill its obligations according 
to all applicable laws and regulations. The sponsor is interested in the publication of the 
results of every study it performs.
The sponsor recognizes the right of the investigator to publish the results upon completion of 
the study. However, the investigator, whilst free to utilize study data derived from his/her 
center for scientific purposes, must obtain written consent of the sponsor on the intended 
publication manuscript before its submission. To this end, the investigator must send a draft 
of the publication manuscript to the sponsor within a time period specified in the contract.
The sponsor will review the manuscript promptly and will discuss its content with the 
investigator to reach a mutually agreeable final manuscript.
All relevant aspects regarding publication will be part of the contract between the sponsor and 
the investigator/institution. 
13.6
Compensation for health damage of patients / insurance
The sponsor maintains clinical trial insurance coverage for this study in accordance with the 
laws and regulations of the country in which the study is performed.
13.7
Confidentiality
All records identifying the patient will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available.
Patient names will not be supplied to the sponsor. Only the patient number will be recorded in 
the eCRF, and if the patient name appears on any other document (e.g. pathologist report), it 
must be obliterated before a copy of the document is supplied to the sponsor. Study findings 
stored on a computer will be stored in accordance with local data protection laws. As part of 
the informed consent process, the patients will be informed in writing that representatives of 
the sponsor, IEC/IRB, or regulatory authorities may inspect their medical records to verify the 
information collected, and that all personal information made available for inspection will be 
handled in strictest confidence and in accordance with local data protection laws.
If the results of the study are published, the patient’s identity will remain confidential.
The investigator will maintain a list to enable patients to be identified.


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of advanced urothelial carcinoma: a retrospective analysis of pooled, prospective 
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15.
Protocol amendments
15.1
Amendment no.3
Amendment no.3 is a global amendment forming integrated protocol version 2.0, dated 09 
MAY 2019.
Overall rationale for the amendment
The protocol was amended in response to issues brought up by DMC, Health Authorities, 
IRBs, and investigators at sites. These changes will allow for clarification of topics and enable 
better accrual at sites.
Changes to the protocol text
Changes to the protocol text are provided in a separate track-changes version.
High-level description of the changes and the affected sections are listed in the table below.
Section # and Name
Description of Change
Brief Rationale
2. Synopsis, 5.2.2 Treatment 
period, 5.4 Justification of the 
design, 6.4.1.3 Withdrawal 
criteria, 7.4.1 Doses, dosing 
schedule and route of 
administration, 7.4.3.1 Dose 
modifications of rogaratinib, 
7.4.3.1.2 Liver toxicity
Maximum planned dose is 
reduced to 600 mg b.i.d. from 
800 mg b.i.d.
Dose levels and dose 
modifications are modified 
accordingly.
The maximum dose is reduced 
as per DMC recommendation 
for study 17403. The range of 
rogaratinib plasma exposures 
after 600 mg b.i.d. and 800 mg 
b.i.d. are expected to be 
similar however with an 
expected safer tolerability at 
600 mg b.i.d.
2. Synopsis, 5.1 Design 
overview, 5.6 Primary 
completion 10.1 General 
considerations, 10.3.1.1 
Primary efficacy variable, 
10.3.1.2 Secondary efficacy 
variables, 10.4 Determination 
of sample size, 10.5 Planned 
interim analyses
Sample size for 2nd interim 
analysis and final analysis is 
updated.
A sensitivity analysis is added 
for OS.
Due to inter-evaluator 
variability in the scoring of 
FGFR test, the sample size is 
changed in order to increase 
the study power. 
2 Synopsis, 6.1 Inclusion 
criteria
The requirement of cytological 
confirmation of urothelial 
carcinoma is removed from the 
inclusion criteria. 
Applicable tumor classification is 
revised. 
Cytological confirmation is not 
accepted in all countries to 
confirm tumor diagnosis and 
data may not be robust 
enough.
Stage T4b is applicable only 
for bladder, but not applicable 
for renal, pelvis and ureters 
and uretha (only T4).


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Section # and Name
Description of Change
Brief Rationale
6.1 Inclusion criteria
Additional wording is added in 
the contraception criterion.
Additional wording was 
requested by health authorities 
and ethics committees to align 
with the SmPC of the 
chemotherapy drugs.
6.2 Exclusion criteria
Exclusion criterion for active 
symptomatic or untreated brain 
metastases is modified: detailed 
clarification is added for patients 
with asymptomatic brain 
metastases. Time frame from 
completion of CNS directed 
therapy to first study drug intake 
is shortened to 12 weeks.
In order to provide detailed 
clarification considering 
patients with asymptomatic 
brain metastases to be 
included in this study and to 
give possibility to treat patients 
with stable and asymptomatic 
brain metastases earlier.
2 Synopsis, 6.2 Exclusion 
criteria
Exclusion criterion regarding 
more than two prior lines of 
systemic anti-cancer therapy for 
urothelial carcinoma is clarified.
Wording is added to further 
clarify that the two lines of prior 
systemic anticancer therapy is 
limited to advanced 
unresectable/metastatic 
disease.
6.2 Exclusion criteria
Immunotherapy is added to the 
definition of prior anti-cancer 
therapy.
To further clarify the criterion.
6.2 Exclusion criteria
An exception is added to 
exclusion criterion #19: 
prophylactic antiviral treatment 
of chronic hepatitis B (e.g. 
entecavir) is allowed.
Standard of care in several 
countries.
5.5 End of study, 7.2 Identity of 
study treatment, 8.2 Post-study 
therapy, 10.1 General 
considerations, 12. Premature 
termination of the study
Protocol is modified to introduce 
a roll-over study.
A roll-over study is introduced 
to allow a possibility to 
continue study treatment 
and/or follow-up in a separate 
study when this trial is stopped 
but benefits are observed for 
individual patients and/or 
follow up of patients is needed.
2 Synopsis, 7.1 Treatments to 
be administered, 
7.2.2 Chemotherapy 
(comparator drugs), 
7.3 Treatment assignment
Treatment guidelines in the 
given country are added to be 
considered when choosing the 
chemotherapy.
To allow treatment of patients 
randomized to the 
chemotherapy arm according 
to local guidance even though 
the drug is not approved in any 
indication in the respective 
country but used as standard 
of care defined by local 
guidance.


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Section # and Name
Description of Change
Brief Rationale
7.2.2 Chemotherapy 
(comparator drugs), 
7.4.3.2 Dose modifications of 
chemotherapy (comparator 
drugs)
Text is added to emphasize 
additional considerations for the 
use of taxanes (docetaxel, 
paclitaxel) and vinflunine 
according to local guidelines.
Local health authorities and 
ethic committees requested, 
that local guidelines should be 
followed for the use of the 
chemotherapy drugs.
9.7.1 Biomarker investigations
Wording is added to clarify that 
tumor material should be 
derived by a biopsy procedure 
associated with a non-significant 
risk and no major organ should 
be biopsied.
To clarify the tumor biopsy 
procedure for biomarker 
testing and to align with the 
wording provided by FDA.
5.2.2 Treatment period
Wording is added to clarify that 
in cases when PIK3CA and/or 
RAS genetic testing results are 
not available before 
randomization, those patients 
with unknown mutation status 
prior to randomization will be 
grouped into the mutation 
“presence” strata in the 
randomization process.
To clarify the stratification of 
PIK3CA/RAS unknown 
patients in the randomization 
process.
3.2.2 Clinical experience with 
rogaratinib, 3.5 Benefit-risk 
assessment, 7.4.3.1 Dose 
modifications of rogaratinib 
(Table 7-3), 
7.4.3.1.1 Hyperphosphatemia, 
9.1 Tabular schedule of 
evaluations, 9.2.1.2 Screening, 
9.2.2.1 Day 1 of Cycle 1, 
9.2.2.2 Day 8 of Cycle 1, 
9.2.2.3 Day 15 of Cycle 1, 
9.2.2.4 Day 1 of Cycle 2, 
9.2.2.5 Day 15 of Cycle 2, 
9.2.2.6 Day 1 of Cycle ≥ 3, 
9.2.2.8 End-of-treatment (EOT) 
visit, 9.2.3.1 Active follow-up, 
9.6.3.1 Laboratory evaluations, 
9.6.3.3 12-lead ECG
Content relevant to dose 
modifications of rogaratinib and 
management for 
hyperphosphatemia is updated.
The management rules for 
hyperphosphatemia are 
modified to reflect the current 
benefit-risk profile of 
rogaratinib and to anticipate 
the “real life” use in the post-
marketing setting.
8.1 Prior and concomitant 
therapy
Concomitant therapies are 
modified to allow continuation of 
bisphophonates and 
denosumab which has been 
started prior to start of study 
treatment but to prohibit start of 
treatment with these drugs 
during the study treatment.
Continuation of supportive 
treatment with denosumab and 
biphophonates should be 
allowed as concomitant 
therapy for patients with bone 
metastases if they have been 
started prior to study treatment 
as these are considred 
standard of care. 


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Section # and Name
Description of Change
Brief Rationale
8.1 Prior and concomitant 
therapy
An exception is added to 
prohibited concomitant 
radiotherapy: a short course of 
radiotherapy due to a 
pathological fracture is allowed 
if the underlying bone lesion is 
not considered as target lesion.
A short course of radiotherapy 
during study treatment due to 
pathological fracture is allowed 
as concomitant therapy, if 
medically needed for 
stabilization of the fracture.
8.1 Prior and concomitant 
therapy
Biotin-containing supplements 
containing more than 30 µg 
daily dose of biotin are added to 
prohibited concomitant 
medication.
Added as per FDA safety 
communication about potential 
interference between 
laboratory tests and drugs that 
contain > 30 µg daily dose of 
biotin.
9.1 Tabular schedule of 
evaluations, 9.2.2.6 Day 1 of 
Cycle ≥ 3, 9.6.3.3 12-lead ECG
Post-dose 12-lead ECG beyond 
cycle 5 is removed.
To lessen the burden for the 
patient. Evaluation of the 
relationship between PK and 
ECG results is only necessary 
up to Cycle 5, after which 
single ECGs only for safety 
reasons are sufficient.
6.4.1.3 Withdrawal criteria, 
9.2.3.1 Active follow-up
Wording is added for PD 
confirmation read by 
independent central imaging 
review.
Clarification to explain the role 
of central PD confirmation 
review.
9.1 Tabular schedule of 
evaluations, 9.2.1.2 Screening, 
9.4.1 Radiological tumor 
assessments.
Requirement of contrast 
enhanced (unless 
contraindicated) CT/MRI scans 
and strong recommendation of 
acquisition of both contrast 
enhanced and unenhanced 
scans for brain imaging at 
screening are added. Reference 
to Image Acquisition Guidelines 
is added.
Acquisition of contrast 
enhanced images is required 
and acquisition of both contrast 
enhanced and unenhanced 
brain images is strongly 
recommended considering 
MRI (or CT) of the brain is 
mandatory at screening to 
exclude active symptomatic or 
untreated brain metastases. 
9.1 Tabular schedule of 
evaluations, 9.2.1.2 Screening, 
9.2.2.1 Day 1 of Cycle 1, 
9.2.2.4 Day 1 of Cycle 2, 
9.2.2.6 Day 1 of Cycle ≥ 3, 
9.2.2.8 End-of-Treatment 
(EOT) visit, 9.2.3.1 Active 
follow-up, 9.6.3.1 Laboratory 
evaluations
Hormones are moved from the 
full clinical chemistry panel to a 
separate hormone panel.
To be in alignment with the 
eCRF and the protocol 
standards.


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Section # and Name
Description of Change
Brief Rationale
9.1 Tabular schedule of 
evaluations, 9.6.3.1 Laboratory 
evaluations
Urinalysis is changed from 
laboratory urinalysis to urine 
chemistry test, and for blood in 
urine it was made more flexible 
to measure RBC or hemoglobin.
The method for urinalysis is 
made more flexible as 
laboratory analysis of all 
parameters can not be done 
quantitatively in local 
laboratories in all countries. 
9.1 Tabular schedule of 
evaluations 
A footnote hh was added to 
clarify that procedures can be 
performed at unscheduled time 
points if deemed clinically 
necessary by the investigator.
To further clarify the 
opportunity to schedule any 
assessments or procedures at 
unscheduled timepoints 
outside the protocol time 
frames, to assess the safety of 
the patient if medically needed.
7.4.3.1.2 Liver toxicity
Wording is added to clarify that 
monitoring of liver function tests 
will be done throughout study 
treatment.
For further clarification.
9.6.1.6 Adverse events of 
special safety interest, 
9.6.3.6 Ophthalmological 
examination, 9.6.3.3 12-lead 
ECG
Wording is modified to ensure 
that examination findings/ 
results will be documented in 
the source documents and in 
the eCRF. 
For clarification and 
consistency.
6.4.1.3 Withdrawal criteria, 
7.4.3.1.3 Retinal disorders
The definition of dose limiting 
toxicity for visual acuity 
decrease is clarified. Clinical 
evaluation of patients with low 
visual acuity at baseline to 
determine the maintenance in 
the study is added.
To take into account the visual 
acuity at baseline and allow 
investigators more flexibility to 
perform an individual 
benefit/risk assessment of 
patients at higher risk of 
developing retinal disorders.
2 Synopsis, 5.1 Design 
overview (Figure 5-1), 
5.2.1 Pre-treatment period, 
9.1 Tabular schedule of 
evaluations, 9.2.1.1 FGFR 
testing, 9.7.1 Biomarker 
investigations, 13.4.1 PI/ICF 
for FGFR testing
Relevent content is modified to 
clarify that PIK3CA and/or RAS 
activating mutations will be 
tested only in FGFR-positive 
patients.
Only an FGFR-positive patient 
can be enrolled on rogaratinib. 
If we would perform the 
PIK3CA/RAS mutation testing 
in parallel to the FGFR test, we 
would waste the FFPE slides 
needed for mutation testing 
from about 50 % of the 
screening population that is 
expected to be FGFR-
negative. In times where more 
and more targeted therapies 
need any kind of pre-selection 
biomarker; we would limit the 
chance of these FGFR-
negative patients to have a 
sufficient amount of FFPE 
slides available for other 


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Section # and Name
Description of Change
Brief Rationale
experimental or standard 
therapies.
13.4.3 PI/ICF for collection of 
data on pregnancy and birth
Wording regarding PI/ICF for 
collection of data on pregnancy 
and birth is modified.
Wording is modified as PI/ICF 
for collection of data on 
pregnancy and birth is only 
used for fertile male patients 
and their female partner in 
case of pregnancy.
9.5 Pharmacokinetics / 
pharmacodynamics
It is further clarified that the 
morning dose of rogaratinib 
must be taken under 
supervision of site staff on 
rogaratinib PK days.
For further clarity.
3.2.2 Clinical experience with 
rogaratinib, 3.4 Rationale of 
the study, 3.5 Benefit-risk 
assessment
Detailed information about 
clinical studies with rogaratinib 
are deleted or updated based 
on the new IB.
Details about rogaratinib 
studies and clinical experience 
are omitted to avoid the need 
to amend the protocol each 
time when IB is updated. All 
details can be found from the 
most recent version of the IB 
for rogaratinib.
9.2.2.1 Day 1 of Cycle 1
Wording is modified to state that 
the procedures that have been 
performed at screening within 3 
days prior to start of study drug 
treatment (rather than of 
randomization) do not need to 
be repeated on Cycle 1 Day 1 
(with exception to blood 
pressure, heart rate and body 
temperature).
Amended to avoid 
inappropriately long time 
periods between screening 
safety assessments and start 
of study drug treatment.
9.2.2.7 Tumor assessments 
during treatment period, 
9.4.1 Radiological tumor 
assessments
Wording is modified to clarify 
that in order to achieve a valid 
response of stable disease, a 
minimum of at least 6 weeks 
from start of treatment is 
mandatory for the 1st “on 
treatment” tumor assessment, 
and to allow an imaging scan at 
an earlier time point in 
exceptional cases when 
deemed clinically necessary by 
the investigator due to safety 
reasons.
To emphasize that a minimum 
of at least 6 weeks from start 
of treatment is required for the 
1st “on treatment” tumor 
assessment in order to achieve 
a valid response of stable 
disease and to allow an 
imaging scan at an earlier time 
point if deemed clinically 
necessary due to safety 
reasons.


