Clinical trial NCT03473756
Conditions: Urothelial Carcinoma
Keywords: Locally advanced or metastatic urothelial carcinoma Bladder cancer Checkpoint inhibition FGFR inhibition
Sponsor: Bayer
Start date: 2018-05-15; Completion date: 2024-07-10
Enrollment: 37 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
FORT-2 is designed to evaluate safety, efficacy, RP2D and PK of rogaratinib in combination with atezolizumab in patients with untreated FGFR-positive urothelial carcinoma. The study originally comprised two separate parts: Phase 1b (Part A) and Phase 2 (Part B). The study parts differ in design, objectives, and treatment.

The primary objectives of this Phase 1b study (Part A) are to determine the safety, tolerability, RP2D and pharmacokinetics of rogaratinib in combination with atezolizumab in these patients.

The primary objective of the Part B is to compare progression-free survival (PFS) according to RECIST v1.1 of rogaratinib in combination with atezolizumab over placebo in combination with atezolizumab in untreated patients with FGFR-positive locally advanced or metastatic urothelial carcinoma.

Of note, patients who participate in Part A are not allowed to participate in Part B.

Part B will be initiated once the data from Part A supports continuation of the study, even if this occurs prior to primary completion of Part A. The sponsor may decide not to continue the study as a whole after completion of Part A if the data do not support further development.

Part B of the study will no longer be conducted.

Detailed description:

Arms: arm 1: Part A: Part A is conducted in patients who are cisplatin-ineligible and have had no prior systemic treatment for locally advanced or metastatic disease.

Patients will receive rogaratinib plus atezolizumab combination treatment.
Interventions: intervention 1: Rogaratinib (BAY1163877) intervention 2: Atezolizumab
Intervention descriptions: intervention 1: Part A:Rogaratinib will be administered orally until disease progression, unacceptable toxicity or consent withdrawal. The starting dose of 800 mg b.i.d. will be confirmed using a dose selection design. intervention 2: Part A: A fixed dose of 1200 mg atezolizumab will be administered through intravenous (i.v.) infusion on Day 1 of each 21-day cycle until disease progression, unacceptable toxicity or consent withdrawal.

Protocol documents:
Prot_000.pdf: 
Document Type: 
Clinical Study Protocol 
 
Official Title: 
An international, multicenter, Phase 1b/2 study of rogaratinib 
(BAY1163877) in combination with atezolizumab as first-line 
treatment in cisplatin-ineligible patients with FGFR-positive 
locally advanced or metastatic urothelial carcinoma 
 
NCT Number: 
NCT03473756 
Document Date: 
23 MAY 2023  
 


 
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Cover page of the integrated protocol 
 
An international, multicenter, Phase 1b/2 study of rogaratinib (BAY 1163877) in 
combination with atezolizumab as first-line treatment in cisplatin-ineligible patients 
with FGFR-positive locally advanced or metastatic urothelial carcinoma 
 
This protocol version is an integration of the following documents/sections of 19131 
Part A: 
• Amendment no. 5 (global amendment described in Section 15.5)  
forming integrated protocol Part A Version 6.0, dated 23 MAY 2023 
• Amendment no. 4 (global amendment described in Section 15.4)  
forming integrated protocol Part A Version 5.0, dated 09 NOV 2022 
• Amendment no. 3 (global amendment described in Section 15.3)  
forming integrated protocol Part A Version 4.0, dated 4 OCT 2021 
• Amendment no. 2 (global amendment described in Section 15.2)  
forming integrated protocol Part A Version 3.0, dated 10 FEB 2021 
• Amendment no. 1 (global amendment described in Section 15.1) 
forming integrated protocol Part A Version 2.0, dated 04 DEC 2018 
• Original protocol Part A, Version 1.0, dated 04 DEC 2017 
This document integrates the original protocol and all global amendments of 19131 Part A. 


 
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1. 
Title page 
An international, multicenter, Phase 1b/2 study of rogaratinib (BAY 1163877) in 
combination with atezolizumab as first-line treatment in cisplatin-ineligible patients 
with FGFR-positive locally advanced or metastatic urothelial carcinoma 
Short title: Phase 1b/2 study of rogaratinib (BAY 1163877) in combination with 
atezolizumab in urothelial carcinoma 
Note: 
Study 19131 originally comprised two separate parts: Phase 1b (Part A) and 
Phase 2 (Part B). The study parts differ in design, objectives, and treatment.  
This part of the protocol is to be used for conducting Part A of the study 
only. Part B of the study will no longer be conducted. 
Acronym: 
FORT-2 
Test drug: 
BAY 1163877 / rogaratinib / pan FGFR inhibitor  
Clinical study phase: 
Part A: Phase 1b  
Part B: Phase 2 
Date: 
23 MAY 2023 
Registration: 
EudraCT: 2017-001483-38 
Version no.: 
6.0 
Sponsor’s study no.: 
19131 
 
 
Sponsor: 
Non-US: 
Bayer AG, D-51368 Leverkusen, Germany 
US: 
Bayer HealthCare Pharmaceuticals Inc.,  
100 Bayer Boulevard, P.O. Box 915,  
Whippany, NJ 07981-0915, US 
Sponsor’s medical expert: 
 
 
 
Bayer HealthCare Pharmaceuticals Inc.,  
100 Bayer Boulevard, P.O. Box 915,  
Whippany, NJ 07981-0915, US 
Telephone no.: 
 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements. 
This is an electronically generated document that does not bear any sponsor signatures.  
The signature of the Sponsor’s medically responsible person is filed in the TMF and 
available on request. 
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


 
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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 
Note: 
Study 19131 originally comprised two separate parts: Phase 1b (Part A) and Phase 2 
(Part B). The study parts differ in design, objectives, and treatment.  
This part of the protocol is to be used for conducting Part A of the study only. 
Part B of the study will no longer be conducted. 
Title 
An international, multicenter, Phase 1b/2 study of rogaratinib 
(BAY 1163877) in combination with atezolizumab as first-line treatment 
in cisplatin-ineligible patients with FGFR-positive locally advanced or 
metastatic urothelial carcinoma 
Short title 
Phase 1b/2 study of rogaratinib (BAY 1163877) in combination with 
atezolizumab in urothelial carcinoma 
Acronym 
FORT-2 
Clinical study phase 
Part A: Phase 1b 
Study objectives 
Primary objectives of Part A: 
• 
To determine the safety and tolerability of rogaratinib in 
combination with atezolizumab in patients with FGFR-positive 
locally advanced or metastatic urothelial carcinoma 
• 
To determine the recommended Phase 2 dose (RP2D) of 
rogaratinib in combination with atezolizumab in this patient 
population. 
Secondary objective of Part A: 
• 
To assess the efficacy of the combination of rogaratinib and 
atezolizumab in this patient population.  
• 
To characterize the pharmacokinetics (PK) of rogaratinib in 
combination with atezolizumab in this patient population 
Exploratory objectives of Part A: 
• 
To assess new potential predictive or prognostic biomarkers and 
their association with tumor-related biomarkers, disease response, 
drug-resistance and patient outcome. 
• 
To evaluate further biomarkers to investigate the drug (i.e. mode-
of-action-related effect and / or safety) and / or the 
pathomechanism of the disease. 
• 
To evaluate the combination of rogaratinib and atezolizumab with 
regard to patient-reported outcomes (PRO). 
Test drug 
Rogaratinib / BAY 1163877 
Name of active ingredient 
Rogaratinib 
Dose 
The RP2D will be determined in Part A of the study. Starting dose level of 
rogaratinib is 800 mg twice daily (b.i.d.), in continuous 21-day cycles. If 
suggested by safety findings, lower doses may be explored. 


 
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Route of administration 
Oral 
Duration of treatment 
Patients will continue dosing until any of the following occurs: 
• 
Radiological disease progression according to Response 
Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) 
o At the investigator’s discretion, study treatment may continue 
beyond radiological progression as defined by RECIST v1.1 
(e.g. in case of suspected pseudoprogression) 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 
• 
Consent withdrawal 
• 
Withdrawal from the study treatment at the discretion of the 
investigator or designated associate(s) 
Combination drug 
Atezolizumab 
Name of active ingredient 
Atezolizumab 
Dose 
1200 mg every 21 days 
Route of administration 
Intravenous (i.v.) infusion 
Duration of treatment 
See test drug above 
Indication 
FGFR-positive locally advanced or metastatic urothelial carcinoma 
Diagnosis and main criteria for 
inclusion /exclusion 
Patients with FGFR-positive locally advanced or metastatic urothelial 
carcinoma who are cisplatin-ineligible and have had no prior systemic 
treatment for locally advanced or metastatic disease.  
Main inclusion criteria: 
• 
Male or female patients ≥ 18 years of age (at least age of legal 
maturity)  
• 
Documented urothelial carcinoma (transitional cell carcinoma) 
including urinary bladder, renal pelvis, ureters, urethra, meeting 
all of the following criteria:  
o Histologically confirmed. 
o Patients with mixed histology are required to have a dominant 
transitional cell pattern.  
o Locally advanced (T4, any N; or any T, N2-3) or metastatic 
disease (any T, any N and M1).  
Note: 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). 
• 
High FGFR1 or 3 mRNA expression levels (RNAscope score of 
3+ or 4+; measurement is part of this protocol) in archival or fresh 
tumor biopsy specimen 