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Section # and Name
Description of Change
Brief Rationale
Title page, Signature of the 
sponsor’s medically 
responsible person, 13.1 
Investigator(s) and other study 
personnel
Sponsor’s medical expert and 
sponsor’s medically responsible 
person are changed. 
The contact details of one of the 
coordinating investigators are 
updated.
Reorganization of sponsor’s 
medical team.
To provide up-to-date contact 
details.
16.4 Estimated glomerular 
filtration rate (eGFR) 
calculation
A website link is added to a 
GFR calculator.
To make the calculation of 
GFR easier for the sites.
2. Synopsis, 5.1 Design 
overview, 5.2.1 Pre-treatment 
period, 5.4 Justification of the 
design, 6. Study population, 
6.1 Inclusion criteria, 
6.4.1.1 Screening failure, 
9.2.1.2 Screening, 
9.7.1 Biomarker investigations
The references for RNAscope 
method and score for analysis 
of FGFR1 or 3 mRNA 
expression levels are removed.
To provide flexibility to adapt 
technology if necessary.
2. Synopsis, 9.7.1 Biomarker 
investigations
The reference to PCR method 
for PIK3CA/RAS analysis is 
removed.
To provide flexibility to adapt 
technology if necessary.
2. Synopsis, 5.1 Design 
overview, 10.4 Determination 
of sample size, 10.5 Planned 
interim analyses
Wording is added to clarify that 
approximately 116 confirmed 
FGFR positive patients are 
needed for first interim analysis.
Due to inter-evaluator 
variability in the scoring of 
FGFR test.
10.1 General considerations
A confirmation test may be 
performed to identify confirmed 
FGFR positive patients.
Due to inter-evaluator 
variability in the scoring of 
FGFR test.
10.5 Planned interim analyses
P-value criterion for interim 
analysis is increased from less 
than 0.1 to less than 0.15.
To re-power the study due to 
inter-evaluator variability.
10.5 Planned interim analyses
Wording is added to clarify that 
additional data may be provided 
to the DMC at all planned 
analysis points.
To provide a totality of 
information to the DMC to 
enable them to make 
decisions.
9.1 Tabular schedule of 
evaluations, 9.2.2.1 Day 1 of 
Cycle 1, 9.2.2.4 Day 1 of Cycle 
2, 9.2.2.6 Day 1 of Cycle ≥ 3, 
9.6.3.3 12-lead ECG
Wording is modified to clarify, 
that for patients on the 
rogaratinib treatment arm, the 
ECGs can be performed 
together with required PK blood 
sampling.
The previous wording referred 
to both treatment arms but this 
is not applicable to the 
chemotherapy arm as no PK 
samples are taken.


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Section # and Name
Description of Change
Brief Rationale
9.2.2.2 Day 8 of Cycle 1, 
9.2.2.3 Day 15 of Cycle 1, 
9.2.2.5 Day 15 of Cycle 2
Wording is modified to clarify 
the timing of the assessments.
The previous wording referred 
to both treatment arms but this 
is not applicable to the 
chemotherapy arm as the 
chemotherapy treatment is not 
administred that day.
9.2.2.2 Day 8 of Cycle 1,
9.2.2.3 Day 15 of Cycle 1,
9.2.2.4 Day 1 of Cycle 2, 
9.2.2.5 Day 15 of Cycle 2, 
9.2.2.6 Day 1 of Cycle ≥ 3
Laboratory procedures are 
allowed to be performed within 3 
days prior to the visit
To allow sites more flexibility.
9.1 Tabular schedule of 
evaluations, 9.2.3.1 Active 
follow-up 
Wording was added to allow 
combination of EOT and Safety 
follow up visits 
To allow sites more flexibility
and prevent unnecessary 
burden to the patient.
11.1 Data recording
Wording is modified to clarify 
that data are recorded from pre-
screening failures and main 
screening failures. 
Requirements of the data to be 
recorded to eCRF are reduced. 
Simplification of the data to be 
recorded to eCRF.
2. Synopsis, 5.2.1 Pre-
treatment period, 6. Study 
population, 6.1 Inclusion 
criteria, 9.1 Tabular schedule 
of evaluations, 9.2.1.1 FGFR 
testing
Time window for FGFR testing 
of patients prior to start of 
screening is removed. Inclusion 
criteria 2 and 3 were combined.
To relax inclusion criteria by 
allowing longer time from 
FGFR testing to start of 
screening.
7.4.3.1 Dose modifications of 
rogaratinib
Wording on the cycle duration is 
modified to state that cycle 
duration will be 21 days instead 
of 21 days of treatment with 
rogaratinib and delays but not 
interruptions will prolong the 
duration of a cycle.
To reflect the standard practice 
in oncology trials.
6.4.1.1 Screening failure, 
6.4.1.2 Re-screening
Patients who have signed the 
pre-screening informed consent 
and have not completed the 
FGFR test are regarded as 
screening failures, but can be 
tested for FGFR expression.
Flexible timelines for FGFR 
tests were suggested per 
feasibility evaluation in order to 
increase the study recruitment.
10.3.1.3 Subgroup analyses
Details of geographic regions 
are removed. 
The geographic regions will be 
detailed in SAP.
9.7.1 Biomarker investigations
FGFR DNA alterations were 
added in the list of examples for
exploratory biomarker analysis.
To further clarify exploratory 
analysis.


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In addition, editorial and administrative changes have been made throughout the document for 
clarity and consistency.
15.2
Amendment no.4
Amendment no.4 is a global amendment forming integrated protocol version 3.0, dated 12 
NOV 2019.
Overall rationale for the amendment
The protocol was amended to reflect the decision of stopping the study enrollment at its Phase 
2 and to add OS as exploratory efficacy variable to the Phase 2.
Changes to the protocol text
Changes to the protocol text are provided in a separate track-changes version.
High-level description of the changes and the affected sections are listed in the table below.
Section # and Name
Description of Change
Brief Rationale
Changes to the Study Conduct
2. Synopsis
5.1 Design overview
5.6 Primary completion
10.1 General considerations
10.3.1.1 Primary efficacy 
variable
10.4 Determination of sample 
size
10.5 Planned interim analyses
Before achieving the criteria for 
the first interim analysis, the 
study recruitment was put on 
hold after a recommendation of 
the study DMC. The sponsor 
decided to stop the recruitment 
permanently and perform a full 
analysis and review of all study 
data. 
Due to the stop of enrollment, 
the study will not move forward 
to its Phase 3 and will remain as 
Phase 2. The study will remain 
open until the survival data is 
considered adequate for 
analysis by the sponsor.
Clarifications are added to
explain the above and to
separate the plans for Phase 2 
and Phase 3 more clearly, while 
details of originally planned 
study design and analyses are 
kept.
In the original design of the 
study, the Phase 2 part was 
expected to end at the time of 
the cut-off for the 1st interim 
analysis. However, the 
sponsor decided to perform an 
ad hoc full analysis and review 
of all study data and stop the 
study enrollment before the 1st
interim analysis cut-off was 
reached. Therefore the study 
will not continue to Phase 3.
The study will remain open as 
a Phase 2 study until the 
survival data is considered 
adequate for analysis by the 
sponsor.


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Section # and Name
Description of Change
Brief Rationale
5.5 End of study,
7.2 Identity of study treatment
8.2 Post-study therapy
Added that patients can 
continue receiving rogaratinib 
treatment in a post-trial access 
program and LPLV can also be 
reached based on the last 
patient changing to a post-trial 
access program.
To offer additional flexibility.
Changes in planned analyses
2. Synopsis
4. Study objectives
5.3 Primary variable
9.4 Efficacy
10.3.1.1 Primary efficacy 
variable
10.3.1.2 Secondary efficacy 
variables
10.3.1.3 Subgroup analyses
10.5 Planned interim analyses
The primary efficacy variable is 
updated as ORR for Phase 2 
part and OS for Phase 3 part of 
the study. OS is considered an 
exploratory efficacy variable for 
the Phase 2 part and will be 
analyzed when the survival data 
is considered adequate for 
analysis by the sponsor. Minor 
modifications in text regarding 
secondary efficacy variables 
PFS, DCR and DOR are made 
accordingly.
Efficacy variables are updated 
as the study remains open as 
Phase 2 study.
10.3.3.3 Patient-reported 
outcomes (PRO)
Primary analysis of PROs will 
be done if there is sufficient 
data.
Due to stop of enrollment, the 
data may not be sufficient to 
conduct the analysis as 
originally planned.
Other changes
1. Title page
13.1. Investigator(s) and other 
study personnel
The contact information of 
sponsor’s medical expert is 
updated.
To provide up-to-date contact 
details.
3.2.2 Clinical experience with 
rogaratinib
Details of clinical experience 
with rogaratinib are deleted and 
the IB for rogaratinib is referred 
to for details.
Updated reference to the latest 
IB.
3.5 Benefit-risk assessment
Added that the results of the full 
review and analysis of FORT-1 
data (cut-off date of 14 JUN 19) 
were also consistent with the 
known safety profile of 
rogaratinib.  
To provide the latest
information relevant to benefit-
risk assessment.


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In addition, editorial and administrative changes have been made throughout the document for 
clarity and consistency.
16.
Appendices
16.1
CYP3A4 inhibitors and inducers
Table 16–1 below provides an overview of strong CYP3A4 inhibitors and inducers.
Table 16–1: Strong CYP3A4 inhibitors and inducers
Strong CYP3A4 inhibitors
Strong CYP3A4 inducers
boceprevir
clarithromycin
cobicistat
conivaptan
danoprevir and ritonavir
diltiazem
elvitegravir and ritonavir
grapefruit juice
idelalisib
indinavir and ritonavir
itraconazole
ketoconazole
lopinavir and ritonavir 
nefazodone
nelfinavir
paritaprevir and ritonavir and (ombitasvir 
and/or dasabuvir)
posaconazole
ritonavir
saquinavir and ritonavir
telaprevir
tipranavir and ritonavir
troleandomycin
voriconazole
carbamazepine
enzalutamide
mitotane
phenytoin 
rifampin
St. John’s Wort
CYP3A4 = Cytochrome P450, family 3, subfamily A, polypeptide 4.
Source (34)
16.2
Response Evaluation Criteria in Solid Tumors (RECIST)
Response and progression will be evaluated in this study using the international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (28). 
Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are 
used in the RECIST v.1.1.
Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are 
used in the RECIST v.1. 1. Rules described in the following for CT are equally valid for MRI.
Measurable disease
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:


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
10 mm by CT scan (CT scan slice thickness no greater than 5 mm)
Chest X-ray will not be accepted in the study, Spiral-CT should be conducted.
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 Schwartz et al. in this special issue (35)). See also notes 
below on ‘Baseline documentation of target and non-target lesions’ for information on lymph 
node measurement.
Non-measurable disease
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 or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques.
Bone lesions, cystic lesions and lesions previously treated with local therapy require particular 
comment:
Bone lesions:

Lytic bone lesions, with an identifiable soft-tissue component, evaluated by CT or MRI
can be considered as measurable lesions if the soft-tissue component otherwise meets the 
definition of measurability

Blastic bone lesions are non-measurable
Cystic lesions:

Lesions that meet radiographic criteria for simple cysts should not be considered 
malignant lesions (neither measurable nor non-measurable)

“Cystic lesions” thought to be cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability. However, if non-cystic lesions are present in 
the same patients, these should be preferably selected for assessment
Lesions with prior local treatment:

Tumor lesions situated in a previously irradiated area, or in an area patiented to other 
loco-regional therapy, are usually not considered measurable. Previously treated lesions 
can only be selected as target lesions when they have progressed until baseline.
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 


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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. 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 diameters. If lymph nodes are to be included in the sum, then as noted above, 
only the short axis is added into the sum. The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable dimension 
of the disease.
Non-target lesions
All other lesions (or sites of disease) including pathological lymph nodes (with short axis 
≥10 mm and < 15 mm) 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’).
Best Response: The best overall response is the best response recorded from the start of the 
study treatment until the end of treatment. The patient’s best overall response assignment will 
depend on the findings of both target and non-target disease and will also take into 
consideration the appearance of new 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 (CR): Disappearance of all target lesions. Disappearance of all non-
target lesions and normalization of tumor marker level. Any pathological lymph nodes 
(whether target or non-target) must have decreased in size to have a short axis of < 10 mm.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions 
taking as reference the baseline sum diameters. 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
Non-CR/Non-PD (to be used for patients with non-target lesions only): Persistence of one or 
more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits.
Progressive Disease (PD): 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. For non-target lesions, unequivocal progression (see 
comments below) of existing lesions represents progressive disease. (Note: the appearance of 
one or more new lesions is also considered progression). 
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 


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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 <10mm.
To achieve unequivocal progression in patients with measurable disease 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 presence of SD or PR in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. A modest ‘increase’ in the size of 
one or more non-target lesions is usually not sufficient to qualify for unequivocal.
In the absence of measurable disease, the same general concepts apply here as noted above.
Table 16–2: Target and non-target lesion response
Target Lesions
Non-Target 
Lesions
New Lesions
Overall 
Response
Best Response requires
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
documented at least once 
≥6 weeks from baseline 
imaging
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PD = progressive disease, PR = partial response, SD = stable disease.
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 the objective progression even after discontinuation of treatment.
Response duration
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 are 
first met for CR until the first date that recurrent disease is objectively documented.
Stable disease duration
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).