 
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• 
At least 1 measurable lesion according to RECIST v1.1 in 
contrast enhanced (unless contraindicated) CT or MRI 
• 
No prior systemic treatment for locally advanced or metastatic 
urothelial carcinoma. For patients who received prior 
adjuvant/neoadjuvant chemotherapy or chemo-radiation for 
urothelial carcinoma, a treatment-free interval > 12 months 
between the last treatment administration and the date of 
recurrence is required in order to be considered treatment-naïve in 
the metastatic setting. Prior local intra-vesical chemotherapy or 
prior local immunotherapy (e.g. with Bacillus Calmette-Guérin 
[BCG]) is allowed if completed at least 4 weeks before first study 
drug administration. 
• 
Ineligibility for cisplatin-based chemotherapy 
• 
Eastern Cooperative Oncology Group Performance Status (ECOG 
PS) 0 or 1 
• 
Adequate hematologic and end organ function 
• 
Recovery to National Cancer Institute’s Common Terminology 
Criteria for Adverse Events, version 4.03 (NCI CTCAE v.4.03) 
Grade 0 or 1 level or recovery to baseline preceding the prior 
treatment from any previous drug / procedure-related toxicity 
(patients with persistent alopecia, anemia [hemoglobin ≥ 9 g/dl], 
any grade peripheral neuropathy, impaired renal function [GFR 
> 30 mL/min/1.73 m2], hearing loss and / or hypothyroidism that 
is adequately controlled by hormone replacement can be 
included) 
Main exclusion criteria: 
• 
Inability to swallow oral medications 
• 
Any malabsorption condition 
• 
Current diagnosis of any retinal disorders including retinal 
detachment, retinal pigment epithelial detachment (RPED), 
central serous retinopathy or retinal vein occlusion  
• 
Previous or concurrent cancer except  
o cervical carcinoma in situ  
o treated basal-cell carcinoma or squamous cell skin cancer 
o localized prostate cancer treated with curative intent and 
known absence of prostate-specific antigen (PSA) relapse or 
incidental prostate cancer (T1/T2a, Gleason score ≤ 6 and 
PSA ≤ 10 ng/mL undergoing active surveillance and 
treatment-naïve) 
o any other cancer curatively treated > 3 years before the first 
study drug administration 
• 
Ongoing or previous treatment with anti-FGFR directed therapies 
(e.g. receptor tyrosine kinase inhibitors including rogaratinib or 
FGFR-specific antibodies) 
• 
Previous assignment to treatment during this study 


 
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• 
Severe (CTCAE v.4.03 Grade ≥ 3) infections within 4 weeks 
before the first study drug administration, including but not 
limited to hospitalization for complication of infection, 
bacteremia, or severe pneumonia 
• 
History of autoimmune disease except: a) autoimmune-related 
hypothyroidism clinically stable on thyroid replacement hormone; 
b) controlled Type-I diabetes mellitus on a stable dose of insulin 
regimen 
• 
History or current condition of uncontrolled cardiovascular 
disease 
• 
Systolic/diastolic blood pressure ≤ 100/60 mmHg and concurrent 
heart rate ≥ 100/min 
• 
Renal failure requiring peritoneal dialysis or hemodialysis 
• 
Current evidence of endocrine alteration of calcium phosphate 
homeostasis (e.g. parathyroid disorder, history of 
parathyroidectomy, tumor lysis, tumoral calcinosis, 
paraneoplastic hypercalcemia) 
• 
Concomitant therapies that are known to increase serum calcium 
or phosphate levels and that cannot be discontinued or switched to 
a different medication before start of study treatment  
• 
Evidence or history of bleeding diathesis or coagulopathy 
• 
Any hemorrhage / bleeding event CTCAE v.4.03 ≥ Grade 3 
within 4 weeks before the first study drug administration 
For the complete list of inclusion and exclusion criteria, please refer to 
Sections 6.1 and 6.2 of this protocol. 
Study design 
 
 
Part A study design 
Part A of the study is an open-label, single-arm, international, multicenter, 
Phase 1b study of rogaratinib in combination with atezolizumab. 
Dose selection: The dose selection part of the study 19131 will assess the 
safety and tolerability of the combination. The maximum tolerated dose 
(MTD) and/or recommended Phase 2 dose (RP2D) for the combination 
will be determined using stepwise dose selection design based on a 
modified toxicity probability interval (mTPI) method (See 
Section 10.3.4.1). After dose selection, further patients (up to 50 in total 
for the whole Part A) will be enrolled to confirm the RP2D.  
The study is composed of the following study periods: 
• 
Pre-treatment period, including 
o 
FGFR testing 


 
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The mRNA expression of FGFR1 or 3 will be investigated using 
archival or fresh tumor biopsy specimen taken before the screening 
procedures are conducted. Only patients with locally advanced or 
metastatic urothelial carcinoma whose tumors are FGFR positive 
(RNAscope score of 3+ or 4+) will be included in the study. 
o 
Screening 
• 
Treatment period 
Patients who meet all study inclusion and exclusion criteria will be eligible 
to start study treatment. 
Patients will receive an oral, single dose of rogaratinib in the morning of 
Cycle 1 on Day 1, followed by single dose serial PK blood sampling for 
8 hours and a second single dose of rogaratinib in the evening. Rogaratinib 
will be administered continuously twice daily on all 21 days in each cycle. 
A fixed dose of 1200 mg atezolizumab will be administered through 
intravenous (i.v.) infusion on Day 1 of each 21-day cycle. 
Patients will continue dosing of both study drugs until any of the 
following occurs: 
• 
Radiological disease progression according to RECIST v1.1 
o At the investigator’s discretion, study treatment may continue 
beyond radiological progression as defined by RECIST v1.1 
(e.g. in case of suspected pseudoprogression) 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 
• 
Consent withdrawal 
• 
Withdrawal from the study treatment at the discretion of the 
investigator or designed associate(s). 
 
• 
Follow-up period 
After primary completion, follow-up information will not be 
collected after the safety assessment visit. 
o 
Active follow-up 
After permanent treatment discontinuation, a safety assessment 
visit must be scheduled for all patients at least 30 (+7) days after 
the last dose of study treatment. 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. In addition, any AEs after the active follow-up 
visit qualifying as SAEs or AESIs with an onset up to 90 days after 
last atezolizumab dosing that are reported to the sites need to be 
documented unless a new anti-cancer therapy has been initiated. 
Up to primary completion, for patients who permanently 
discontinue study treatment without radiological disease 
progression, drug-related AEs will continue to be collected and 
follow-up tumor evaluations will be performed (by CT or MRI with 


 
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contrast unless contraindicated) until progression of malignancy 
and/or start of subsequent systemic anti-cancer treatment, 
whichever comes first, or any other criterion for withdrawal from 
study is met. 
o 
Long-term follow-up 
After completion of the active follow-up, patients will be followed 
up for survival status and start of subsequent systemic anti-cancer 
therapy approximately every 3 months (±14 days) until the end of 
the study (i.e. until last patient’s last visit [LPLV]). In addition, any 
AEs after the active follow-up visit qualifying as SAEs or AESIs 
with an onset up to 90 days after last atezolizumab dosing that are 
reported to the sites need to be documented unless a new anti-
cancer therapy has been initiated. Long-term follow-up will not be 
performed after primary completion. 
Methodology 
Part A (Phase 1b) of the study will evaluate safety, tolerability, maximum 
tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D), 
pharmacokinetics and efficacy of rogaratinib in combination with 
atezolizumab in FGFR-positive locally advanced or metastatic urothelial 
carcinoma.  
Doses for each study drug and the schedule of treatment are specified 
above in the study design. 
Primary and secondary variables will be assessed as specified below. 
Safety 
Safety and tolerability evaluations will include monitoring of all serious 
and non-serious adverse events, physical examinations, vital signs, ECOG 
performance status, electrocardiogram (ECG) readings, radiologic 
imaging, laboratory tests and concomitant medications. In addition, 
ophthalmological examinations will be performed regularly, according to 
the schedule of evaluations. Patient data will be analyzed for evidence of 
cumulative toxicity with repeated cycles of treatment. Each patient will be 
regularly assessed for potential adverse events, dose-limiting toxicities 
(DLTs) and disease related signs and symptoms. Adverse events will be 
reported using Medical Dictionary for Regulatory Activities (MedDRA) 
terms (version 20.0 or later) and their severity will be graded according to 
the NCI CTCAE version 4.03.  
Determination of MTD  
Stepwise dose selection design based on a modified toxicity probability 
interval (mTPI) method will be used to determine the MTD for the 
combination treatment. No decision is made before data of at least 
4 patients are available on the first dose level and are evaluable for DLTs 
assessment. The sponsor in consultation with the investigators will decide 
how many additional patients need to be evaluable for DLTs on the same 
dose level before the next decision. The decision on the number of 
additional patients and on the next dose level will be based on the 
recommendations from the mTPI, clinical assessment, all available PK and 
safety data. 
The dose selection part will be finished after 20 patients are valid for the 
MTD assessment. The RP2D will be defined once sufficient data is 