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Methods of measurement
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.
When lesions can be evaluated by both clinical exam and imaging, imaging evaluation should 
be undertaken since it is more objective.
Chest X-ray will not be accepted in the study, Spiral-CT should be conducted.
Computed tomography (CT)/ magnetic resonance imaging (MRI) - CT and MRI might be the 
best currently available and reproducible methods to measure target lesions selected for 
response assessment. As a general rule, the minimum size of a measurable lesion at baseline 
should be no less than double the slice thickness and also have a minimum size of 10 mm. 
This applies to the chest, abdomen and pelvis. Head & neck and extremities usually require 
specific protocols.
Ultrasound – Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised. If there is concern about the radiation exposure at CT, MRI may be 
used instead of CT in selected instances. 
Tumor markers: tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit, however, they must normalize for a patient 
to be considered in complete response. 
When effusions are known to be a potential adverse effect of treatment (e.g. angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment can be considered if the measurable tumor has met criteria for 
response or stable disease in order to differentiate between response (or stable disease) and 
progressive disease.


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16.3
New York Heart Association (NYHA) classification
Table 16–3: New York Heart Association (NYHA) categories
Class
NYHA Functional Capacity
I
Patients have cardiac disease but without the resulting limitations of physical activity. Ordinary 
physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain.
II
Patients have cardiac disease resulting in slight limitation of physical activity. They are 
comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal 
pain.
III
Patients have cardiac disease resulting in marked limitation of physical activity. They are 
comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnea, or 
anginal pain.
IV
Patients have cardiac disease resulting in inability to carry on any physical activity without 
discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even 
at rest. If any physical activity is undertaken, discomfort is increased.
16.4
Estimated glomerular filtration rate (eGFR) calculation
In accordance with established nephrology practice and guidelines, renal function at baseline 
and throughout the study will be assessed by means of the estimated Glomerular filtration rate 
(GFR), calculated using the Modification of Diet in Renal Disease (MDRD) study 
abbreviated formula.
This equation of 4 variables (serum creatinine level [SCR], age, sex, and race) is 
recommended by the National Kidney Foundation for use in individuals 18 years or older.
The GFR calculator can be found at the following website (36): 
http://www.kidney.org/professionals/kdoqi/gfr_calculator.
NOTE: This equation should be used only with those creatinine methods that have not been 
recalibrated to be traceable to isotope dilution mass spectroscopy (IDMS).
The above result should be multiplied by 1.212 for African-Americans and by 1.227 for 
Chinese (mainland China, Taiwan and Hong Kong). Due to the lack of confirmed information 
on Korean patients the results for these patients will not be multiplied by any factor (37).

SAP_001.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
A randomized, open label, multicenter Phase 2/3 study to evaluate 
the efficacy and safety of rogaratinib (BAY1163877) compared to 
chemotherapy in patients with FGFR-positive locally advanced or 
metastatic urothelial carcinoma who have received prior platinum-
containing chemotherapy 
NCT Number: 
NCT03410693 
Document Date: 
19 AUG 2020 
 


Statistical Analysis Plan
Protocol No.: BAY 1163877 / 17403
Page: 1 of 27
Reference Number: RD-OI-0119
Supplement Version: 8
A randomized, open label, multicenter Phase 2/3 study to evaluate the efficacy 
and safety of rogaratinib (BAY 1163877) compared to chemotherapy in patients 
with FGFR-positive locally advanced or metastatic urothelial carcinoma who 
have received prior platinum-containing chemotherapy
[Phase 2/3 study of rogaratinib (BAY 1163877) vs chemotherapy in patients with FGFR-
positive locally advanced or metastatic urothelial carcinoma]
Bayer study drug
BAY 1163877 / rogaratinib
[Study purpose:]
Assess the efficacy and safety of rogaratinib compared to chemotherapy
Clinical study phase:
Phase 2/3
Date:
17MAY2019
Study No.:
17403
Version:
Final 1.0
Author:
Confidential
The information provided in this document is strictly confidential and is intended solely for the 
guidance of the clinical investigation. Reproduction or disclosure of this document, whether in 
part or in full, to parties not associated with the clinical investigation or its use for any other 
purpose without the prior written consent of the sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed.
Hence, the appearance of product names without these symbols does not imply that these names 
are not protected.
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures.
The approval of the Statistical Analysis Plan is documented in a separate Signature Document.
PPD


Statistical Analysis Plan
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Reference Number: RD-OI-0119
Supplement Version: 8
Table of Contents
1.
Introduction........................................................................................................................5
2.
Study Objectives.................................................................................................................6
3.
Study Design.......................................................................................................................6
3.1
Study periods and duration...............................................................................................7
3.2
Schedule of procedures.....................................................................................................8
3.3
Determination of sample size ...........................................................................................8
4.
General Statistical Considerations ...................................................................................8
4.1
General Principles.............................................................................................................8
4.2
Handling of Dropouts .......................................................................................................9
4.3
Handling of Missing Data.................................................................................................9
4.3.1
Time-to-event variables.................................................................................................9
4.3.2
Response rates.............................................................................................................10
4.3.3
Adverse Event Start Date ............................................................................................10
4.4
Interim Analyses and Data Monitoring ..........................................................................11
4.5
Data Rules.......................................................................................................................11
4.5.1
Time intervals..............................................................................................................11
4.5.2
Baseline .......................................................................................................................12
4.5.3
Repeated measures ......................................................................................................12
4.5.4
Stratification................................................................................................................12
4.5.5
Region .........................................................................................................................12
4.6
Validity Review..............................................................................................................13
5.
Analysis Sets .....................................................................................................................13
5.1
Assignment of analysis sets............................................................................................13
6.
Statistical Methodology ...................................................................................................13
6.1
Population characteristics...............................................................................................13
6.1.1
Disposition ..................................................................................................................13
6.1.2
Protocol deviation .......................................................................................................14
6.1.3
Demographics and other baseline characteristics........................................................14
6.1.4
Medical history............................................................................................................15
6.1.5
Prior and concomitant medication, Prior local Anti-cancer therapy, Systemic Anti-cancer 
Therapy during follow-up, Diagnostic and Therapeutic procedures, and Radiotherapy15
6.1.6
Extent of  Exposure.....................................................................................................17
6.2
Efficacy...........................................................................................................................17
6.2.1
Primary Efficacy Variable ..........................................................................................17
6.2.2
Secondary Efficacy Analysis ......................................................................................19
6.2.3
Statistical test strategy for secondary endpoints .........................................................23
6.2.4
Subgroup Analyses......................................................................................................24
6.3
Safety..............................................................................................................................24
6.3.1
Adverse events (AEs)..................................................................................................24
6.3.2
Clinical laboratory evaluations....................................................................................26


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6.3.3
Other safety measures .................................................................................................26
6.3.4
Pharmacokinetics/pharmacodynamics ........................................................................26
6.3.5
Biomarker evaluation ..................................................................................................27
6.3.6
Patient-reported outcomes (PRO) ...............................................................................27
7.
Document history and changes in the planned statistical analysis..............................27
8.
References.........................................................................................................................27
Abbreviations


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AE
Adverse event
AESI
AE of special interest
AJCC
American Joint Committee on Cancer
ALT
Alanine aminotransferase
ANCOVA
Analysis of Covariance
AP
Asia Pacific
AST  
Aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC
Area under curve
b.i.d. 
Twice daily, bis in die
BMI
Body mass index
CI
Confidence interval
CMH 
Cochran-Mantel- Haenszel  
CR
Complete Response
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DCR
Disease-control rate
dL 
Deciliter
DOR
Duration of response
DMC
Data Monitoring Committee
EORTC
European Organisation for Research and Treatment of Cancer
e.g. 
For example, exempli gratia
ECOG
Eastern Cooperative Oncology Group
EOT
End of treatment
EQ-5D-3L
EuroQol Group’s five dimensions questionnaire
FGFR
Fibroblast growth factor receptor
FAS
Full Analysis Set
GCP
Good Clinical Practice
GMS
Global Medical Standards
GFR
glomerular filtration rate
HEOR
Health Economics, Outcomes & Reimbursement
HRQoL 
Health-related Quality of Life
HLT
Higher level term
ICH
International Committee on Harmonization
ICF
patient information/informed consent form  
ITT
Intent to treat
i.v.
Intravenous(ly)
IxRS 
Interactive voice/web response system
i.e.  
That is, id est
kg
kilograms
KM
Kaplan-Meier
LKAD
Last known alive date
LOS
Listing only set
MedDRA
Medical Dictionary for Regulatory Activities
m 
Meter
mg 
Milligram 
MRI
Magnetic resonance imaging
M&S
Modelling and Simulation
N/A
Not applicable
NCI 
National Cancer Institute


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NE
Non evaluable
OEE
Overall extent of exposure
ORR
Objective response rate
OS
Overall Survival
PI
patient information 
p.o.
Orally, per os
PFS
Progression-free survival
PIK3CA
Phosphatidylinositol-3-kinase catalytic subunit alpha  
PR
Partial Response
PRO
Patient-Reported outcome
PT
Preferred Term
RAS
Rat sarcoma
RECIST v.1.1
Response evaluation criteria in solid tumors Version 1.1
RNA-ISH
RNA in situ hybridization
QLQ-C30
30 item Quality of Life Questionnaire
QoL
Quality of Life
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical Analysis Plan
SAS
Statistical Analysis Software
SOC
System Organ Class
SD
Stable disease
TA
Therapeutic Area
TEAE
Treatment-emergent adverse event
TNM
Classification of Malignant Tumors (T = tumor, N = lymph node, M = metastasis)
ULN
Upper limit of normal
WHO-DD
World Health Organization Drug Dictionary
WT
Wild type
1.
Introduction
Rogaratinib (BAY 1163877) is an oral pan-FGFR inhibitor. It shows potent FGFR1, -2, -3 and -4 
inhibition in biochemical assays that translates into strong inhibition of cellular downstream pERK 
resulting in inhibition of FGF2-stimulated tumor cell proliferation. Inhibition of cell proliferation by 
rogaratinib strongly correlates with expression of mRNA of FGFR isoforms as well as activation by 
somatic mutations. The high in-vitro potency and mode of action translates into strong in-vivo 
efficacy in tumor models which have an activated FGFR signaling in non-small-cell lung cancer, 
small-cell lung cancer, bladder, head and neck as well as breast cancer. In-vivo efficacy is correlated 
with effective inhibition of tumor FGFR phosphorylation and inhibition of FGFR downstream 
signaling as shown by pERK inhibition. Moreover, rogaratinib exhibits strong in-vivo anti-tumor 
efficacy in monotherapy in FGFR mRNA overexpressing xenograft models with good tolerability. 
Efficacy in inhibition of tumor growth as well as the respective mode of action of inhibition of 
FGFR signalling such as phosphorylation of ERK1/2 was also strongly correlated with abundant 
expression levels of FGFR isoforms in tumor cells or tumor tissues. In addition, rogaratinib 
demonstrated additive activity with standard-of-care therapy in lung and urothelial carcinoma 
models.
So far, clinical experience with rogaratinib is available from two clinical trials, study 16443 and 
study 16958. The encouraging results of Study 16443 support the continuation of the development 


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of rogaratinib in urothelial carcinoma. Study 17403 forms part of the sponsor’ s clinical 
development program for rogaratinib. It is intended to generate the pivotal data in support of 
rogaratinib’ s registration for the urothelial carcinoma indication in FGFR positive patients.
This Statistical Analysis Plan (SAP) v1.0 is based on the following documentation:
Document
Date
Version
Protocol
29November 2017
1.0
Protocol Amendment (global amendment)
09 May 2019
2.0
2.
Study Objectives
The objectives of the study are provided below:
Primary objective:

To demonstrate the superiority of rogaratinib over chemotherapy in terms of prolonging 
overall survival of urothelial carcinoma patients with FGFR positive tumors.
Secondary objectives:

To evaluate additional efficacy including the following variables

progression-free survival (PFS)

objective response rate (ORR)

disease control rate (DCR)

duration of response (DOR)

To evaluate the safety of rogaratinib (adverse events)
Tertiary objectives:

Patient-reported outcome (PRO)

Evaluate biomarkers to investigate the drug (i.e. mode-of-action-related effect and/or safety) 
and/or the pathomechanism of the disease

Pharmacokinetics
The objective for the Phase 2 part of the study is to demonstrate the early signal of efficacy of 
rogaratinib over chemotherapy in terms of objective response rate of urothelial carcinoma patients 
with FGFR positive tumors in PIK3CA/RAS WT (referred as WT hereafter) patients.
3.
Study Design
This is a randomized, open-label, multicenter Phase 2/3 study to evaluate the efficacy and safety of 
rogaratinib (BAY 1163877) compared to chemotherapy in patients with FGFR-positive locally 
advanced or metastatic urothelial carcinoma who have received prior platinum-containing 
chemotherapy.