 
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available. The final decision about the RP2D will be made by the sponsor 
in consultation with the investigators. 
Pharmacokinetics 
Blood samples will be collected to measure rogaratinib pharmacokinetics 
in combination with atezolizumab. Pharmacokinetics of rogaratinib will be 
evaluated on Cycle 1 Day 1 after single dosing up to 8 hours post dose. In 
addition, blood (plasma) samples will be collected for exposure-response 
assessment on Day 1 of Cycles 2 to 5. 
For monitoring purposes of atezolizumab, blood (plasma) samples will be 
collected on Cycle 1 Day 1 at pre-dose, 1 (end of infusion [EOI]), 4 and 
8 hours and on Cycle 1 Day 15 (approximately 336 hours post-dose).  
Efficacy 
Tumor assessments will be performed using computed tomography (CT) or 
magnetic resonance imaging (MRI) (with contrast unless contraindicated), 
and patient survival will be followed up to determine the efficacy variables 
of this study: objective response rate (ORR), disease control rate (DCR), 
duration of response (DOR), best overall response (CR, PR, SD, Non 
CR/Non PD, PD), progression-free survival (PFS) and overall survival 
(OS). Tumor response will be evaluated using the RECIST v1.1. In 
addition, modified RECIST v1.1 for immune-based therapeutics 
(iRECIST) will be documented and used as supportive evidence for the 
detection of pseudoprogression and the determination of progressive 
disease for treatment decision.  
Tumor scans will be performed at screening (baseline), and then every 
9 weeks (±7 days) starting from Cycle 1 Day 1 until radiological disease 
progression or end of the study. After primary completion, scans will be 
performed every 14 weeks (±14 days). A minimum of at least 9 weeks 
from start of treatment is mandatory for the 1st “on treatment” tumor 
assessment. If the investigator considers radiographic changes secondary to 
drug-induced inflammation and not to tumor progression, the investigator 
may postpone a diagnosis of progressive disease until the next 
radiographic evaluation in the study. Radiological tumor assessments will 
be performed locally by investigators. To facilitate an independent 
evaluation of outcome in this study, tumor assessment imaging data will be 
collected, image quality controlled and stored for a potential central review 
of tumor evaluation by independent readers. The decision to perform the 
central review will be based on the outcome of the local efficacy 
assessments. Central review will not be used for treatment decisions. 
Up to primary completion, patients who discontinue the study treatment for 
any reason other than radiological PD will be followed for progression 
during active follow-up (which includes the safety follow-up period) until 
confirmed PD for this patient is observed.  
Patient reported outcome (PRO) 
Patient reported outcomes will be assessed using EORTC QLQ-C30 (at 
screening, on Day 1 of every cycle, at the EOT, and at the safety 
assessment visit of the active follow-up). After primary completion, PROs 
will not be required. 
Type of control 
Not applicable 


 
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Data Monitoring Committee 
No 
Number of patients 
In Part A, approximately a total of 26-30 patients will be treated. 
Approximately 20 additional patients may be enrolled up to a total of 
50 patients for the whole Part A. 
Primary variables 
• 
The incidence of DLTs will be used to determine the MTD and/or 
RP2D. 
• 
The incidence of treatment-emergent adverse events (TEAEs), 
treatment-emergent drug-related TEAEs, and treatment-emergent 
serious adverse events. 
Time point/frame of 
measurement for primary 
variables 
The incidence of DLTs will be determined in the first cycle.  
The incidence of TEAEs will be assessed for individual patients regularly 
in all cycles. 
Plan for statistical analysis 
For Part A (Phase 1b) of the study, all data will be listed and study 
summary tables will be provided where appropriate. Quantitative data will 
be described by the following summary statistics: arithmetic mean, 
standard deviation, median, minimum and maximum. Where appropriate, 
summary statistics will be provided for the original data as well as for the 
changes versus baseline. Graphical illustrations will be provided where 
appropriate. Frequency tables will be provided for qualitative data.  
Time-to-event endpoints will be analyzed using Kaplan–Meier 
methodology.  
The dose selection will be performed using the modified toxicity 
probability interval method (mTPI).  
Due to the exploratory character of this study, no confirmatory analysis 
will be performed. All calculated p-values and confidence intervals are to 
be interpreted in the exploratory sense. 
The statistical evaluation will be performed by using the software package 
SAS (SAS Institute Inc., Cary, NC, USA) with the release to be specified 
in the statistical analysis plan. 
More detailed information of the planned statistical analyses can be found 
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 principal investigator ....................................................................................... 3 
2. 
Synopsis ............................................................................................................................ 4 
Table of contents ................................................................................................................... 12 
Table of tables ....................................................................................................................... 16 
Table of figures ..................................................................................................................... 16 
List of abbreviations ............................................................................................................. 17 
Definitions of terms .............................................................................................................. 22 
3. 
Introduction ................................................................................................................... 24 
3.1 
Study set up: Part A ..................................................................................................... 24 
3.2 
Background .................................................................................................................. 24 
3.3 
Rogaratinib ................................................................................................................... 27 
3.4 
Atezolizumab ............................................................................................................... 29 
3.5 
Rationale of the study .................................................................................................. 29 
3.6 
Benefit-risk assessment ................................................................................................ 30 
4. 
Study objectives ............................................................................................................. 31 
5. 
Study design ................................................................................................................... 32 
5.1 
Design overview .......................................................................................................... 32 
5.2 
Study periods ............................................................................................................... 34 
5.2.1 
Pre-treatment period ................................................................................................. 34 
5.2.2 
Treatment period....................................................................................................... 34 
5.2.3 
Follow-up periods ..................................................................................................... 35 
5.3 
Primary variable(s) ...................................................................................................... 36 
5.4 
Justification of the design ............................................................................................ 36 
5.5 
End of study ................................................................................................................. 36 
5.6 
Primary completion ...................................................................................................... 37 
6. 
Study population ........................................................................................................... 37 
6.1 
Inclusion criteria .......................................................................................................... 37 
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 
6.4.1.3 
Withdrawal criteria ................................................................................................ 47 
6.4.1.4 
General procedures ................................................................................................ 51 
6.4.2 
Replacement ............................................................................................................. 51 


 
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6.5 
Patient identification .................................................................................................... 52 
7. 
Treatments ..................................................................................................................... 52 
7.1 
Treatments to be administered ..................................................................................... 52 
7.2 
Identity of study treatment ........................................................................................... 52 
7.2.1 
Rogaratinib – test drug ............................................................................................. 53 
7.2.2 
Atezolizumab – combination drug ........................................................................... 53 
7.3 
Treatment assignment .................................................................................................. 54 
7.4 
Dosage and administration ........................................................................................... 54 
7.4.1 
Doses, dosing schedule and route of administration ................................................ 54 
7.4.1.1 
Rogaratinib – test drug .......................................................................................... 54 
7.4.1.2 
Atezolizumab – combination drug ........................................................................ 54 
7.4.2 
Justification of selected doses................................................................................... 55 
7.4.3 
Dose modifications ................................................................................................... 56 
7.4.3.1 
Dose limiting toxicities (DLTs) ............................................................................ 56 
7.4.3.2 
Dose modifications of rogaratinib ......................................................................... 57 
7.4.3.2.1 
Hyperphosphatemia ........................................................................................... 59 
7.4.3.2.2 
Liver toxicity ...................................................................................................... 60 
7.4.3.2.3 
Retinal disorders ................................................................................................ 62 
7.4.3.3 
Dose modifications of atezolizumab ..................................................................... 62 
7.4.4 
Treatment duration ................................................................................................... 80 
7.5 
Blinding ....................................................................................................................... 81 
7.6 
Drug logistics and accountability................................................................................. 81 
7.7 
Treatment compliance .................................................................................................. 81 
8. 
Non-study therapy ......................................................................................................... 82 
8.1 
Prior and concomitant therapy ..................................................................................... 82 
8.2 
Post-study therapy ........................................................................................................ 84 
9. 
Procedures and variables ............................................................................................. 85 
9.1 
Tabular schedule of evaluations .................................................................................. 85 
9.2 
Visit description ........................................................................................................... 93 
9.2.1 
Pre-treatment period ................................................................................................. 93 
9.2.1.1 
FGFR testing ......................................................................................................... 93 
9.2.1.2 
Screening ............................................................................................................... 94 
9.2.2 
Treatment period....................................................................................................... 96 
9.2.2.1 
Cycle 1 ................................................................................................................... 97 
9.2.2.2 
Cycles 2 – 4 ......................................................................................................... 101 
9.2.2.3 
Cycles ≥ 5 ............................................................................................................ 104 
9.2.2.4 
Tumor assessments during treatment period ....................................................... 105 
9.2.2.5 
End-of-treatment (EOT) visit .............................................................................. 105 
9.2.3 
Follow-up periods ................................................................................................... 107 
9.2.3.1 
Active follow-up ................................................................................................. 107 
9.2.3.2 
Long-term follow-up ........................................................................................... 108 
9.3 
Population characteristics .......................................................................................... 109 
9.3.1 
Demographic .......................................................................................................... 109 
9.3.2 
Medical history ....................................................................................................... 109 


 
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9.3.3 
Other baseline characteristics ................................................................................. 109 
9.4 
Efficacy ...................................................................................................................... 111 
9.5 
Pharmacokinetics / pharmacodynamics ..................................................................... 114 
9.5.1 
Drug measurements ................................................................................................ 114 
9.5.2 
Non-compartmental pharmacokinetic evaluation ................................................... 115 
9.6 
Safety ......................................................................................................................... 115 
9.6.1 
Adverse events ........................................................................................................ 116 
9.6.1.1 
Definitions ........................................................................................................... 117 
9.6.1.2 
Classifications for adverse event assessment ...................................................... 118 
9.6.1.2.1 
Seriousness ....................................................................................................... 118 
9.6.1.2.2 
Intensity ............................................................................................................ 118 
9.6.1.2.3 
Causal relationship ........................................................................................... 119 
9.6.1.2.4 
Action taken with study treatment ................................................................... 120 
9.6.1.2.5 
Other specific treatment(s) of adverse events .................................................. 121 
9.6.1.2.6 
Outcome ........................................................................................................... 121 
9.6.1.3 
Assessments and documentation of adverse events ............................................ 121 
9.6.1.4 
Reporting of serious adverse events .................................................................... 123 
9.6.1.5 
Expected adverse events ...................................................................................... 124 
9.6.1.6 
Adverse events of special safety interest ............................................................. 124 
9.6.2 
Pregnancies ............................................................................................................. 126 
9.6.3 
Further safety .......................................................................................................... 126 
9.6.3.1 
Laboratory evaluations ........................................................................................ 126 
9.6.3.2 
Physical examinations ......................................................................................... 128 
9.6.3.3 
Body height, weight and BMI ............................................................................. 128 
9.6.3.4 
12-lead ECG ........................................................................................................ 128 
9.6.3.5 
Vital signs ............................................................................................................ 129 
9.6.3.6 
ECOG and Karnofsky performance status .......................................................... 130 
9.6.3.7 
Ophthalmological examination ........................................................................... 131 
9.6.3.8 
Chest X-ray ......................................................................................................... 132 
9.7 
Other procedures and variables .................................................................................. 132 
9.7.1 
Biomarker investigations ........................................................................................ 132 
9.7.2 
Patient-reported outcomes (PRO) ........................................................................... 135 
9.8 
Appropriateness of procedures / measurements ........................................................ 135 
10. Statistical methods and determination of sample size ............................................. 135 
10.1 General considerations ............................................................................................... 135 
10.2 Analysis sets .............................................................................................................. 136 
10.3 Variables and planned statistical analyses ................................................................. 136 
10.3.1 Disposition of patients ............................................................................................ 136 
10.3.2 Demographic and other baseline characteristics .................................................... 136 
10.3.3 Efficacy variables ................................................................................................... 136 
10.3.3.1 Secondary efficacy variable ................................................................................ 137 
10.3.3.2 Exploratory efficacy variables ............................................................................ 137 
10.3.4 Safety variables....................................................................................................... 137 
10.3.4.1 Determination of MTD ........................................................................................ 137 


 
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10.3.4.2 Adverse events (AEs) .......................................................................................... 140 
10.3.4.3 Clinical laboratory evaluations ............................................................................ 140 
10.3.4.4 Other safety measures ......................................................................................... 140 
10.3.5 Pharmacokinetic variables ...................................................................................... 140 
10.3.6 Biomarker variables ................................................................................................ 141 
10.3.7 Patient-reported outcomes (PRO) ........................................................................... 141 
10.4 Determination of sample size..................................................................................... 141 
10.5 Planned interim analyses ........................................................................................... 142 
11. Data handling and quality assurance ........................................................................ 142 
11.1 Data recording ............................................................................................................ 142 
11.2 Monitoring ................................................................................................................. 145 
11.3 Data processing .......................................................................................................... 146 
11.4 Missing data ............................................................................................................... 146 
11.5 Audit and inspection .................................................................................................. 146 
11.6 Archiving ................................................................................................................... 146 
12. Premature termination of the study .......................................................................... 147 
13. Ethical and legal aspects ............................................................................................. 148 
13.1 Investigator(s) and other study personnel .................................................................. 148 
13.2 Funding and financial disclosure ............................................................................... 149 
13.3 Ethical and legal conduct of the study ....................................................................... 149 
13.4 Patient information and consent ................................................................................ 150 
13.4.1 PI/ICF for FGFR testing ......................................................................................... 150 
13.4.2 PI/ICF for study treatment eligibility ..................................................................... 150 
13.4.3 PI/ICF for collection of data on pregnancy and birth ............................................. 152 
13.4.4 PI/ICF on study updates ......................................................................................... 152 
13.5 Publication policy and use of data ............................................................................. 152 
13.6 Compensation for health damage of patients / insurance .......................................... 152 
13.7 Confidentiality ........................................................................................................... 153 
14. Reference list ................................................................................................................ 154 
15. Protocol amendments .................................................................................................. 157 
15.1 Amendment no.1 ........................................................................................................ 157 
15.2 Amendment no.2 ........................................................................................................ 163 
15.3 Amendment no.3 ........................................................................................................ 165 
15.4 Amendment no.4 ........................................................................................................ 170 
15.5 Amendment no.5 ........................................................................................................ 171 
16. Appendices ................................................................................................................... 172 
16.1 CYP3A4 inhibitors and inducers ............................................................................... 172 
16.2 Response Evaluation Criteria in Solid Tumors (RECIST and iRECIST) ................. 172 
16.3 New York Heart Association (NYHA) classification ................................................ 180 
16.4 Estimated glomerular filtration rate (eGFR) calculation ........................................... 181 
 


 
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Table of tables 
Table 7–1: Identity of test drug (IMP): rogaratinib (BAY 1163877) ...................................... 53 
Table 7–2: Dose levels of rogaratinib (BAY 1163877) .......................................................... 58 
Table 7–3: Guidance for dose modification of rogaratinib due to toxicity (excluding 
hyperphosphatemia, liver toxicity, retinal disorders) ............................................ 59 
Table 7–4 Dose modifications of rogaratinib and management for hyperphosphatemia ....... 59 
Table 7–5: Dose modifications of rogaratinib and atezolizumab for liver toxicity ................. 61 
Table 7–6:  Management guidelines for pulmonary events, including pneumonitis ................ 66 
Table 7–7:  Management guidelines for immune-mediated gastrointestinal events (diarrhea or 
colitis) .................................................................................................................... 68 
Table 7–8: Management guidelines for endocrine events ....................................................... 69 
Table 7–9: Management guidelines for neurologic disorders ................................................. 72 
Table 7–10: 
Management guidelines for pancreatic events, including pancreatitis ............. 74 
Table 7–11: 
Management guidelines for immune-mediated cardiac events ........................ 76 
Table 7–12: 
Management guidelines for renal events .......................................................... 77 
Table 7–13: 
Management guidelines for immune-related myositis ..................................... 78 
Table 9–1: Schedule of evaluations: Pre-treatment period (FGFR testing and screening) ..... 86 
Table 9–2: Schedule of evaluations: Treatment and follow-up periods .................................. 88 
Table 9–3: Definitions for ECOG PS and Karnofsky PS grading ......................................... 131 
Table 9–4: FGFR1/3 RNA-ISH test (RNAscope® Assay): Preliminary stain intensity criteria
 ............................................................................................................................. 133 
Table 10–1: 
Possible dose finding actions .......................................................................... 139 
Table 16–1: 
Strong CYP3A4 inhibitors and inducers ........................................................ 172 
Table 16–2: 
Target and non-target lesion response ............................................................ 175 
Table 16–3: 
New York Heart Association (NYHA) categories ......................................... 180 
 
Table of figures 
Figure 5–1: Study 19131 Part A – Design overview ................................................................ 33 
 
 


 
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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 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
AZD4547 
Fibroblast growth factor receptor (FGFR) tyrosine kinase family inhibitor 
BAL 
Bronchoscopic alveolar lavage 
BC 
Bladder cancer 
BCG 
Bacillus Calmette-Guérin 
BCRP 
Breast cancer resistance protein 
b.i.d. 
Twice daily, bis in die 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
°C 
Degree(s) Celsius 
C 
Cycle 
Ca x PO4 
Calcium-phosphorus product 
CBC 
Complete blood count 
CD137 
Cluster of differentiation 137 (inducible T-cell costimulatory receptor, member of the 
tumor necrosis factor receptor [TNFR] superfamily) 
CD8A 
Cluster of differentiation 8A (T-cell surface protein) 
CHF 
Congestive heart failure 
CL/F 
Apparent oral clearance 
cm 
Centimeter 
Cmax 
Maximal plasma concentration 
cMet 
Tyrosine-protein kinase Met 
cMyc 
v-Myc myelocytomatosis viral oncogene homolog 
CNS 
Central nervous system 
CR 
Complete response 
CRO 
Contract research organization 
CRP 
C-reactive protein 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating tumor DNA 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 


 
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CYP3A4 
Cytochrome P450, family 3, subfamily A, polypeptide 4 
D 
Day 
dB 
Decibel(s) 
DCR 
Disease control rate 
ddMVAC 
Dose-dense methotrexate, vinblastine, doxorubicin and cisplatin therapy 
dL 
Deciliter 
DL 
Dose level 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECMO 
Extracorporeal membrane oxygenation 
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 
EMA 
European Medicines Agency 
EOI 
End of infusion 
EORTC 
European Organisation for Research and Treatment of Cancer 
EOT 
End of treatment 
ERK 
Extracellular-signal-regulated kinase 
EU 
European Union 
EudraCT 
European Clinical Trials Database 
°F 
Degree(s) Fahrenheit 
FDA 
Food and Drug Administration 
FFPE 
Formalin-fixed, paraffin-embedded 
FGF(R) 
Fibroblast growth factor (receptor) 
FiH 
First-in-human 
FSH 
Follicle stimulating hormone 
FU 
Follow-up 
g 
Gram 
GC 
Gemcitabine plus cisplatin 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GMP 
Good Manufacturing Practice 
HBcAb 
Hepatitis B core antibody 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCG 
β-human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HDPE 
High-density polyethylene 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 


 
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HRAS 
Harvey rat sarcoma viral oncogene homolog 
HRQoL 
Health-related Quality of Life 
IB 
Investigator’s brochure 
IC 
Tumor-infiltrating immune cell status 
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
iCPD 
Confirmed progressive disease according to iRECIST 
iCR 
Confirmed response according to iRECIST 
IDMS 
Isotope dilution mass spectroscopy 
i.e. 
That is, id est 
IEC 
Independent Ethics Committee 
IFN 
Interferon 
IHC 
Immunohistochemistry 
IL 
Interleukin 
IMP 
Investigational medicinal product 
INN 
International Nonproprietary Names 
INR 
International normalized ratio 
iPR 
Partial response according to iRECIST 
IR 
immediate release 
IRB 
Institutional Review Board 
iRECIST 
Response Evaluation Criteria in Solid Tumors modified for Immune-based therapeutics 
iSD 
Stable disease according to iRECIST 
ISH 
In situ hybridization 
IUD 
Intrauterine device 
iUPD 
Unconfirmed progressive disease according to iRECIST 
IUS 
Intrauterine hormone-releasing system 
i.v. 
Intravenous(ly) 
IxRS 
Interactive voice/web response system 
kg 
Kilogram 
L 
Liter 
LDH 
Lactic dehydrogenase 
LFT 
Liver function test 
LLOQ 
Lower limit of quantification 
LLT 
MedDRA lowest level term 
LPFV 
Last patient’s first visit 
LPLV 
Last patient’s last visit 
LSH 
Life Science Data Hub 
MD 
Medical doctor 
MDRD 
Modification of Diet in Renal Disease 
MDS 
Myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MI 
Myocardial infarction 
MIBC 
Muscle-invasive bladder cancer 