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At randomization, patients will have locally advanced or metastatic urothelial carcinoma and have 
received at least one prior platinum-containing chemotherapy regimen. Only patients with FGFR1 or 
3 positive tumors can be randomized into the study. Archival tumor tissue is adequate for testing of 
FGFR1 and 3 mRNA expression, which will be determined centrally using an RNA in situ
hybridization (RNA-ISH) test.
All tumor images need to be submitted continuously for independent central imaging review.
3.1
Study periods and duration
The study will comprise the following periods:
1) Pre-treatment period, including FGFR testing and screening;
2) Treatment period;
3) Active Follow-up period: including a safety follow-up at least 30 days ( up to +7 days) after the 
last administration of study treatment), and both safety and efficacy information will be collected for
patients who discontinue study treatment without diseases progression;
4) Long-term follow-up period: patients will be contacted every month(+/- 7 days) to collect 
survival status and subsequent systemic anti-cancer treatment. 
The Phase 2 and 3 parts of the study follow the same screening, treatment and follow-up assessment 
schedule. 
Patients will be considered “on study” during the pre-treatment, treatment and active follow-up 
periods. During the long-term follow-up period, the patients will be considered “off study” (i.e. no 
study-related procedures with the patient). An overview of the study design is presented in Figure 
3-1.


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Figure 3-1: Study 17403 - Design overview
b.i.d. = Twice daily, bis in die; FGFR = Fibroblast growth factor receptor; i.v. = intravenously; mg = Milligram; PIK3CA = Phosphoinositide 
3-kinase, catalytic subunit alpha isoform; p.o. = Orally, per os; RAS = Rat sarcoma; mRNA = Messenger ribonucleic acid.
a: During FGFR testing period, patients will be tested for FGFR1 and 3 mRNA expression levels and, after a positive FGFR test result 
was obtained, these patients are also tested for presence or absence of potential FGFR inhibitor resistance mutations, PIK3CA
and/or RAS. PIK3CA and/or RAS mutation status will not affect patient eligibility, but will be used for patient stratification.
b: Only FGFR-positive patients (high expression of at least FGFR1 or 3) can enter screening.
c: Safety information is collected for all discontinued patients for at least 30 (up to +7) days after the last administration of study 
treatment, and both safety and efficacy information is collected for patients who discontinue study treatment without disease progression
3.2
Schedule of procedures
Refer to Protocol Table 9-1 for the detailed schedule for the assessments.
3.3
Determination of sample size
Refer to Protocol Section 10. 4 for the details about sample size calculation.
4.
General Statistical Considerations
4.1
General Principles
Statistical analyses will be conducted by or under the supervision of the sponsor’s Study Statistician, 
except for the analysis of biomarker data and pharmacokinetics/pharmacodynamics data, which will 
be performed by or under the direction of the sponsor’s Genomics and Biomarker Statistical Expert,
and PK experts. The details of those analysis will be described in a separate analysis Plan. and 
results will be provided in a separate report outside of the clinical study report (CSR).
The statistical evaluation will be performed by using the software package SAS release 9.2 or higher 
(SAS Institute Inc., Cary, NC, USA). All variables will be analyzed by descriptive statistical 
methods. The number of data available and missing data, mean, standard deviation, minimum, 
quartiles, median, and maximum will be calculated for continuous data. Frequency tables will be 
generated for categorical data.


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All analyses for population characteristics (Section 6.1) and safety (Section 6.3) will be performed 
for WT patients first and will also be repeated for all study population if the test for primary 
endpoint OS in WT population is positive. For the order of efficacy analyses, refer to Section 6.2
for the details.
4.2
Handling of Dropouts
A patient who discontinues study participation prematurely for any reason is defined as a “dropout” 
if the patient has already been randomized, even if no study drug has been taken, patients who drop 
out will not be replaced. 
Patients must be withdrawn from the study treatment, active follow-up or long-term follow-up if any 
of the withdrawn criteria is met. See Protocol Section 6.4.1.3 for pre-specified withdrawn criteria. 
A subject who terminates the study before randomization but after completing Pre-screening (FGFR 
testing) is regarded as a 'screening failure'. A subject who fails to complete  pre-screening  (FGFR 
testing) period is a 'pre-screening failure’. All patients will enter the active follow-up period upon 
discontinuation of the study treatment, except for those who object to follow-up data collection.
Safety information is collected during the Active Follow-up for all discontinued patients for at least 
30 (up to +7) days after the last administration of study treatment. In addition, for those patients who 
discontinue study drug due to reasons other than death or PD (In case disease progression is not 
confirmed by central review, it is strongly recommended that patients go into active follow-up for 
tumor assessments until central imaging has confirmed disease progression), active follow-up 
assessments including  both efficacy and safety  information shall continue until disease progression 
is documented or new anti-tumor treatment is administered, whichever occurs first (and obviously 
death).  Tumor assessments from the Active follow-up will also be used for primary and secondary 
analyses.
4.3
Handling of Missing Data
In order to achieve the goal of a well conducted clinical trial according to Good Clinical Practice 
(GCP), every effort will be made to resolve incomplete or missing dates during the course of the 
study (i.e. edit checks, data cleaning / monitoring etc.). However, despite best efforts, it may be 
inevitable that missing or incomplete data are reported. All missing or partial data will be presented 
in the patient data listing as they are recorded on the Case Report Form (CRF). Unless specifically 
specified, missing data will not be carried forward or otherwise imputed in any statistical analysis.
The following rules will be implemented where appropriate so as not to exclude patients from
statistical analyses due to missing or incomplete data:
4.3.1
Time-to-event variables
For time-to-event analyses, the censoring mechanism is assumed to be non-informative. Patients will 
be handled as right-censored in time-to-event analyses, if applicable.
Missing or unevaluable tumor assessments (including a scheduled assessment that was not done and 
an incomplete assessment that does not result in an unambiguous tumor response according to 
RECIST v.1.1) will not be used in the calculation of derived efficacy variables related to tumor 
assessments unless a new lesion occurred or the lesions that were evaluated already showed 


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progressive disease. No imputation will be performed for missing lesion assessment and tumor 
response.
Overall survival (OS) of patients alive at the time of analysis will be censored at the last date they 
were known to be alive (last known alive date: LKAD).
The LKAD is derived from the main data sources. Data reported during cleaning for the time after 
the data cut will not be considered in the derivation of LKAD. The last available date across all key 
data panels will be picked as the LKAD, e.g. visit dates, exposure information, laboratory 
measurements, tumor assessment dates and disposition events or follow up assessments will be used 
to determine survival status.
If a death date is partially or completely missing, it will be imputed following the imputation rules 
below:
1. If there is an adverse event (AE) with outcome 'Death', the date of death will be imputed by 
the end date of the AE.
2. If there is no AE with outcome 'Death' and only the day of death is missing, it will be 
imputed by the first day of the month unless the LKAD is later than this date; in which case 
the LKAD will be used for imputation. If both day and month are missing, then the LKAD 
will be used for imputation.
If a tumor assessment date is partially missing, it will be imputed following the imputation rules 
below:
1. If only the day is missing, it will be imputed by the first day of the month.
2. If day and month are missing, it will be imputed by the date of the last previous tumor 
assessment plus 21 days unless the LKAD is earlier than this date; in which case the LKAD 
will be used for imputation.
4.3.2
Response rates
If a patient has no post-baseline tumor assessment available, i.e. the overall best response 
assessment is missing,  the patient will be included into denominator for the calculation of objective 
tumor response rate (ORR) and disease control rate (DCR).
4.3.3
Adverse Event Start Date
The general principle for imputing incomplete or missing adverse event start dates will be to assume 
the start date occurs at the earliest time on-treatment, whenever possible.  
If the start date is completely missing, then the start date will be imputed using the date of the first 
dose of study medication.
If the incomplete start date has day and month missing, then the following will be applied: 

If the year is same as the year of first dose date, then the day and month of the first dose date 
will be assigned to the missing fields.


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
If the year is prior to the year of first dose date, then December 31 will be assigned to the 
missing fields.

If the year is after the year of first dose date, then January 01 will be assigned to the missing 
fields.    
If the incomplete start date has missing day only, then the following will be applied:

If the month and year are same as the year and month of first dose date, then the day of first 
dose will be assigned to the missing day.

If the month and year are before the year and month of first dose date, then the last day of the 
month will be assigned to the missing day.

If the month and year are after the year and month of first dose date, then the first day of the 
month will be assigned to the missing day.
4.4
Interim Analyses and Data Monitoring
A Data Monitoring Committee (DMC) will be instituted in order to ensure ongoing safety of study 
patients with respect to a risk/benefit assessment during periodic data review meetings, review 
results from the planned interim analysis and provide a formal recommendation for
continuation/termination of the study and monitor study conduct to ensure the overall integrity of 
trial in maintained.
Two interim analyses and one final analysis are planned for this study as described in Section 10.5 
in the protocol and DMC charter. 
Recommendation for trial continuation will be guided by the monitoring boundaries at the formal 
interim analysis as well as safety evaluations from all data review meetings according to the DMC 
charter. All analyses to be presented to DMC to aid recommendations for trial continuation will be 
explicated in the DMC charter.
The DMC will be explicitly asked to give recommendations on the continuation or termination of 
the trial. Decisions on trial termination, amendment or cessation of patient recruitment based on risk 
benefit assessments will be made after recommendations from the DMC have been assessed by the 
sponsor.
4.5
Data Rules
4.5.1
Time intervals
If time intervals are to be displayed other than days in statistical evaluations, then one year is 
considered to have 365.25 days (average length of a year, including leap years), one month is 
considered to have 30.4375 days (average length of a month, including leap years), one week is 
considered to have 7 days, and one cycle is considered to have 21 days (i.e. 3 weeks).


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4.5.2
Baseline
Randomization baseline value for efficacy parameters: is defined as the last non-missing value 
on or before the date of randomization.  
Baseline value for safety parameters: is defined as the last non-missing value on or before the date 
of first dose.
4.5.3
Repeated measures
If there are repeated measurements per time point (e.g. laboratory values, vital signs, etc.), the 
following rules will be used (unless otherwise specified):

In case of repeated measurements at any post baseline time point, the first measurement at 
scheduled visits will be used. Unscheduled visits will be used, if there are no measurements 
at scheduled visits. If the latter is the case, the first unscheduled visit will be used.
4.5.4
Stratification
Randomization will be stratified by:

PIK3CA and/or RAS activating mutations (presence vs. absence)

Prior immunotherapy (yes vs. no)

Modified 4-factor Bellmunt risk score (high vs. low)
The following rule will be applied for WT and mutant subgroups to potentially remove some 
stratification factors from the subgroups to avoid over-stratification: if the smallest group within one 
stratification factor (other than activating mutation status) is less than 15% of all randomized 
patients in either subgroup (450 patients for WT, and the corresponding number of mutant patients 
for mutant subgroup), and all study population (with the exception of always including activating 
mutation status for all population ), then this stratification factor will not be introduced into the 
model for the stratified statistical analysis of efficacy endpoints. As the majority of patients are 
anticipated to be randomized by the time of the planned formal interim analysis, this rule will be 
applied to both 2nd interim analysis and final analysis of OS for consistency.
In case of discrepancies between stratification factors entered in the interactive voice/web response 
system (IxRS) and information entered in CRF, the information from IxRS will be used for primary 
analysis.
4.5.5
Region
For demographics overview and subgroup analyses, patients are grouped together into regions. The 
following regions are defined:

Asia


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
North America/ Western Europe/ Israel/ Australia

Rest of the world
4.6
Validity Review
The results of the Blinded Data Review Meeting will be documented in the Blinded Data Review 
Report and may comprise decisions and details relevant for statistical evaluation. Any changes to the 
statistical analysis prompted by the results of the Blinded Data Review meeting will be documented 
in an amendment and, if applicable, in a supplement to this SAP.
5.
Analysis Sets
5.1
Assignment of analysis sets
Final decisions regarding the assignment of patients to analysis sets will be made during the review 
of study data and documented in the final list of important deviations, validity findings and 
assignment to analysis set(s) (see section 4.6).
Full analysis set (FAS)
The FAS population is defined as all randomized patients. Patients will be analyzed as randomized, 
meaning even if a patient was randomized and received no drug or if randomized and received 
incorrect study drug at any time, these patients will still be analyzed for efficacy endpoints 
according to the treatment to which they were randomized based on IXRS.
The FAS analysis set as a primary population for efficacy analysis is identical to the Intent-to-treat 
(ITT) analysis set. 
Safety analysis set (SAF)
The SAF population is defined as all patients who received at least one dose of study treatment 
(rogaratinib or chemotherapy). Patients will be included in the analyses according to the actual 
treatment they received..
The SAF population will be used for the safety analysis.. 
6.
Statistical Methodology
6.1
Population characteristics
6.1.1
Disposition
The number of patients pre-screened, screened, randomized,  treated and entered active and long-
term follow up period will be summarized by treatment group and overall. In addition, the number 
of subjects pre-screened, screened and included in each analysis population will be displayed overall 
and by region, country and investigator.
The number of FGFR testing failures and screening failures who terminate the study before 
randomization during pre-treatment period with the primary reason for discontinuation will be 
presented. The number of patients discontinuing the treatment, active and long-term follow-up 


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periods with the primary reason for discontinuation will be presented by treatment group and 
overall.
6.1.2
Protocol deviation
The number of patients with important protocol deviations will be presented by deviation coded 
term, treatment group and overall.
6.1.3
Demographics and other baseline characteristics
Demographic variables and baseline cancer characteristics will be summarized by treatment group 
and overall for the FAS and Safety analysis set. Quantitative data will be summarized by arithmetic 
mean, SD, median, minimum and maximum. Frequency tables will be provided for qualitative data. 
In addition, the frequencies of stratification factors will be summarized per IXRS data. The 
discordance for each stratification factor between CRF and IXRS data will be presented  in a shift 
table.
Demographic variables include age, gender, race, ethnicity, region (Asia/North America/ Western 
Europe/ Israel/ Australia; Rest of the world), body weight(kg), body height(cm), body mass index 
(BMI), systolic and diastolic blood pressure, heart rate and temperature. Age and BMI will each be 
analyzed as continuous variable and in addition categorized with the following categories:

Age group (years): 18 - <65, ≥65 - <85, ≥85

BMI group (kg/m²): <18.5, ≥18.5- <30, ≥30
The following baseline cancer characteristics will be analyzed:

Cancer Category

Location of primary cancer

Time from initial diagnosis to the date of the randomization (months)

Time since first progression/ relapse (months) to randomization

Type of assessment of first progression/relapse 

Time from most recent progression/ relapse to the date of randomization (months))

Type of assessment of most recent progression/relapse 

Histology of tumor

Staging at initial diagnosis / Staging system at initial diagnosis (concatenated)

AJCC Grading at initial diagnosis

Residual primary tumor status at study entry

If primary tumor was resected, status of surgical margin

Stage at study entry/ Staging system at study entry (concatenated)

Number of lesions (number of target and non-target lesions) at baseline –investigator


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
Number of lesions (number of target and non-target lesions) at baseline – central reader

PIK3CA and/or RAS activating mutations from CRF data (presence vs. absence)

Modified 4-factor Bellmunt risk score (0, 1, 2, 3, 4) and prognostic factors tested within 7 
days before randomization

ECOG performance status (0 vs. 1)

Hemoglobin level (0: ≥10 g/dL vs. 1: < 10 g/dL)

Liver metastases (0: absent vs. 1: present)

Time from last systemic anti-cancer therapy dose (0: ≥90 days vs. 1: < 90 days)

Smoking history
6.1.4
Medical history
Medical history findings will be coded by Medical Dictionary for Regulatory Activities (MedDRA) 
version 20.1 or later. Medical history will be presented for each MedDRA Primary System Organ 
Class (SOC),) and Preferred Term (PT) for FAS population by treatment group and overall.
6.1.5
Prior and concomitant medication, Prior local Anti-cancer therapy, Systemic 
Anti-cancer Therapy during follow-up, Diagnostic and Therapeutic 
procedures, and Radiotherapy
All investigator-reported non-study medications taken before and/or during the study will be coded 
by Anatomical Therapeutic Chemical (ATC) classification system according to the World Health 
Organization Drug Dictionary (WHO-DD) version 2017SEP. 
Non-study medications taken before and/or during the study will be categorized as prior 
medications, concomitant medications, and post treatment medications. 
A non-study medication that started before the first administration of study treatment is considered 
as prior.  Post treatment medications are defined as non-study medications taken on or after the last 
dose of study treatment. 
Concomitant medications include:
Non-study medications with a start or stop date after the date of the first
dose of study treatment but before the date of last study treatment
Non-study medications that started prior to the first dose of study
treatment and are ongoing after the start of study treatment;
Detailed classifications of prior, concomitant and post medication are illustrated in Table 6–1.


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If a start date is missing, the medication will be assumed to start prior to first dose of study drug. If 
the end date is unknown and ‘ongoing’ was not checked in CRF, the medication will be assumed to 
end at the last visit date, death date or withdrawal from study date, whichever is the latest.  
Medications with missing start and stop date but flagged as being ongoing at end of study will be 
considered to have started prior to start of study medication and ended after stop of study 
medication.
All prior, concomitant and post-treatment medications will be listed, including verbatim descriptions 
and coded terms, and flags for prior/concomitant/post-treatment medications.  
Prior, concomitant, and post-treatment medications will be summarized by ATC class, subclass and 
preferred term. For each patient, multiple records of the same concomitant medication will be 
counted once within a drug class and generic drug name.. Note that the same medication can appear 
multiple times in the table as it can have several ATC codes.
Additional Summaries will also be produced for prior/concomitant/post-treatment anti-cancer 
therapies (local therapy, systemic therapy and radiotherapy).  The number of patients with local and 
systemic anti-cancer therapy will be presented by intent of procedure and number of regimens, and 
also by type and number of regimens for each treatment group, respectively.   
The number of patients with radiotherapy will be presented by location, intent of procedure and 
number of regimens, and also by location, type and number of regimens, respectively.   
The diagnostic and therapeutic procedure will be summarized using frequencies of patients 
undergoing each type of procedure by treatment group and overall. 
All the summaries will be generated for the FAS population.
Table 6–1 Medication Classification
Prior to 
study 
drug
Study 
drug 
started
Treatment 
with study 
drug
Study 
drug 
stopped
Follow 
up
Prior 
Medication?
Concomitant 
Medication?
Post-treatment 
Medication?
C1
Yes
No
No
C2
Yes 
Yes
No
C3
No
Yes
Yes
C4
Yes 
Yes
Yes
C5
No
No
Yes 
C6
No
Yes 
No 
C7
No
Yes 
No 
C8
No
Yes 
No 
C1= medication started before date of first dose of study drug and ended on or before the date of first study drug 
C2= medication started before date of first dose of study drug and ended before or on the date of last study drug 
C3= medication started on or after date of first dose of study drug and ended/ongoing after date of last study drug 
C4= medication started before date of first study drug and ended/ongoing after date of last study drug administration 
C5= medication started on or after date of last dose of study drug and ended/ongoing after date of last dose of study drug
C6= medication started on or after date of first study drug and ended before or on the date of last study drug administration
       C7= medication started and ended on date of first dose of study drug
       C8= medication started and ended on date of last dose of study drug


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6.1.6
Extent of  Exposure
Following randomization, rogaratinib (BAY 1163877) is planned to be taken orally (p.o.) twice a 
day (b.i.d.), on every day during a 21-day treatment cycle.
Following randomization, the assigned chemotherapy (monotherapy) is planed to be given as 
intravenous (i.v.) infusion once every three weeks (on day 1 of a 21-day cycle). The cycle ends with 
the next infusion.
Descriptive statistical summaries will be provided by treatment group for the following variables: 

Duration of treatment: will be calculated in months as (the date of the last dose of study 
treatment – date of the first dose of study treatment + 1 )/30.4375

Number of cycles 

Number of doses for rogaratinib arm and number of infusions for chemotherapy arm 

Total amount of dose administered (sum of dosage of all doses administered in mg for 
rogaratinib, and mg/m2 for infusions)

Percent of planned dose received = Total amount dose administered (mg) / Planned dose(mg) 
× 100%. 
The planned dose will be calculated as: sum of all planned doses for rogartinib arm, and all 
doses calculated for chemotherapy arm between the date of first dose and last dose of study 
treatment

Number and percent of patients with dose modifications (i.e., number (%) of patients with at 
least one dose modification, at least one dose interruption/delay, at least one dose reduction, 
or at least one dose re-escalation)

Total number of dose interruptions/delays, reductions and re-escalations.

The reason for dose interruptions/delays, reductions and re-escalations.

Number of interruptions/delays, reductions and re-escalations per patient
All the summaries will be done in SAF by treatment group .
As a general rule, and in accordance with the Oncology Therapeutic Area Standard, leading '0mg' 
(prior to the first positive amount of drug) and trailing '0 mg' records (not followed by any positive 
amount of drug), will not be included in the calculation of any drug duration or amount. Interruption 
without resumption of study treatment is not counted as an interruption.
6.2
Efficacy
Efficacy analyses will be performed as randomized in the FAS.
6.2.1
Primary Efficacy Variable 
Primary efficacy variable for this study is overall survival(OS). OS is defined as the time from 
randomization to death due to any cause. See Table 6– below for detailed censoring rules. 


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Table 6–2 Overall Survival censoring rules
Situation
End Date 
Censored
Reason for Censoring
Death on or prior to database cut off date  
Date of Death
No
N/A
Not known to have died as of database cut 
off date   
Last known alive date 
(LKAD) on or prior to 
database cutoff  
Yes
No Death
Lost to follow-up prior to database cutoff  
Last known alive date 
(LKAD)
Yes
Lost to follow up
If no assessment was done after 
randomization, then the patient will be 
censored at randomization date.
Randomization date
Yes
No 
assessment 
after 
randomization
Primary analysis of OS
For the analyses of overall survival, a stratified log-rank test controlling type
I error at a level of 0.025 (one-sided) will be conducted for the WT population first (step 1).
A full alpha of 0.025 (one-sided) will be passed on to OS in all study population and some
selected secondary endpoints (step 2) if and only if the null hypothesis of OS for WT
population is rejected. In case of failing to reject null hypothesis of OS for WT population,
step 2 will not be tested. The following hypothesis will be tested for the PIK3CA and RAS WT 
patients first and then all study population by using a stratified log-rank test controlling type I error 
at a level of 0.025 (one-sided):

H0,OS: hazard ratio (rogaratinib / chemotherapy) ≥ 1
versus

H1,OS: hazard ratio (rogaratinib / chemotherapy) < 1
Details on controlling family-wise type I error will be specified in section 6.2.3.
In addition to the stratified log-rank tes for the PIK3CA and RAS WT patients first and then all 
study population, the hazard ratio (rogaratinib / chemotherapy) for OS and its 95% confidence 
interval will be calculated using the Cox model, stratified by the same factors as log-rank test stated 
above. Kaplan-Meier curves will be generated, and median survival time together with the 25th and 
75th percentiles and associated 95% CIs will be presented. The KM estimates at time points such as 
3 months, 6 months etc. together with corresponding 95% confidence intervals as well as the 
differences of these estimates will also be calculated between the rogaratinib arm and the 
chemotherapy arm. 
Sensitivity analysis of OS
WT and all study population: A sensitivity analysis will be performed by only including confirmed
FGFR positive patients for PIK3CA and RAS WT population and all study population, respectively.  
All subject enrolled to this study are expected to have FGFR positive testing results. Due to inter-
evaluator variability in the scoring of FGFR test , a confirmation test may be done at discretion of 


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the sponsor to identify the FGFR positive subjects which will be referred as confirmed FGFR 
positive.
Mutant subgroup: Three sensitivity analyses will be performed for mutant subgroup:

First analysis will include all subjects with both known or unknown PIK3CA and RAS  
mutation status, per IxRS randomization scheme. 

Second analysis will only include subjects with known PIK3CA and RAS mutant.

Third analysis will be performed for confirmed FGFR positive subjects with both known or 
unknown  PIK3CA and RAS  mutation status
In case of discrepancies between stratification factors entered in the interactive voice/web response 
system (IxRS) and information entered in CRF, sensitivity analyses may be performed for OS 
analysis based on information entered in CRF for both WT and all study population, respectively. 
6.2.2
Secondary Efficacy Analysis
6.2.2.1
Secondary efficacy endpoints
Progression-free survival (PFS) is defined as the time (days) from randomization to date of first 
observed disease progression (radiological or clinical assessment or both ) or death due to any 
cause(if death occurs before progression is documented). Clinical progression refers to symptomatic 
deterioration as defined in the protocol Section 6.4.1.3.  
The actual date that the tumor scan was performed will be used for this calculation. If a tumor 
assessment is performed over more than one day (e.g. scans for chest and abdomen done on different 
days for a same evaluation), the earliest date will be used for the calculation of PFS. 
Censoring Rules
The detailed censoring rules for PFS are described in Table 6– below. 
Table 6–3 Censoring for progression-free survival(PFS)
Situation
End Date 
Censored
Reason for Censoring
No  baseline  radiological tumor 
assessments
Date of Randomization
Yes
No baseline assessment.
No post-baseline  radiological 
assessment, or symptomatic 
deterioration or death
Date of Randomization
Yes
No post-baseline 
radiological assessment, 
symptomatic deterioration, 
or death
No progression and no death 
(with a post baseline tumor 
assessment) at data cut-off
Date of last tumor assessment
prior or on data cut-off date
Yes
No Progression or death
Subject lost to follow-up or 
discontinued from study without 
progression or death
Date of last tumor assessment
Yes
Lost to follow-up or 
discontinued study due to a 
reason other than PD or 
death


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New non-protocol permitted 
systemic anti-cancer treatment 
started before progression or death
Date of last radiological 
assessment before starting 
new systemic anti-cancer 
treatment
Yes 
New systemic anti-cancer 
treatment started
Subjects discontinued from study 
due to PD, but no documented date 
of PD
Date of last radiological 
assessment
Yes
Subjects discontinued from 
study due to PD, but no 
documented date of PD
Death or progression after two or 
more consecutive  missed 
radiological  assessments*
Date of last adequate tumor 
assessment before missed 
assessments
Yes 
Missed two or more 
consecutive tumor 
assessments
Subject had a progression after  
randomization (no 2 consecutive 
missing radiological assessments*)
Date of first progression event 
(symptomatic deterioration or 
radiological progression, 
whichever comes earlier). If a 
tumor assessment was done 
on multiple days, use the 
earliest date for that visit
No
N/A
Death without documented 
progression and without missing 
two or more consecutive 
radiological assessment prior to 
death
Date of Death
No
N/A
* Two consecutive missing disease assessments is defined as the time interval in days between two consecutive tumor 
assessments. This number is greater than 140 days =2 × (63+7), where 63-day is the longest scheduled frequency for 
tumor assessment and 7-day is the protocol-allowed window.
Note: Progression in the table above refers to radiological progression or symptomatic deterioration
Objective response rate (ORR) is defined as the percentage of patients with complete response 
(CR) or partial response (PR). Patients for whom  best overall response is not CR or PR, as well as 
patients without any post-baseline tumor assessment will be considered non-responders.
Disease-control rate (DCR) is defined as the percentage of patients, whose overall best response 
was not progressive disease (i.e. CR, PR, SD or Non CR/Non PD). Tumor assessments that is 
performed earlier than 6 weeks from the start of treatment will not be taken into account in the 
assessment of SD.
Duration of response (DOR) (for subjects with PR and CR only) is defined as the time from the 
first documented objective response of PR or CR, whichever is noted earlier, to disease progression 
(including symptomatic deterioration) or death whichever is earlier. The censoring rules for DOR 
are described in Table 6-4. 
Table 6–4 Censoring for duration of response(DOR) 
Situation
End Date 
Censored
Reason for Censoring
No progression and no death 
at data cut-off
Date of last tumor 
assessment before data 
cut-off
Yes
No Progression or death
Subject lost to follow-up or 
discontinued from study without 
Date of last tumor 
assessment
Yes
Lost to follow-up or 
discontinued study due to 


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progression or death
a reason other than PD or 
death
New non-protocol permitted 
systemic anti-cancer treatment 
started before progression or 
death
Date of last radiological 
assessment before 
starting new systemic 
anti-cancer treatment
Yes 
New systemic anti-cancer 
treatment started
Subjects discontinued from 
study due to PD, but no 
documented date of PD
Date of last radiological 
assessment
Yes
Subjects discontinued 
from study due to PD, but 
no documented date of PD
Death or progression after two 
or more consecutive  missed 
radiological  assessments*
Date of last adequate 
tumor assessment 
before missed 
assessments
Yes 
Missed two or more 
consecutive tumor 
assessments
Subject had a progression after  
achieving CR or PR (no 2 
consecutive missing 
radiological assessments*)
Date of first progression 
event (symptomatic 
deterioration or 
radiological 
progression, whichever 
comes earlier). If a 
tumor assessment was 
done on multiple days, 
use the earliest date for 
that visit
No
N/A
Death without documented 
progression and without missing 
two or more consecutive 
radiological assessment prior to 
death
Date of Death
No
N/A
* Two consecutive missing disease assessments is defined as the time interval in days between two consecutive tumor 
assessments. This number is greater than 140 days =2 × (63+7), where 63-day is the longest scheduled frequency for 
tumor assessment and 7-day is the protocol-allowed window.
Note: Progression in the table above refers to radiological progression or symptomatic deterioration
6.2.2.2
Analysis of secondary efficacy endpoints
Depending on study success in the primary efficacy variable in the WT subgroup, the secondary 
efficacy variables based on final database will be tested in the WT subgroup and all study population 
according to the multiple testing strategy outlined in Section 6.2.3.
The central reviewer will evaluate the radiological imaging produced by the investigator. The 
primary analysis of radiological endpoints (ORR, PFS, DCR, DOR) will be based on the central 
radiological reviewer assessments.  Investigator assessments will be provided as sensitivity analysis.
Analysis of PFS
Rogaratinib and chemotherapy treatment arms will be compared using a log-rank test stratified by 
the same stratification factors as used in the analyses of the primary variable OS.