 
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microRNA 
Micro ribonucleic acid 
min 
Minute(s) 
mIU 
Milli international unit 
MIUC 
Muscle-invasive urothelial carcinoma 
mL 
Milliliter 
mm 
Millimeter 
mmHg 
Millimeter of mercury 
mmol 
Millimole 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
MSKCC 
Memorial Sloan Kettering Cancer Center 
MTD 
Maximum tolerated dose 
mTPI 
Modified toxicity probability interval 
MVAC 
Methotrexate, vinblastine, doxorubicin, cisplatin 
n 
Number of patients 
NC 
North Carolina 
NCA 
Non-compartmental analysis 
NCI 
National Cancer Institute 
NE 
Not evaluable 
ng 
Nanogram 
NJ 
New Jersey 
NK 
Natural killer (cells) 
NLNT 
New lesion – non-target 
NLT 
New lesion – target 
NMIBC 
Non-muscle-invasive bladder cancer 
No. 
Number 
NSCLC 
Non-small-cell lung carcinoma 
NY 
New York 
NYHA 
New York Heart Association 
OCT 
Optical coherence tomography 
ORR 
Objective response rate 
OS 
Overall survival 
P 
Probability value 
p53 
Tumor suppressor 
PD 
Progressive disease 
PD-1 
Programmed death protein 1 
PD-L1 
Programmed death-ligand 1 
pERK 
Phosphorylated extracellular-signal-regulated kinase 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
P-gp 
P-glycoprotein 
pH 
Hydrogen ion concentration 
PID 
Patient identification number 
PI/ICF 
Patient information/informed consent form 


 
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PIK3C 
Phosphoinositide 3-kinase, catalytic domain 
PIK3CA 
Phosphoinositide 3-kinase, catalytic subunit alpha isoform 
PK 
Pharmacokinetic(s) 
PKS 
Pharmacokinetic(s) analysis set 
PleurX 
Drainage system 
PP 
Polypropylene 
PR 
Partial response 
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 
Quality of Life Questionnaire Core 30 
QoL 
Quality of Life 
RAS 
Rat sarcoma 
RAVE 
Data collection tool 
RB 
Retinoblastoma 
RBC 
Red blood cell (count) 
RECIST 
Response evaluation criteria in solid tumors 
Rend 
Last time point for apparent terminal rate constant, calculated from the last slope of a log-
linear regression of the unweighted data considering the last concentration-time points 
>LLOQ (lower limit of quantification)  
RNA 
Ribonucleic acid 
RP2D 
Recommended Phase 2 dose 
RPED 
Retinal pigment epithelial detachment 
RR 
Respiratory rate 
Rstart 
First time point for apparent terminal rate constant, calculated from the last slope of a log-
linear regression of the unweighted data considering the last concentration-time points 
>LLOQ (lower limit of quantification) 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical Analysis Plan 
SCCHN 
Squamous cell carcinoma of the head and neck 
sCD25 
Soluble cluster of differentiation 25 (soluble IL-2 receptor) 
SCR 
Serum creatinine level 
SD 
Stable disease 
SIA 
Systemic immune activation 
SJS 
Stevens-Johnson syndrome 
SmPC 
Summary of Product Characteristics 
SOD 
Sum of diameters 
sqNSCLC 
Squamous NSCLC 
SUSAR 
Suspected, unexpected, serious adverse reaction 
t 
Time 


 
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T3 
Triiodothyronine 
T4 
Thyroxine 
TC-99m 
Technetium-99m 
TCGA 
The Cancer Genome Atlas 
TEADR 
Treatment-emergent drug-related adverse events 
TEAE 
Treatment-emergent adverse event 
TEN 
Toxic epidermal necrolysis 
TL 
Target lesion 
tlast 
Time of last plasma concentration above LLOQ 
TM 
Trademark 
tmax 
Time to reach maximum drug concentration in plasma after single (first) dose 
TNF 
Tumor necrosis factor 
TNM 
Classification of Malignant Tumors (T = tumor, N = lymph node, M = metastasis) 
TP53 
Tumor protein p53 
TSH 
Thyroid-stimulating hormone 
TURBT 
Transurethral resection of bladder tumors 
UBC 
Urothelial bladder cancer 
UC 
Urothelial carcinoma 
ULN 
Upper limit of normal 
UPM 
Unit probability mass 
US / USA 
United States / United States of America 
VAD 
Ventricular assist device 
VZ/F 
Apparent volume of distribution after extravascular administration 
WBC 
White blood cell (count) 
WinNonlin 
Pharmacokinetic software package 
WOCBP 
Woman of childbearing potential 
Definitions of terms 
 
Term 
Definition 
Pseudoprogression 
An increase in the size of lesions, or the visualization of new 
lesions, followed by a response, which might be durable. 
Pseudoprogression phenomena might be observed during 
treatment with immunotherapeutic agents. 
Study drug 
The term “study drug” refers to any of protocol-stipulated drugs, 
i.e. rogaratinib or atezolizumab. 
Study treatment 
The term “study treatment” refers to all protocol-stipulated 
treatments, i.e. rogaratinib and atezolizumab.  
Test drug 
In this protocol the term “test drug” refers to rogaratinib only. 


 
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Combination drug 
In this protocol the term “combination drug” refers to 
atezolizumab only. 


 
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3. 
Introduction 
3.1 
Study set up: Part A  
Study 19131 is designed to evaluate safety, efficacy, RP2D and PK of rogaratinib in 
combination with atezolizumab in patients with untreated FGFR-positive urothelial 
carcinoma.  
 
This part of the protocol is to be used for conducting Part A of the study only.  
 
3.2 
Background 
Urothelial carcinoma 
Bladder cancer (BC) is the most frequent among urothelial carcinomas (UC) that also include 
the less common UC arising from renal pelvis, ureters and urethra. It is the ninth most 
common cancer in the world, the sixth most common cancer in the United States and the 
second most common genitourinary tumor. It is a major cause of morbidity and mortality 
worldwide, causing approximately 429,000 new cases resulting in 165,000 deaths annually 
(1). An estimated 79,030 new cases of urinary bladder cancer (60,490 men and 18,540 
women) will be diagnosed in the United States in 2017 with approximately 16,870 deaths 
(12,240 men and 4630 women) occurring during this same period (2). Approximately three 
times more men than women are diagnosed with bladder cancer; the majority of patients are 
> 65 years old. Approximately 4% of the patients have metastatic disease at the time of 
diagnosis (3). Additionally, about half of all patients relapse after cystectomy depending on 
the pathologic stage of the tumor and nodal status. Local recurrences account for about 10% 
to 30% of relapse, whereas distant metastases are more common.  
Over the past two decades, there has been no significant improvement in survival of BC with 
5-year relative survival rates for locally advanced and metastatic disease of 33% and 5%, 
respectively (4). The majority (90%) of bladder cancers are composed of urothelial carcinoma 
(UBC [urothelial bladder cancer]). Seventy percent of the cases are diagnosed as non-muscle-
invasive bladder cancer (NMIBC) with a favorable prognosis following transurethral 
resection and intravesical chemotherapy or immunotherapy with Bacillus Calmette-Guérin 
(BCG) (5). Nevertheless, approximately 40% of these patients will progress to muscle-
invasive disease at five years depending on tumor pathological features (6). When considering 
the prognosis of muscle-invasive bladder cancer, even after optimal treatment with 
neoadjuvant chemotherapy and surgery, only 60% of these patients will be alive 5 years later 
due to distant recurrence (7). This aggressive biological behavior coupled with limited 
therapeutic options results in a median survival of 15 months for patients with metastatic 
disease (8). Therefore, there is an urgent need to improve outcomes with innovation or 
application of new treatments.  


 
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Traditionally, UBC is classified in 2 distinct types according to the grade. Low-grade tumors 
usually tend to recur locally with low risk of progression to invasive tumors. These tumors are 
characterized by oncogenic mutations in the fibroblast growth factor receptor 3 (FGFR, 70%), 
HRAS (30-40%) and PIK3C (10%) genes (9). In contrast, high grade invasive lesions harbor 
frequent loss of function alterations in TP53 and RB genes. In 2014, The Cancer Genome 
Atlas (TCGA) project provided advances in the landscape of genomic alterations within 
MIUC (10).  
Fibroblast growth factors (FGF) and their corresponding receptor family (FGFR) drive crucial 
oncogenic signaling pathways including cell proliferation, survival and migration (11, 12). 
FGFRs are commonly altered in various human cancers including FGFR1 amplification in 
non-small cell lung cancer (e.g. sqNSCLC) (11, 12) and squamous cell carcinoma of the head 
and neck (SCCHN) (11, 12), or activating mutations of FGFR3 in bladder cancers (BC) (11, 
12). These changes contribute to tumor cell growth, sustained angiogenesis, invasion and 
metastasis and resistance against other therapies.  
Dysregulation of FGFRs has been identified in bladder cancers of all grades and stages. In 
NMIBC, activating point mutations of FGFR3 are common (70%). In MIBC, point mutations 
are less common (12-16%) but many tumors (> 40%) show upregulated expression of non-
point mutated FGFR3 protein. Preclinical studies have confirmed FGFR3 as a relevant 
therapeutic target in bladder cancer; most cell lines show a cytostatic rather than cytotoxic 
response. Early results indicate responses to selective FGFR inhibitors in some bladder cancer 
patients. Rogaratinib is an oral pan-FGFR inhibitor that showed potent antitumor activity in 
preclinical models of FGFR mRNA overexpression tumors, including urothelial carcinoma, 
and promising clinical efficacy. 
Treatment options 
Cisplatin-based chemotherapy has been the standard of care in patients with newly diagnosed 
metastatic disease with an OS of approximately 15 months (8, 13). However, patients that are 
not eligible to be treated with cisplatin have poorer outcome with an OS of approximately 
9 months with alternative treatment regimens based on carboplatin (13). 
In the first-line setting, the selection of the chemotherapy regimen partially depends on the 
presence or absence of medical comorbidities, such as cardiac disease and renal dysfunction, 
along with the risk classification of the patient based on disease extent. In general, long-term 
survival with combination chemotherapy alone has been reported only in good-risk patients, 
defined as those with good performance status, no visceral (i.e. liver, lung) or bone disease, 
and normal alkaline phosphatase or lactic dehydrogenase levels. Poor-risk patients, defined as 
those with poor performance status or visceral disease, have consistently shown very poor 
tolerance to multi-agent combination programs and few complete remissions, which are 
prerequisite for cure. 
Gemcitabine plus cisplatin (GC) and dose-dense methotrexate, vinblastine, doxorubicin and 
cisplatin (ddMVAC) are recommended first-line regimens for metastatic disease. A 
randomized Phase 3 trial comparing GC to MVAC confirmed, in a 5-year update analysis, 
that GC was not inferior to MVAC in term of overall survival (OS 13% vs 15.3%; PFS 9.8% 


 
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vs 11.3% respectively) (14). Another large randomized Phase 3 trial compared ddMVAC to 
standard MVAC (15, 16). At a median follow-up of 7.3 years, 24.6% of patients were alive in 
the ddMVAC cohort compared with 13.2% in the standard MVAC cohort. MVAC is inferior 
to ddMVAC in terms of toxicity and efficacy, and is inferior to GC in terms of toxicity; 
therefore, standard MVAC is no longer used.  
The performance status of the patients is a major determinant in the selection of a regimen. 
Regimens with lower toxicity profiles are recommended in patients with compromised liver 
or renal status or serious comorbid conditions. Alternative first-line regimens include 
carboplatin or taxane-based regimens or single agent chemotherapy. In patients with a 
glomerular filtration rate (GFR) less than 60mL/min, carboplatin may be substituted for 
cisplatin. A Phase 2/3 study assessed 2 carboplatin-containing regimens in medically unfit 
patients (PS 2). The objective response rate (ORR) was 42% for gemcitabine plus carboplatin 
and 30% for methotrexate, carboplatin, and vinblastine. However the response rates dropped 
to 26% and 20% respectively, with increased toxicity among patients who were both unfit and 
had renal impairment (GFR < 60mL/min) (13). 
Carboplatin has been replaced in patients ineligible for cisplatin treatment in the first-line 
setting after the recent introduction of checkpoint inhibitors. Only limited data are available as 
to the value of carboplatin-containing chemotherapy in patients that failed prior treatment 
with checkpoint inhibitors. Retrospective analyses on small cohorts indicate that 
chemotherapy-naïve patients who receive chemotherapy after checkpoint inhibitor treatment 
maintain a high response rate to platinum (17). This treatment is however associated with 
considerable toxicity leaving a high unmet medical need. Approximately 20% of patients 
discontinue treatment due to adverse events. Myelotoxicity is very frequent with leucopenia 
Grade 3 or higher in more than a third of patients, sometimes coupled with febrile 
neutropenia. 
Several new agents for the treatment of metastatic urothelial carcinoma are being investigated 
in clinical trials. 
PD-1 and PD-L1 checkpoint inhibitors have garnered attention based on clinical trial data. 
The PD-L1 inhibitor atezolizumab (Tecentriq) and the PD-1 inhibitor nivolumab (Opdivo) 
received accelerated approval for the treatment of patients with locally advanced or metastatic 
UC who have disease progression during or following platinum-containing chemotherapy or 
within 12 months of neoadjuvant or adjuvant treatment with platinum-containing 
chemotherapy, regardless of PD-L1 expression level (18, 19). Recently, also the PD-1 
inhibitor pembrolizumab (Keytruda) reported positive OS data versus standard of care 
chemotherapy in this indication (20). In addition, atezolizumab and pembrolizumab also 
received accelerated approval as a first-line treatment for patients with locally advanced or 
metastatic urothelial carcinoma who are not eligible for cisplatin-based chemotherapy. More 
recently, based on tumor response rate and duration of response, FDA also granted 
accelerated approval to two newer PD-L1 inhibitors, avelumab (Bavencio) and durvalumab 
(Imfinzi) for patients with locally advanced or metastatic urothelial carcinoma whose disease 
progressed during or following platinum-containing chemotherapy or within 12 months of 
neoadjuvant or adjuvant platinum-containing chemotherapy (21, 22). 


 
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Despite promising clinical data of checkpoint inhibitors, only a fraction of patients 
(approximately 25%) are responding to this treatment type. There is limited information about 
the optimal therapy for patients that progress on checkpoint inhibitor treatment. 
Given the current treatment options, there is still a high unmet medical need for the treatment 
of UC. 
It was previously published that FGFR3 expression is associated with a non-T-cell-inflamed 
tumor microenvironment (23), leading to a poorer response to inhibition of the PD-L1 axis. 
Our clinical data confirm that FGFR3 expression is inversely correlated with PD-L1 
expression in urothelial bladder cancer (unpublished data). This represents the framework for 
testing the combination of rogaratinib and atezolizumab. The aim is to explore if rogaratinib, 
inhibiting FGFR, is able to induce a T-cell-inflamed phenotype, restoring sensitivity to PD-L1 
inhibitors and improving their efficacy in urothelial carcinoma. 
3.3 
Rogaratinib 
Rogaratinib (BAY 1163877) is a selective 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 such as non-small-cell lung cancer, small-cell lung cancer, 
urothelial carcinoma, head and neck cancer as well as breast cancer. In-vivo efficacy is 
correlated with effective inhibition of downstream signaling analyzed by pERK inhibition. 
Moreover, rogaratinib exhibits strong in-vivo anti-tumor efficacy in monotherapy in tumor 
xenograft models addicted to various FGFR alterations 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 bladder cancer 
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) (24, 25). 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%) (26). 
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 (27, 28). However, clinical benefits from FGFR 
inhibitor treatment have also been reported in a urothelial carcinoma patient with high FGFR1 
mRNA expression levels (29) and in a patient with high FGFR2 protein expression (30), 
although FGFR1 and FGFR2-positive UC tumors are more rare compared to FGFR3-positive 


 
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tumors. In the FiH Study 16443 (see below), out of > 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, on the basis that FGFR2 expression is considerably 
low in urothelial carcinoma patients, patient selection for Study 19131 will be based on 
FGFR1 and FGFR3 expression only. For the test device, FGFR1 and FGFR3 will be tested in 
parallel in one kit. 
Clinical experience with rogaratinib 
Details of ongoing and completed studies 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:  
Retinal disorders 
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 phosphate level ≥ 7 mg/dL beyond the critical level defined 
as calcium phosphate product higher than 70 mg2/dL2 (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.  
Further details on other undesirable effects of rogaratinib as well as on clinical efficacy can be 
found in the latest available version of the IB of rogaratinib, which contains comprehensive 
information on the test drug. 


 
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3.4 
Atezolizumab 
Atezolizumab (Tecentriq) is a programmed death-ligand 1 (PD-L1) blocking antibody. PD-L1 
is expressed by many cancer cells; PD-L1 and PD-L2 are ligands to programmed cell death 
protein 1 (PD-1) that is a cell surface receptor belonging to the immunoglobulin superfamily 
expressed on T cells, B cells, monocytes and natural killer (NK) cells when these cells are 
activated. Thus, the expression of PD-1 in a tumor is a marker of T-cell activation. Binding of 
PD-L1 to PD-1 receptor on T-cells results in suppression of T-cell migration, proliferation 
and function, as well as induction of suppressive regulatory T-cells. This PD-L1-PD-1 axis is 
used to regulate tolerance of “self” and thereby protect healthy tissues from autoimmune 
destruction. The cancer cells effectively utilize this regulation of peripheral tolerance to 
prevent T-cell mediated destruction of tumor cells by promoting the PD-L1-PD-1 axis. This 
understanding has led to the development of immune checkpoint inhibitors such as 
atezolizumab, nivolumab and pembrolizumab that inhibit the PD-L1-PD-1 axis and are 
approved for use in solid cancers. 
Previous clinical studies with atezolizumab in urothelial carcinoma 
The pivotal single-arm, multicenter, Phase 2 trial of atezolizumab (IMvigor210) in patients 
with locally advanced and metastatic urothelial cancer enrolled two cohorts of patients. In 
cohort 2, 310 patients previously treated with platinum-based chemotherapy received 
atezolizumab 1,200 mg intravenously every 3 weeks. The results of this large single arm 
Phase 2 study showed that atezolizumab induced durable anti-tumor responses in patients 
with advanced urothelial carcinoma whose tumors have progressed during or after treatment 
with platinum-based chemotherapy. Based on these results atezolizumab received accelerated 
FDA approval in May 2016 for the treatment of metastatic urothelial carcinoma in second-line 
after progression on platinum-based chemotherapy (19, 31). 
Cohort 1 of IMvigor210 comprised patients who had not received previous treatment in the 
metastatic setting and were judged to be ineligible for cisplatin treatment. 123 patients were 
enrolled, of whom 119 received one or more doses of atezolizumab. At 17.2 months’ median 
follow-up, the objective response rate was 23% and the complete response rate was 9%. 
Median response duration was not reached. Response occurred across all PD-L1 and poor 
prognostic factor subgroup. Median PFS was 2.7 months and median overall survival was 
15.9 months. Tumor mutation load was associated with response. Treatment-related adverse 
events that occur in 10% or more of patients were fatigue (30%), diarrhea (12%), and pruritus 
(11%). One treatment-related death (sepsis) occurred. Nine (8%) patients had an adverse 
event leading to treatment discontinuation. Immune-mediated events occurred in 12% patients 
(18). 
Details of ongoing and completed studies with atezolizumab can be found in the latest 
available version of the IB for atezolizumab. The IB in its most current version is available in 
the study file. 
3.5 
Rationale of the study 
The Study 19131 is planned to evaluate the safety, tolerability, PK and efficacy of oral twice 
daily rogaratinib in combination with atezolizumab in patients with FGFR-positive locally 