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The hazard ratio (rogaratinib / chemotherapy) and 95% confidence intervals will be provided. KM 
estimates and KM curves will also be presented for each treatment arm. The KM estimates at time 
points such as 3 months, 6 months etc. together with corresponding 95% confidence intervals as 
well as the differences of these estimates between the rogaratinib arm and the chemotherapy arm 
will also be calculated.
Analysis of ORR and DCR
ORR will be compared between treatment arms using the Cochran-Mantel- Haenszel (CMH) test[1]
adjusting for the same stratification factors as used in the analyses of the primary variable OS for 
both WT and all study population.
Estimates and 95% confidence intervals will be computed for each treatment arm. The differences in 
ORR between the rogaratinib and chemotherapy arms and the corresponding 95% confidence 
intervals will also be calculated.
Summary statistics will be displayed for all best response categories: CR, PR, SD, Non CR/Non PD, 
PD by central radiographic imaging, and PD by clinical judgment. Frequency counts and 
percentages with exact 95% confidence intervals will be displayed.
Same analyses stated above will be done for DCR based on independent central review as well.
Analysis of DOR
Since the responders are not a randomized group, no statistical testing will be performed for DOR. 
Analysis of DOR will be descriptive in nature based on central review assessments. KM estimates 
and KM curves will be displayed for each treatment arm.
6.2.2.3
Sensitivity Analysis of Secondary Efficacy Endpoints
The following sensitivity analysis will be performed: 
1) The analyses of ORR, PFS, DCR and DOR based on investigator’s  assessments will be 
conducted using the similar methodology as described in the section above.
2) The analyses of ORR, PFS, DCR and DOR for confirmed FGFR positive WT subjects, and 
all population
3) In case of discrepancies between stratification factors entered in the interactive voice/web 
response system (IxRS) and information entered in CRF, sensitivity analyses may be 
performed for all secondary analysis based on information entered in CRF. 
4) For all secondary efficacy endpoints, two supportive  analyses will be performed for  
PIK3CA and RAS mutant patients: First analysis will be performed by including mutant  
patients and those with unknown mutation status, per IxRS randomization scheme; Second 
analyses will only include known PIK3CA and RAS mutant patients.
5) For this study, in exceptional cases, when it is deemed clinically necessary by the 
investigator due to safety reasons, an imaging scan at an earlier time point than 6 weeks from 


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start of treatment for the 1st ‘on treatment’ tumor assessment is allowed. If extremely 
imbalanced such early scans occur between treatment arms, a sensitivity analysis will be 
performed for PFS to take the first assessment date as 6 weeks for both treatment groups, 
when they occur before 6 weeks. 
6.2.3
Statistical test strategy for secondary endpoints
When targeted death events are reached in PIK3CA and RAS WT patients, final statistical 
analysis will be performed for both primary endpoint (OS) and key secondary endpoints 
(ORR, PFS) controlling family wise type I error rate (α) of one-sided 0.025. 
A graphical summary of the testing strategy including primary and secondary endpoints 
mentioned above for PIK3CA and RAS WT patients and all study population is displayed in 
the figure below, using the methodology as outlined in “A graphical approach to sequentially 
rejective multiple test procedures” by Bretz F. et al[1].
In this testing strategy, OS in PIK3CA and RAS WT will be tested at significance level of one-
sided 0.025 as the first step. If OS in PIK3CA and RAS wt patients is positive with the given 
significance level, OS in all study population (referred as “OS all” in the graph and below) will 
be tested (at significance level of one-sided 0.02, 4/5 of full α) in parallel with the ORR in 
PIK3CA and RAS WT patients (referred as ORR WT in the graph and below; at one-sided 
significance level of 0.005, 1/5 of full α). If either endpoint (OS all or ORR WT) is positive, 
the respective α level from the positive endpoint will be propagated to the other endpoint, 
which can be re-tested at full α level (except for a small close-to-zero ε, set to 0.0001 of full 
α). After test (and potentially re-test), if both OS all and ORR WT are positive, three 
endpoints, ORR in all study population (referred as ORR all in the graph), PFS in PIK3CA and 
RAS wt patients (referred as PFS WT in the graph) and PFS in all study population (referred 
as PFS all in the graph) will be tested at the significance level of one-sided 0.025 sequentially 
with the fixed sequence as just mentioned. In another words, among the three endpoints, only 
if the endpoint mentioned earlier in the sequence tested positive, can the latter endpoint be 
tested. 


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Reference Number: RD-OI-0119
Supplement Version: 8
6.2.4
Subgroup Analyses
Subgroup analyses will be performed in a descriptive fashion for the primary efficacy endpoint (OS) 
as well as the secondary efficacy endpoints ORR, PFS, DCR and DOR. For time to event variables, 
hazard ratio estimates with 95% CI for PFS and DOR will be provided at least within each category 
of the subgroup, provided there are sufficient numbers of events within the subgroup across the 
treatment arms. Kaplan-Meier estimates of median times (including 95% CI) and Kaplan-Meier 
curves will be provided. For ORR and DCR, response rate estimates and 95% confidence intervals 
will be computed for each treatment arm within the subgroup. 
Subgroup levels to be analyzed are:

Planned dose  for rogartinib arm  (600 mg vs. 800 mg)

Stratification factors at randomization (according to IxRS); However, in case of 
discrepancies between stratification factors entered in the interactive voice/web response 
system (IxRS) and information entered in CRF, the information from IxRS will be used for 
primary  analysis but information from CRF will also be summarized

Region (Asia vs. North America [NA]/Western Europe [W EU]/Israel/Australia vs. Rest of 
World [RoW])

Age (<65 vs. ≥ 65, calculated at the date of randomization using date of birth)

ECOG performance status (0 vs. 1)

Gender (male vs. female)

Race

Ethnicity (Hispanic or Latino vs. non-Hispanic and non-Latino)

Renal function (GFR <45 vs. 45 - <60 vs. ≥60 mL/min/1.73m²)

hepatic function (AST and ALT each categorized by ≤ULN vs. >ULN ULN )
6.3
Safety
6.3.1
Adverse events (AEs)
Summary of adverse events is considered a secondary objective for this study. All AEs, whether 
considered drug-related or not, will be reported on the eCRF with start / stop dates, dates of any 
grade change, action taken, whether treatment was discontinued, any corrective measures taken, and 
outcome. For all events, the relationship to treatment and the severity of the event will be 
determined by the investigator. Adverse events will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA) terms (version 20.0 or later), and graded according to National 
Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03.
A treatment-emergent AE (TEAE) is defined as any event arising or worsening after start of study 
drug administration until 30 days after the last study drug intake (end of safety follow-up).
Descriptive summary tables (frequency and percentage of patients, not of events) will be presented 
by treatment arm and MedDRA terms and NCI CTCAE v.4.03 worst grade for the following: 


Statistical Analysis Plan
Protocol No.: BAY 1163877 / 17403
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Reference Number: RD-OI-0119
Supplement Version: 8

Incidence rate of pre-treatment AEs   

Incidence rate of all treatment-emergent AEs (TEAEs) 

Incidence rate of treatment-emergent drug-related AEs  

Incidence rate of treatment-emergent serious AEs (SAEs)

Incidence rate of serious treatment-emergent drug-related AEs

Interval-specific and cumulative event rates for the more common AEs for treatment 
emergent adverse events

Incidence rate of treatment-emergent AEs of special interest (AESIs) 
Deaths and serious adverse events (SAEs)
The incidence of deaths in the study, and especially deaths up to 30 days of last dose of study drug, 
will be summarized by treatment arm and cause of death. All deaths up to 30 days of last dose of 
study drug will be listed by patient with start and stop date of study treatment, date of death, and 
cause of death for both populations.
In addition to the above mentioned incidence table of all treatment-emergent SAEs, these events will 
be listed by patient with investigator AE term, start and stop date of study drug administration, start 
and stop date of AE, drug relationship, worst NCI CTCAE grade, action taken and outcome.
AEs leading to discontinuation of study treatment and/or withdrawal from the study and other 
significant AEs
The incidence of AEs leading to permanent discontinuation of study treatment and / or withdrawal 
from the study will be summarized by treatment arm for both populations, and be listed by patient 
with investigator AE term, start and stop date of study drug administration, start and stop date of 
AE, drug relationship, worst NCI CTCAE grade, action taken and outcome. In addition, incidence of 
AEs that caused dose reduction or interruption will be summarized separately by treatment arm.
Adverse Events of Special Interest
Signs and symptoms suggestive for soft-tissue mineralization, and retinal disorders (classified 
analog to CTCAE v.4.03 as Grade ≥ 2) are defined as AEs of special interest (AESI).
Soft-tissue mineralization related AESIs  includes any events consistent with ectopic calcification
(eg.MedDRA lowest level terms as following: tissue calcification, metastatic calcification, 
calcification of muscles, intestinal calcification, cutaneous calcification).
Any symptomatic retinal disorders including retinal detachment / retinal pigment epithelial
detachment / serous retinopathy / retinal vein occlusion (classified analog to CTCAE v.4.03
as Grade ≥ 2) should be reported as AESI.


Statistical Analysis Plan
Protocol No.: BAY 1163877 / 17403
Page: 26 of 27
Reference Number: RD-OI-0119
Supplement Version: 8
AESIs will be summarized by treatment arm,  MedDRA terms and CTCAE v.4.03 worst grade. The 
corresponding listing will be provided as well. 
6.3.2
Clinical laboratory evaluations
The following laboratory parameters will be summarized for the safety analysis set: hematology 
panel, coagulation panel, biochemistry panel, hormone panel, and urinalysis test.
Worst grades for hematological and biochemical toxicities will be calculated according to CTCAE 
v.4.03 based on laboratory measurements. It should be noted that in the process of assigning toxicity 
grades of those lab parameters for which additional clinical information potentially can also 
influence the toxicity grade, this clinical information is in general not available and only the lab 
measurements are used for toxicity grading
Hematological and biochemical laboratory toxicities assigned by the investigator that include 
clinical assessments are available in Adverse Events database and are summarized in Adverse Event 
tables. 
Quantitative laboratory data will be described by the following summary statistics: number of 
observations, arithmetic mean, and standard deviation, median, minimum, and maximum. These 
summary statistics will be presented by treatment group for the original data as well as for the 
change from baseline. 
Frequency tables will be provided for qualitative urinalysis data.
Laboratory data outside the reference range will be listed with abnormal values / alert ranges 
flagged. The incidence of laboratory data outside the reference range (low, high) will be summarized 
by treatment group in frequency tables.  
For hematology and biochemical laboratory values, the incidence of laboratory toxicities will be 
summarized by worst CTCAE v4.03 grade and by treatment group. Shift tables will be also provided
for the changes of worst CTCAE v4.03 grade after start of treatment vs. baseline.
6.3.3
Other safety measures
Quantitative data (vital signs and 12-Lead ECG) will be described by the following summary 
statistics: number of observations, arithmetic mean, standard deviation, median, minimum, and 
maximum. These summary statistics will be presented by treatment group for the original data as 
well as for the change from baseline if applicable.
Frequency tables will be provided for qualitative data (e.g. ECOG performance status, Pregnancy 
test ,  ECG interpretation, and overall assessment from ophthalmologic examination).
6.3.4
Pharmacokinetics/pharmacodynamics
The details of pharmacokinetic analysis and results will be described in the separate analysis plan 
and report. 


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Reference Number: RD-OI-0119
Supplement Version: 8
6.3.5
Biomarker evaluation
Biomarker analyses and results will be provided in the separate analysis plan and report. 
6.3.6
Patient-reported outcomes (PRO)
PRO data as measured by the EORTC QLQ-C30 and EQ-5D will be analyzed to assess differences 
in health-related Quality of Life (HRQoL) and health utility values between treatment arms based on 
time-adjusted Area Under the Curve (AUC) using all available data[2,3]. Summary statistics will be 
presented for each of the PRO endpoints at each assessment time point and for change from baseline 
by treatment group for both populations.
Primary Analysis of PROs: An analysis of covariance (ANCOVA) model will be used to compare 
the time-adjusted AUCs between the two treatment groups with covariates for baseline HRQoL 
score and the same stratification factors as used in the primary efficacy endpoint at the end of the 
study for both populations. Least-squares mean estimates; standard errors and 95% CIs will be 
estimated for each treatment group and for the treatment group difference for both populations. The 
treatment by covariate interactions will be explored in the ANCOVA models and the consistency of 
the treatment effect on HRQoL across different subsets defined by the covariates in the model will 
be assessed. In the event that the ANCOVA model assumptions (e.g., normality and homogenous
variance of the error terms, equality of slopes for different treatment regression lines) are not 
satisfied, the rank analysis of covariance may be used [4, 5).
Secondary Analyses of PROs: Sensitivity analysis using different imputation methods for imputing 
missing assessments may be performed. Additional exploratory analyses may be carried out using 
the linear mixed effect models to explore the effects of treatment, time and other covariates on the 
endpoints, assuming the missing data mechanism is missing at random.
7.
Document history and changes in the planned statistical analysis
None
8.
References
1. Frank B., Willi M., Werner B, and Martin P. A graphical approach to sequentially rejective 
multiple test procedures. Statisics in Medicine, 28:586-604(2009).
2. EORTC. QLQ-C30 Scoring Manual. 2001 (Brussels);Third edition.
3. Oppe M RR, deCharro F. EuroQol EQ-5D User Guide. www.euroqol.org. 2007;Version 1.
4. Koch GG, Carr GJ, Amara IA, Stokes ME, Uryniak TJ. Categorical data analysis, in 
Statistical Methodology in the Pharmaceutical Sciences, ed. D.A. Berry, New York:Marcel 
Dekker Inc. 1990:391-475.
5. Quade D. Rank Analysis of Covariance. J Am Stat Assoc. 1967/12/01;62(320):1187-200


Supplement Statistical Analysis Plan
BAY 1163877 / 17403
Page: 1 of 10
Title page
A randomized, open label, multicenter Phase 2/3 study to evaluate the 
efficacy and safety of rogaratinib (BAY 1163877) compared to 
chemotherapy in patients with FGFR-positive locally advanced or 
metastatic urothelial carcinoma who have received prior platinum-
containing chemotherapy
Phase 2/3 study of rogaratinib (BAY 1163877) vs chemotherapy in patients with FGFR-
positive locally advanced or metastatic urothelial carcinoma
Bayer study drug
BAY 1163877 / rogaratinib
Study purpose:
Assess the efficacy and safety of rogaratinib compared to 
chemotherapy
Clinical study phase:
Phase 2/3
Date:
24 APR 2020
Study No.:
17403
Version:
1.0
Author:
Confidential
The information provided in this document is strictly confidential and is intended solely 
for the guidance of the clinical investigation. Reproduction or disclosure of this document, 
whether in part or in full, to parties not associated with the clinical investigation or its use 
for any other purpose without the prior written consent of the sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures.
The approval of the Statistical Analysis Plan is documented in a separate Signature Document.
PPD


Supplement Statistical Analysis Plan
BAY 1163877 / 17403
Page: 2 of 10
Table of Contents
Title page................................................................................................................................... 1
1.
Introduction....................................................................................................................... 3
2.
Study Objectives................................................................................................................ 3
3.
Study Design ...................................................................................................................... 4
3.1
Study periods and duration .............................................................................................. 4
3.2
Schedule of procedures.................................................................................................... 4
3.3
Determination of sample size........................................................................................... 4
4.
General Statistical Considerations .................................................................................. 4
4.1
General Principles............................................................................................................ 4
4.1.1
Changes in analyses for population characteristics and safety..................................... 4
4.2
Handling of Dropouts ...................................................................................................... 4
4.3
Handling of Missing Data................................................................................................ 5
4.3.1
Time-to-event variables................................................................................................ 5
4.3.2
Response rates .............................................................................................................. 5
4.3.3
Adverse Event Start Date ............................................................................................. 5
4.4
Interim Analyses and Data Monitoring ........................................................................... 5
4.5
Data Rules........................................................................................................................ 5
4.5.1
Time intervals............................................................................................................... 5
4.5.2
Baseline ........................................................................................................................ 5
4.5.3
Repeated measures ....................................................................................................... 5
4.5.4
Stratification ................................................................................................................. 5
4.5.5
Region........................................................................................................................... 6
4.6
Validity Review ............................................................................................................... 6
5.
Analysis Sets ...................................................................................................................... 6
6.
Statistical Methodology .................................................................................................... 6
6.1
Population characteristics ................................................................................................ 6
6.1.1
Disposition.................................................................................................................... 6
6.1.2
Protocol deviation......................................................................................................... 6
6.1.3
Demographics and other baseline characteristics......................................................... 6
6.1.4
Medical history............................................................................................................. 6
6.1.5
Prior and concomitant medication, Prior local Anti-cancer therapy, Systemic Anti-
Cancer Therapy during follow-up, Diagnostic and Therapeutic procedures, and 
Radiotherapy................................................................................................................. 6
6.1.6
Extent of Exposure ....................................................................................................... 6
6.2
Efficacy............................................................................................................................ 7
6.2.1
Changes in Primary Efficacy Variable ......................................................................... 7
6.2.2
Secondary Efficacy Analysis........................................................................................ 8
6.2.3
Changes in Statistical test strategy for secondary endpoints........................................ 9
6.2.4
Exploratory Efficacy Analysis ..................................................................................... 9
6.2.5
Subgroup Analyses....................................................................................................... 9
6.3
Safety ............................................................................................................................... 9
6.3.1
Adverse events (AEs)................................................................................................... 9


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6.3.2
Clinical laboratory evaluations................................................................................... 10
6.3.3
Other safety measures................................................................................................. 10
6.3.4
Pharmacokinetics/pharmacodynamics........................................................................ 10
6.3.5
Biomarker evaluation ................................................................................................. 10
6.3.6
Changes in Patient-reported outcomes (PRO)............................................................ 10
7.
Document history and changes in the planned statistical analysis............................. 10
8.
References ........................................................................................................................ 10
Abbreviations
AE
Adverse event
AESI
AE of special interest
CRF
Case Report Form
CSR
Clinical Study Report
DCR
Disease-control rate
DOR
Duration of response
DMC
Data Monitoring Committee
ECOG
Eastern Cooperative Oncology Group
FGFR
Fibroblast growth factor receptor
IxRS 
Interactive voice/web response system
PFS
Progression-free survival
PIK3CA
Phosphatidylinositol-3-kinase catalytic subunit alpha  
PRO
Patient-Reported outcome
SAP
Statistical Analysis Plan
ULN
Upper limit of normal
WT
Wild type
1.
Introduction
This Statistical Analysis Plan (SAP) supplement is based on the operational changes reflected 
in Protocol Amendment 4 (Integrated Protocol v. 3.0) dated 12 NOV 2019. This 
Supplemental SAP version 1.0 is a supplement of main SAP version 1.0 dated 17 MAY 2019.
The study was originally designed as Phase 2/3 study with two interim analyses. However, 
before achieving the criteria for the first interim analysis at the end of Phase 2 part, the study 
recruitment was put on hold after a recommendation of the study DMC. The sponsor decided 
to perform a full analysis and review of all study data and stopped the recruitment 
permanently. Due to the stop of enrollment and full data analysis, the study will not move 
forward to its Phase 3 part and will remain as Phase 2. 
This Supplemental SAP describes analyses that were not included in the main SAP but may 
be used for CSR. Changes to planned analyses in the SAP v1.0 are also described in this 
Supplemental SAP.
2.
Study Objectives
Refer to main SAP v1.0 dated 17 MAY 2019 for the objectives of original study design.


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The objective for the Phase 2 part of the study is to demonstrate the efficacy of rogaratinib
over chemotherapy in terms of objective response rate of urothelial carcinoma patients with
FGFR positive tumors. The Phase 3 part of the study will no longer be conducted, therefore 
OS will be considered as an exploratory efficacy variable for Phase 2.
3.
Study Design
Refer to the Integrated Protocol v3.0 (dated 12 NOV 2019) Section 5 for study design.
3.1
Study periods and duration
Refer to main SAP v1.0 dated 17 MAY 2019.
3.2
Schedule of procedures
Refer to the Integrated Protocol v3.0 (dated 12 NOV 2019) Table 9-1 for the detailed 
schedule for the assessments.
3.3
Determination of sample size
Refer to the Integrated Protocol v3.0 Section 10.4 (dated 12 NOV 2019) for the details about 
sample size calculation.
4.
General Statistical Considerations
4.1
General Principles
Refer to main SAP v1.0 dated 17 MAY 2019
4.1.1
Changes in analyses for population characteristics and safety 
Original planned analysis in main SAP v1.0:
All analyses for population characteristics (Section 6.1) and safety (Section 6.3) will be 
performed for WT patients first and will also be repeated for all study population if the test 
for primary endpoint OS in WT population is positive.  For the order of efficacy analyses, 
refer to Section 6.2 for the details.
New proposed analysis:
Given that the study was terminated at Phase 2 part, OS is not the primary efficacy endpoint 
any more, therefore, previously proposed step-wise analysis of OS will not be performed. All 
analyses for population characteristics (Section 6.1) and safety (Section 6.3) will be 
performed for all study population. For demographic and baseline characteristics variables, 
summary will also be provided for WT population.
4.2
Handling of Dropouts
Refer to main SAP v1.0 dated 17 MAY 2019


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4.3
Handling of Missing Data
Refer to main SAP v1.0 dated 17 MAY 2019
4.3.1
Time-to-event variables
Refer to main SAP v1.0 dated 17 MAY 2019
4.3.2
Response rates
Refer to main SAP v1.0 dated 17 MAY 2019
4.3.3
Adverse Event Start Date
Refer to main SAP v1.0 dated 17 MAY 2019
4.4
Interim Analyses and Data Monitoring
Two interim analyses and one final analysis were originally planned for this study as 
described in Section 10.5 in the Integrated Protocol v3.0 (dated 12 NOV 2019) and DMC 
charter. 
Before achieving the criteria for the first interim analysis, the study recruitment was put on 
hold after a recommendation of the study DMC. The sponsor decided to perform a full 
analysis and review of all study data and stopped the recruitment permanently. 
4.5
Data Rules
4.5.1
Time intervals
Refer to main SAP v1.0 dated 17 MAY 2019
4.5.2
Baseline
Refer to main SAP v1.0 dated 17 MAY 2019
4.5.3
Repeated measures
Refer to main SAP v1.0 dated 17 MAY 2019
4.5.4
Stratification
Refer to main SAP v1.0 dated 17 MAY 2019


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4.5.5
Region
Refer to main SAP v1.0 dated 17 MAY 2019
4.6
Validity Review
Refer to main SAP v1.0 dated 17 MAY 2019
5.
Analysis Sets
Refer to main SAP v1.0 dated 17 MAY 2019
6.
Statistical Methodology
6.1
Population characteristics
6.1.1
Disposition
Refer to main SAP v1.0 dated 17 MAY 2019
6.1.2
Protocol deviation
Refer to main SAP v1.0 dated 17 MAY 2019
6.1.3
Demographics and other baseline characteristics
Refer to main SAP v1.0 dated 17 MAY 2019
6.1.4
Medical history
Refer to main SAP v1.0 dated 17 MAY 2019
6.1.5
Prior and concomitant medication, Prior local Anti-cancer therapy, 
Systemic Anti-Cancer Therapy during follow-up, Diagnostic and Therapeutic 
procedures, and Radiotherapy
Refer to main SAP v1.0 dated 17 MAY 2019
6.1.6
Extent of Exposure
Changes for calculating duration of treatment for Chemotherapy arm:


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Old algorithm:
Duration of treatment: for rogaratinib arm: will be calculated in months as (the date of the 
last dose of study treatment – date of the first dose of study treatment + 1)/30.4375
New algorithm:
Duration of treatment: for rogaratinib arm: will be calculated in months as (the date of the 
last dose of study treatment – date of the first dose of study treatment + 1)/30.4375. for 
chemotherapy arm: will be calculated in months as: (the date of the last dose of study 
treatment – date of the first dose of study treatment + 21)/30.4375
New analysis added:
The overall treatment duration will be summarized under 800mg, 600mg and 400 mg dosage 
for rogaratinib arm.
6.2
Efficacy
6.2.1
Changes in Primary Efficacy Variable 
Overall survival (OS) was the primary efficacy variable for the planned Phase 3 part. Given 
that the study will not move forward to Phase 3 part, the primary efficacy variable for Phase 2 
part is objective response rate (ORR) based on central assessment. Overall survival will be 
considered as exploratory efficacy variable for Phase 2. 
Primary analysis of ORR
ORR will be compared between treatment arms using Fisher exact test for both WT and all 
study population.
Sensitivity analysis of ORR
1) The analyses of ORR based on investigator’s assessments will be conducted for WT 
and all population as described in Section 6.2.2 in main SAP v1.0 dated 17 MAY
2019.
2) The analyses of ORR for confirmed FGFR positive subjects in WT and all analysis 
population at the sponsor’s discretion, as described in Section 6.2.2 in main SAP v1.0 
dated 17 MAY 2019. 
3) A sensitivity analysis will be performed by only including FGFR DNA-positive 
patients.
Mutant subgroup: 
Two sensitivity analyses will be performed for ORR of mutant subgroup as described in 
Section 6.2.2 in main SAP v1.0 dated 17 MAY 2019.

First analysis will include all subjects with both known or unknown PIK3CA and RAS  
mutation status, per IxRS randomization scheme. 


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
Second analysis will only include subjects with known PIK3CA and RAS mutant, per 
IxRS randomization scheme.
6.2.2
Secondary Efficacy Analysis
6.2.2.1
Changes in Secondary efficacy endpoints
ORR is considered as primary efficacy endpoint for Phase 2 part. The remaining secondary 
efficacy endpoints include PFS, DCR, and DOR and will be analyzed as described in main 
SAP v1.0 dated 17 MAY 2019.
6.2.2.2
Analysis of secondary efficacy endpoints
The secondary efficacy variables based on final database will be tested in the WT subgroup 
and all study population.  No step-wise hypothesis test will be performed.
Analysis of PFS
Refer to main SAP v1.0 dated 17 MAY 2019
Analysis of DCR
Refer to main SAP v1.0 dated 17 MAY 2019
Analysis of DOR
Refer to main SAP v1.0 dated 17 MAY 2019
6.2.2.3
Sensitivity Analysis of Secondary Efficacy Endpoints
Refer to main SAP v1.0 dated 17 MAY 2019 for analyses of PFS, DCR and DOR.  
Changes in sensitivity analyses for mutant patients:
Two supportive analyses were originally proposed for PIK3CA and RAS mutant patients: 
First analysis will be performed by including mutant  patients and those with unknown 
mutation status, per IxRS randomization scheme; second analysis will only include known 
PIK3CA and RAS mutant patients.
However, due to very small number of enrolled subjects with known mutant status at 
randomization, for time to event endpoints (PFS and DOR), the supportive analyses will only 
be performed by combing mutant patients and those with unknown mutation status, per IxRS 
randomization scheme. 