 
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advanced or metastatic urothelial carcinoma who are cisplatin-ineligible and have had no 
prior systemic treatment for locally advanced or metastatic disease. 
Urothelial cancer is a highly immunogenic tumor, in large part as a result of the relatively 
high level of mutations, which represent at least one of the mechanisms for the generation of 
tumor neo-antigens for the host immune system to recognize. PD-L1 overexpression in the 
tumor microenvironment and its binding to programmed death receptor-1 (PD-1) on tumor 
antigen-specific T cells is a mechanism for immune escape in urothelial cancer (32). 
Dysregulation of FGFRs has been identified in bladder cancer as compared with normal 
bladder. Increased expression was associated with mutation, 85% of mutant tumors showed 
high level expression, overall 42% of tumors with no detectable mutation showed over-
expression including many muscle invasive. This may represent a non-mutant subset of 
tumors in which FGFR3 signaling contributes to the transformed phenotype and which may 
benefit from FGFR-targeted therapy (33).  
It was shown that FGFR3 expression is associated with a non-T-cell-inflamed phenotype in 
tumor tissue of patients with UBC (23). Expression analysis of PD-L1 in archival biopsy 
samples collected in Study 16443, showed that PD-L1 level is lower in patients with FGFR 
mRNA overexpression. A similar correlation was detected in patients with NSCLC using 
publically available TCGA data sets. It is assumed that a causal relationship between FGFR 
expression and T-cell exclusion leads to the observed findings and to a poorer response to 
inhibition of the PD-L1 axis by recently approved checkpoint inhibitors. Potentially, 
inhibition of FGFR can overcome this interaction and render tumors targetable by the immune 
system. 
Atezolizumab is a PD-L1 antibody that demonstrated durable responses in urothelial bladder 
cancer as first-line and second-line treatment for patients with locally advanced or metastatic 
urothelial carcinoma. It is assumed that patients with FGFR overexpression exhibit a poorer 
response to atezolizumab treatment based on the non-T-cell-inflamed phenotype. Therefore, it 
is hypothesized, that a combination of rogaratinib and atezolizumab can overcome this 
immune evasion improving immune-checkpoint inhibitor efficacy and disease response. 
3.6 
Benefit-risk assessment 
The pre-clinical information on rogaratinib provides a sound rationale for its activity in 
several tumor models including urothelial carcinoma. This is confirmed by preliminary 
efficacy data from the Phase 1 Study 16443 showing signs of activity in advanced UBC with 
an ORR which compares favorably to existing therapies. During that trial, the overall safety 
profile was manageable with dose modifications; it was in line with what is expected and 
acceptable in the target population. Thus, the available data support the investigation of 
rogaratinib in advanced urothelial carcinoma.  
Patients enrolled in Part A of study 19131 will receive rogaratinib at a starting dose of 800 mg 
b.i.d. that has been chosen for further clinical development concomitantly with the 
recommended dose of atezolizumab (1200 mg intravenous every 21 days). Due to distinctly 
different elimination pathways of rogaratinib and antibody atezolizumab, a pharmacokinetic 
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Furthermore, the safety profiles of both drugs do not show relevant overlapping toxicities 
other than diarrhea and fatigue.  
All patients will be followed closely for safety and efficacy; the planned examinations are part 
of general medical practice and do not expose study participants to an undue risk or burden.  
Based on the above considerations, the benefit/risk ratio for study participation can be 
regarded as positive, and the study appears justified in the planned patient population. 
 
4. 
Study objectives 
The primary objectives of this Part A of the study are: 
• To determine the safety and tolerability of rogaratinib in combination with 
atezolizumab in patients with FGFR-positive locally advanced or metastatic urothelial 
carcinoma. 
• To determine the recommended Phase 2 dose (RP2D) of rogaratinib in combination 
with atezolizumab in this patient population. 
 
The secondary objectives of this Part A of the study are: 
• To assess the efficacy of the combination of rogaratinib and atezolizumab in this 
patient population. 
• To characterize the pharmacokinetics (PK) of rogaratinib in combination with 
atezolizumab in this patient population. 
 
The exploratory objectives of this Part A of the study are: 
• To assess new potential predictive or prognostic biomarkers and their association with 
tumor-related biomarkers, disease response, drug-resistance and patient outcome.  
• To evaluate further biomarkers to investigate the drug (i.e. mode-of-action-related 
effect and / or safety) and / or the pathomechanism of the disease. 
• To evaluate the combination of rogaratinib and atezolizumab with regard to patient-
reported outcomes (PRO). 
The procedures and variables used to address these objectives are specified in Sections 9, and 
10.3, respectively. 
 


 
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5. 
Study design 
5.1 
Design overview 
This study 19131 Part A is an open-label, single-arm, international, multicenter, Phase 1b 
study of rogaratinib in combination with atezolizumab in patients with FGFR-positive locally 
advanced or metastatic urothelial carcinoma.  
The primary objectives of this Phase 1b study (Part A) are to determine the safety, tolerability, 
RP2D and pharmacokinetics of rogaratinib in combination with atezolizumab in these 
patients. For all study objectives, see Section 4. 
Before entering the screening, patients are to be tested for FGFR1 and 3 mRNA expression 
levels. Only patients with FGFR-positive tumors (RNAscope score of +3 or +4) can enter the 
study.  
The study will comprise the following periods (see more in Section 5.2):  
• Pre-treatment period, including FGFR testing and screening, 
• Treatment period, and  
• Follow-up period, including active follow-up and long-term follow-up.  
o After primary completion, follow-up information will not be collected after the 
safety assessment visit. 
An overview of the study design is presented in Figure 5–1. 
The study is conducted in patients who are cisplatin-ineligible and have had no prior systemic 
treatment for locally advanced or metastatic disease. 
Patients will receive rogaratinib plus atezolizumab combination treatment. 
 


 
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Figure 5–1: 
Study 19131 Part A – Design overview 
Informed 
consent for
FGFR testing
1st dosing of 
study treatment
Last protocol-
stipulated 
procedure
Discontinuation of 
study treatment 
(End of Treatment)
Treatment
Active follow-up b
Long term follow-up
Pre-treatment
Rogaratinib + Atezolizumab
Informed 
consent for
 study treatment 
eligibility
FGFR testing
Screening a
Follow-up
 
FGFR = Fibroblast growth factor receptor 
a: Only FGFR positive patients can enter screening. 
b: 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 radiological disease progression. 
Dose selection 
The dose selection part of the study 19131 will assess the safety and tolerability of the 
combination. The MTD will be determined by using stepwise dose selection design based on 
a modified toxicity probability interval (mTPI) method. Dose selection will stop after 20 valid 
patients are available and are evaluable for the MTD assessment. At the end of the DLT 
observation period of 20 patients the recommendations from the mTPI will be regarded as 
guidance and will be integrated with the clinical assessments of the available PK and safety 
data to determine the MTD. A total of approximately 26-30 evaluable patients will be enrolled 
to obtain additional safety data for confirming the MTD and determine the RP2D.  
The mTPI provides a practical dose-finding scheme guided by the posterior inference for a 
simple Bayesian model. The maximum tolerated dose (MTD) is defined as the highest dose 
level that could be given so that the toxicity probability is below 30%. The starting dose of 
rogaratinib will be 800 mg b.i.d. Initially, at least 4 (4-6) patients will be enrolled. The next 
group of patients will be enrolled once the decision regarding the next dose level is made 
based on all available PK and safety data and the occurrence of DLTs (for details see 
Section 10.3.4). The decision about time of enrollment and the number of patients evaluable 
for DLTs on a dose level will be made by the sponsor in consultation with investigators 
during regularly held safety calls. 
Safety will be regularly assessed during each cycle for potential adverse events, dose-limiting 
toxicities (DLTs) and disease-related sign and symptoms. Rogaratinib dosing will be 
interrupted/delayed or reduced in case of clinically significant toxicities. Atezolizumab dosing 
will not be adjusted, however dosing will be interrupted or delayed in case of clinically 
significant toxicity. For more detailed information on dose modifications see Section 7.4.3.  
The mTPI method will recommend de-escalation, re-escalation or expansion of the current 
dose level on basis of the observed DLTs. The first dose finding action on a dose level will be 
performed after at least 4 patients are available on that dose level and are evaluable for DLTs. 
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dose level (800 mg b.i.d. being the highest possible dose), ‘S’=stay at the current dose level, 
‘D’=de-escalate to next lower dose level and ‘DU’= de-escalate to next lower dose level and 
exclude the current and higher dose levels from the further dose escalation due to 
unacceptably high toxicity (see Table 7–2 for rogaratinib dose levels). If the probability that a 
dose is above the MTD is greater than 95%, the dose will be declared as toxic and only lower 
doses will be given in subsequent cohorts. If the highest dose is reached, escalation (‘E’) leads 
to staying at that dose. At the lowest dose level de-escalation (‘D’) or de-escalation with 
unacceptable high toxicity (‘DU’) lead to stop of the study. Details are provided in 
Section 10.3.4.1 
Intra-patient dose escalation is not permitted.  
 