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6.2.3
Changes in Statistical test strategy for secondary endpoints
The proposed sequential test strategy in main SAP will not be applied. 
6.2.4
Exploratory Efficacy Analysis
Changes in analysis of OS
The Step-wise hypothesis test and analysis of overall survival proposed in the main SAP will 
not be performed. OS will be analyzed in a similar way to PFS for WT and all population. 
6.2.5
Subgroup Analyses
Subgroup analyses will be performed in a descriptive fashion for ORR, DCR, PFS and OS. 
For ORR and DCR, subgroup analysis will only be performed within the subgroup which has 
at least 10 subjects in total across two arms. For PFS and OS, subgroup analysis will only be 
provided if there is at least 10 events in total within the subgroups across two arms. Both 
central and investigator assessment will be used for ORR, DCR and PFS.
Subgroup levels to be analyzed are:

Stratification factors at randomization (according to IxRS); However, in case of 
significant discrepancies between stratification factors entered in the interactive 
voice/web response system (IxRS) and information entered in CRF, the information 
from IxRS will be used for primary analysis but information from CRF will also be 
summarized

Region (Asia vs. North America [NA]/Western Europe [W EU]/Israel/Australia vs. 
Rest of World [RoW])

Age (<65 vs. ≥ 65, calculated at the date of randomization using date of birth)

ECOG performance status (0 vs. 1)

Gender (male vs. female)

Race

Renal function (GFR <45 vs. 45 - <60 vs. ≥60 mL/min/1.73m²)

hepatic function (AST and ALT each categorized by ≤ULN vs. >ULN ULN)
6.3
Safety
6.3.1
Adverse events (AEs)
Refer to main SAP v1.0 dated 17 MAY 2019
New analysis added:
The summary of TEAEs will be provided for following subjects:

For subjects with FGFR positive reading at enrollment but considered negative by 
confirmation reading. 


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
For subjects with FGFR score that went from 3+/4+ by original reading at enrollment
to 0 by confirmation reading

For subjects with FGFR score that went from 3+/4+ by original reading at enrollment
to 0/1/2 by confirmation reading
Adverse Events of Special Interest
Refer to main SAP v1.0 dated 17 MAY 2019.  
6.3.2
Clinical laboratory evaluations
Refer to main SAP v1.0 dated 17 MAY 2019
New analysis added: 
Summary of subjects with >ULN phosphate will be provided by treatment arm.
6.3.3
Other safety measures
Refer to main SAP v1.0 dated 17 MAY 2019
6.3.4
Pharmacokinetics/pharmacodynamics
Refer to main SAP v1.0 dated 17 MAY 2019
6.3.5
Biomarker evaluation
Refer to main SAP v1.0 dated 17 MAY 2019.
6.3.6
Changes in Patient-reported outcomes (PRO)
An analysis of covariance (ANCOVA) as well as other sensitivity analysis proposed in main 
SAP will not be performed.
7.
Document history and changes in the planned statistical analysis
1. Main SAP v1.0 dated 17 MAY 2019
8.
References
Not applicable.


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Page: 1 of 8
Title page
A randomized, open label, multicenter Phase 2/3 study to evaluate the 
efficacy and safety of rogaratinib (BAY 1163877) compared to 
chemotherapy in patients with FGFR-positive locally advanced or 
metastatic urothelial carcinoma who have received prior platinum-
containing chemotherapy
Phase 2/3 study of rogaratinib (BAY 1163877) vs chemotherapy in patients with 
FGFR-positive locally advanced or metastatic urothelial carcinoma
Bayer study drug
BAY 1163877 / rogaratinib
Study purpose:
Assess the efficacy and safety of rogaratinib compared to 
chemotherapy
Clinical study 
phase:
Phase 2/3
Date:
19 AUG 2020
Study No.:
17403
Version:
2.0
Author:
Confidential
The information provided in this document is strictly confidential and is intended solely 
for the guidance of the clinical investigation. Reproduction or disclosure of this 
document, whether in part or in full, to parties not associated with the clinical 
investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures.
The approval of the Statistical Analysis Plan is documented in a separate Signature Document.
PPD


Supplement Statistical Analysis Plan
BAY 1163877 / 17403
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Table of Contents
Title page................................................................................................................................... 1
1.
Introduction....................................................................................................................... 3
2.
Study Objectives................................................................................................................ 3
3.
Study Design ...................................................................................................................... 3
3.1
Study periods and duration .............................................................................................. 3
3.2
Schedule of procedures.................................................................................................... 3
3.3
Determination of sample size........................................................................................... 3
4.
General Statistical Considerations .................................................................................. 4
4.1
General Principles............................................................................................................ 4
4.1.1
Population characteristics and safety............................................................................ 4
4.2
Handling of Dropouts ...................................................................................................... 4
4.3
Handling of Missing Data................................................................................................ 4
4.3.1
Time-to-event variables................................................................................................ 4
4.3.2
Response rates .............................................................................................................. 4
4.3.3
Adverse Event Start Date ............................................................................................. 4
4.4
Interim Analyses and Data Monitoring ........................................................................... 4
4.5
Data Rules........................................................................................................................ 4
4.5.1
Time intervals............................................................................................................... 4
4.5.2
Baseline ........................................................................................................................ 4
4.5.3
Repeated measures ....................................................................................................... 5
4.5.4
Stratification ................................................................................................................. 5
4.5.5
Region........................................................................................................................... 5
4.6
Validity Review ............................................................................................................... 5
5.
Analysis Sets ...................................................................................................................... 5
6.
Statistical Methodology .................................................................................................... 5
6.1
Population characteristics ................................................................................................ 5
6.1.1
Disposition.................................................................................................................... 5
6.1.2
Protocol deviation......................................................................................................... 5
6.1.3
Demographics and other baseline characteristics......................................................... 5
6.1.4
Medical history............................................................................................................. 6
6.1.5
Prior and concomitant medication, Prior local Anti-cancer therapy, Systemic Anti-
Cancer Therapy during follow-up, Diagnostic and Therapeutic procedures, and 
Radiotherapy................................................................................................................. 6
6.1.6
Extent of Exposure ....................................................................................................... 6
6.2
Efficacy............................................................................................................................ 6
6.2.1
Primary Efficacy Variable............................................................................................ 6
6.2.2
Secondary Efficacy Analysis........................................................................................ 6
6.2.3
Statistical test strategy for secondary endpoints........................................................... 6
6.2.4
Exploratory Efficacy Analysis ..................................................................................... 6
6.2.5
Subgroup Analyses....................................................................................................... 7
6.3
Safety ............................................................................................................................... 7
6.3.1
Adverse events (AEs)................................................................................................... 7


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6.3.2
Clinical laboratory evaluations..................................................................................... 7
6.3.3
Other safety measures................................................................................................... 7
6.3.4
Changes in Pharmacokinetics/pharmacodynamics....................................................... 7
6.3.5
Biomarker evaluation ................................................................................................... 8
6.3.6
Patient-reported outcomes (PRO)................................................................................. 8
7.
Document history and changes in the planned statistical analysis............................... 8
8.
References .......................................................................................................................... 8
Abbreviations
AE
Adverse event
CSR
Clinical Study Report
PRO
Patient-Reported outcome
SAP
Statistical Analysis Plan
1.
Introduction
This Supplemental SAP describes analyses that were not included in the main SAP version 
1.0 (dated 12 NOV 2019) and SAP supplement version 1.0 (dated 24 APR 2020) but may be 
used for CSR. 
2.
Study Objectives
Refer to main SAP v1.0 dated 17 MAY 2019 and SAP supplement version 1.0 (dated 24 APR
2020).
3.
Study Design
Refer to the Integrated Protocol v3.0 (dated 12 NOV 2019) Section 5 for study design.
3.1
Study periods and duration
Refer to main SAP v1.0 dated 17 MAY 2019.
3.2
Schedule of procedures
Refer to the Integrated Protocol v3.0 (dated 12 NOV 2019) Table 9-1 for the detailed 
schedule for the assessments.
3.3
Determination of sample size
Refer to the Integrated Protocol v3.0 Section 10.4 (dated 12 NOV 2019) for the details about 
sample size calculation.


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4.
General Statistical Considerations
4.1
General Principles
Refer to main SAP v1.0 dated 17 MAY 2019
4.1.1
Population characteristics and safety 
Refer to main SAP v1.0 dated 17 MAY 2019 and SAP supplement version 1.0 (dated 24 APR
2020).
4.2
Handling of Dropouts
Refer to main SAP v1.0 dated 17 MAY 2019
4.3
Handling of Missing Data
Refer to main SAP v1.0 dated 17 MAY 2019
4.3.1
Time-to-event variables
Refer to main SAP v1.0 dated 17 MAY 2019
4.3.2
Response rates
Refer to main SAP v1.0 dated 17 MAY 2019
4.3.3
Adverse Event Start Date
Refer to main SAP v1.0 dated 17 MAY 2019
4.4
Interim Analyses and Data Monitoring
Refer to main SAP v1.0 dated 17 MAY 2019 and SAP supplement version 1.0 (dated 24 APR
2020).
4.5
Data Rules
4.5.1
Time intervals
Refer to main SAP v1.0 dated 17 MAY 2019
4.5.2
Baseline
Refer to main SAP v1.0 dated 17 MAY 2019


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4.5.3
Repeated measures
Refer to main SAP v1.0 dated 17 MAY 2019
4.5.4
Stratification
Refer to main SAP v1.0 dated 17 MAY 2019
4.5.5
Region
Refer to main SAP v1.0 dated 17 MAY 2019
4.6
Validity Review
Refer to main SAP v1.0 dated 17 MAY 2019
5.
Analysis Sets
Refer to main SAP v1.0 dated 17 MAY 2019
6.
Statistical Methodology
6.1
Population characteristics
6.1.1
Disposition
Refer to main SAP v1.0 dated 17 MAY 2019
6.1.2
Protocol deviation
Refer to main SAP v1.0 dated 17 MAY 2019
New analysis added:
Only three subjects were impacted by Covid-19 for this study. The protocol deviations 
associated with Covid-19 will be listed.
6.1.3
Demographics and other baseline characteristics
Refer to main SAP v1.0 dated 17 MAY 2019


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6.1.4
Medical history
Refer to main SAP v1.0 dated 17 MAY 2019
6.1.5
Prior and concomitant medication, Prior local Anti-cancer therapy, 
Systemic Anti-Cancer Therapy during follow-up, Diagnostic and 
Therapeutic procedures, and Radiotherapy
Refer to main SAP v1.0 dated 17 MAY 2019
6.1.6
Extent of Exposure
Refer to main SAP v1.0 dated 17 MAY 2019 and SAP supplement version 1.0 dated 24 APR
2020.
6.2
Efficacy
6.2.1
Primary Efficacy Variable 
Refer to main SAP v1.0 dated 17 MAY 2019 and SAP supplement version 1.0 dated 24 APR
2020.
6.2.2
Secondary Efficacy Analysis
6.2.2.1
Secondary efficacy endpoints
Refer to main SAP v1.0 dated 17 MAY 2019 and SAP supplement version 1.0 dated 24 APR
2020.
6.2.2.2
Sensitivity Analysis of Secondary Efficacy Endpoints
Refer to main SAP v1.0 dated 17 MAY 2019 and SAP supplement version 1.0 dated 24 APR
2020.
6.2.3
Statistical test strategy for secondary endpoints
Refer to main SAP v1.0 dated 17 MAY 2019 and SAP supplement version 1.0 dated 24 APR
2020.
6.2.4
Exploratory Efficacy Analysis
Refer to main SAP v1.0 dated 17 MAY 2019 and SAP supplement version 1.0 dated 24 APR
2020.


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6.2.5
Subgroup Analyses
Refer to main SAP v1.0 dated 17 MAY 2019 and SAP supplement version 1.0 dated 24 APR
2020.
6.3
Safety
6.3.1
Adverse events (AEs)
Refer to main SAP v1.0 dated 17 MAY 2019 and SAP supplement version 1.0 dated 24 APR
2020.
Adverse Events of Special Interest
Refer to main SAP v1.0 dated 17 MAY 2019.  
6.3.2
Clinical laboratory evaluations
Refer to main SAP v1.0 dated 17 MAY 2019 and SAP supplement version 1.0 dated 24 APR
2020.
6.3.3
Other safety measures
Refer to main SAP v1.0 dated 17 MAY 2019
6.3.4
Changes in Pharmacokinetics/pharmacodynamics
Old text in main SAP dated 17 MAY 2019:
The details of pharmacokinetic analysis and results will be described in the separate analysis 
plan and report. 
New analysis added:
Plasma samples for measurement of rogaratinib (BAY 1163877) concentrations will be 
collected from all rogaratinib-treated patients as follows:

Day 1 of Cycle 1, 2, 3, 4 and 5:

at pre-dose (before supervised dose administration)

1 (±0.5h) hour post-dose (between 0.5 and 1.5 after dose administration)


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In the clinical study report, only plasma concentration data of individual subject for all 
analytes will be listed.
6.3.5
Biomarker evaluation
Refer to main SAP v1.0 dated 17 MAY 2019.
6.3.6
Patient-reported outcomes (PRO)
Refer to main SAP v1.0 dated 17 MAY 2019 and SAP supplement version 1.0 dated 24 APR
2020.
7.
Document history and changes in the planned statistical analysis
1. Main SAP v1.0 dated 17 MAY 2019
2. SAP supplement v1.0 dated 24 APR 2020.
8.
References
Not applicable.