5.2 
Study periods 
5.2.1 
Pre-treatment period 
FGFR testing 
Patients with urothelial carcinoma will be tested for mRNA expression levels of FGFR1 and 3 
using archival or fresh tumor biopsy specimen. Before FGFR testing, patients must sign a 
patient information/informed consent form (PI/ICF) (see Section 13.4), and have to meet all 
eligibility criteria for FGFR testing (see Sections 6.1 and 6.2).  
Only patients with FGFR-positive tumors (high expression [RNAscope score of 3+ or 4+] of 
FGFR1 and/or 3) will be eligible for the study and can continue to screening. See more about 
FGFR testing in Section 9.7.1. 
Screening 
The screening period for the study will start after the patient has signed the PI/ICF for study 
treatment eligibility (see Section 13.4). The screening will be scheduled within 28 days before 
start of study treatment. Please refer to Table 9–1 for the detailed schedule for screening 
assessments.  
5.2.2 
Treatment period 
Patients who satisfy all selection criteria (see Sections 6.1 and 6.2) will be eligible to start study 
treatment. 
The start of the treatment period is defined by the first administration of study treatment. 
Patients will receive rogaratinib plus atezolizumab combination treatment.  
All details on dosing are provided in Section 7.4.1. 
The length of a cycle is 3 weeks (21 days). 
Patients will continue dosing of both study drugs until any of the discontinuation criteria 
specified in Section 7.4.4 occurs. 


 
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After discontinuation from study treatment, the 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 
No further analysis is planned for this study after primary completion. After ending treatment, 
patients are no longer expected to continue the active follow-up after safety assessment visit 
and/or enter the long-term follow-up period. 
Active follow-up 
After permanent treatment discontinuation, a safety assessment visit must be scheduled for all 
patients at least 30 (up to +7) days after the last dose of study treatment. If the 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. In addition, any AEs 
after the active follow-up visit qualifying as SAEs or AESIs with an onset up to 90 days after 
last atezolizumab dosing that are reported to the sites need to be documented unless a new 
anti-cancer therapy has been initiated.  
Up to primary completion, for patients who permanently discontinue study treatment without 
radiological disease progression, drug-related AEs will continue to be collected and follow-up 
tumor evaluations will be performed (by CT or MRI with contrast unless contraindicated) 
until confirmed 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 every 9 weeks up to one year 
(from the previous scan date); after primary completion no tumor assessments will be 
performed (see Table 9–2). 
Long-term follow-up 
After completion of the active follow-up, all patients will be contacted (telephone contact by 
site is sufficient) to determine the survival status and subsequent systemic anti-cancer therapy 
approximately every 3 months (±14 days) until the end of the study (i.e. until last patient’s 
last visit [LPLV]). 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. In addition, any AEs after the active follow-up visit qualifying as SAEs and 
AESIs with an onset up to 90 days after last atezolizumab dosing that are reported to the sites 
need to be documented unless a new anti-cancer therapy has been initiated. Long-term follow-
up will not be performed after primary completion.  
 


 
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5.3 
Primary variable(s) 
The primary variables of this Part A of the study are: 
• Safety: 
o The incidence of DLTs will be used to determine the MTD and/or RP2D. 
o The incidence of treatment-emergent adverse events (TEAEs), drug-related 
TEAEs, and treatment-emergent serious adverse events. 
See Section 10.3.4 for the planned statistical analyses of the safety variables. 
5.4 
Justification of the design 
Level of blinding: The study is performed in a non-blinded design because this is considered 
adequate to meet the study objectives. 
Justification of the patient selection: The FGFR1/3 RNAscope (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 either FGFR1 or 
FGFR2 or FGFR3 scores of 3+ or 4+ by RNAscope demonstrated significant (> 50%) anti-
tumor efficacy upon rogaratinib treatment. Preliminary data from Phase 1 FiH 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 an RNAscope score of 3+ or 4+. Therefore, 
having at least one FGFR isoform with a score of at least 3+ was selected as inclusion 
criterion for FGFR-positivity for this Study 19131. 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, 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. For FGFR testing 
please see Section 9.7.1.  
For justification of the drug dosages, see Section 7.4.2. 
For justification of the sample size, see 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 
The end of the study 19131 will be reached as soon as the last visit of the last patient (LPLV) 
has been reached in all centers in all participating countries (EU and non-EU). 
LPLV is defined by the completion of the safety assessment visits determined by the last 
patient stopping study treatment, switching to a roll-over study, or any other form of 
continued study drug supply.  
Decisions on trial termination can be made by the sponsor guided by strategic expectations for 
the study compounds after primary completion has been reached. 


 
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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 and other forms of 
continued study drug supply. 
5.6 
Primary completion 
As safety is the primary objective of Part A, the primary completion event for Part A will be 
its LPLV or 9 months after LPFV, whichever occurs first.  
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). 
 
6. 
Study population 
Eligible patients for this study will be patients with locally advanced or metastatic urothelial 
carcinoma, who are cisplatin-ineligible and have had no prior systemic treatment for locally 
advanced or metastatic disease. 
Patient eligibility will be checked at two sequential time points: 
1. At FGFR testing: 
• FGFR testing of patients will be performed at the investigators’ discretion prior to start 
of screening (i.e. before signing of informed consent for study treatment eligibility). 
• 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. Investigators should ensure 
all patients will be eligible in terms of clinical condition, disease status and lines of 
treatment. For “FGFR testing failure” (those that are FGFR test negative and/or those 
that do not meet the inclusion/exclusion criteria) see Section 11.1. 
2. At screening: 
• FGFR1 or 3 positive patients (RNAscope score of 3+ or 4+) will be checked for final 
eligibility using all further selection criteria specified below. For “screening failure” 
see Section 11.1. 
6.1 
Inclusion criteria  
The following inclusion criteria are applicable for all patients: 
Inclusion criteria 
to be checked at 
 
FGFR 
testing 
Screening 
1. Male or female patients ≥ 18 years of age (at least age of legal 
maturity) 
⚫ 
 


 
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Inclusion criteria 
to be checked at 
 
FGFR 
testing 
Screening 
2. Ability to understand and signing of the written patient 
information/informed consent form (PI/ICF) for FGFR testing 
⚫ 
 
 
3. 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. 
 
⚫ 
 
4. Existence of archival or fresh tumor biopsy specimen for FGFR1/3 
mRNA expression testing 
• Patients who submit transurethral resection of bladder tumors 
(TURBT) specimens will be required to submit specimens 
containing muscle invasive component of the bladder tumor as 
verified by pathology review. If the TURBT specimens do not 
contain a muscle invasive component (i.e. T2 or greater), the 
specimens obtained at the time of 
cystectomy/nephroureterectomy or metastatic spread (i.e. sample 
from a metastatic lesion) will be required.  
• Patients who do not have archival tissue specimens meeting 
eligibility requirements may undergo a biopsy. The tumor 
material should be derived by a biopsy procedure associated with 
a non-significant risk (see Section 9.7.1). 
⚫ 
 
5. Documented urothelial carcinoma (transitional cell carcinoma) 
including urinary bladder, renal pelvis, ureters, urethra, meeting all 
of the following criteria:  
• Histologically confirmed  
• Patients with mixed histology are required to have a dominant 
transitional cell pattern.  
• Locally advanced (T4, any N; or any T, N2-3) or metastatic 
disease (any T, any N, and M1). 
Note: 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). 
⚫ 
⚫ 
6. At least 1 measurable lesion according to Response Evaluation 
Criteria in Solid Tumors version 1.1 (RECIST v1.1) in contrast 
enhanced (unless contraindicated) CT or MRI. Previously irradiated 
lesions should not be counted as target lesions unless there has been 
demonstrated progression in the lesion since radiotherapy before 
study enrollment and no other lesions are available for selection as 
target lesions. Patients with resected primary tumors who have 
documented metastases are eligible. 
⚫ 
 
⚫ 
7. High FGFR1 or 3 mRNA expression levels (RNAscope score of 3+ 
or 4+; measurement is part of this protocol) in archival or fresh 
tumor biopsy specimen 
 
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Inclusion criteria 
to be checked at 
 
FGFR 
testing 
Screening 
8. No prior systemic treatment for locally advanced or metastatic 
urothelial carcinoma. For patients who received prior 
adjuvant/neoadjuvant chemotherapy or chemo-radiation for 
urothelial carcinoma, a treatment-free interval > 12 months between 
the last treatment administration and the date of recurrence is 
required in order to be considered treatment-naïve in the metastatic 
setting. Prior local intra-vesical chemotherapy or prior local 
immunotherapy (e.g. with Bacillus Calmette-Guérin [BCG]) is 
allowed if completed at least 4 weeks before the first study drug 
administration. Regionally available standard of care options must 
be considered for all patients. 
⚫ 
 
9. Ineligibility for cisplatin-based chemotherapy as defined by any one 
of the following criteria: 
• Impaired renal function (GFR > 30 but < 60 mL/min/1.73 m2) 
according to the modification of diet in renal disease (MDRD) 
abbreviated formula  
• A hearing loss (measured by audiometry) of > 25 dB at two 
contiguous test frequencies in at least one ear 
• Grade ≥ 2 peripheral neuropathy (i.e. sensory alteration or 
paresthesia including tingling) 
⚫ 
⚫ 
10. Recovery to National Cancer Institute’s Common Terminology 
Criteria for Adverse Events, version 4.03 (NCI CTCAE v.4.03) 
Grade 0 or 1 level or recovery to baseline preceding the prior 
treatment from any previous drug / procedure-related toxicity 
(patients with persistent alopecia of any grade, anemia [hemoglobin 
≥ 9 g/dL], any grade peripheral neuropathy, impaired renal function 
[GFR > 30 mL/min/1.73 m2], hearing loss and/or hypothyroidism 
that is adequately controlled by hormone replacement can be 
included). 
 
⚫ 
11. Eastern Cooperative Oncology Group Performance Status (ECOG 
PS) 0 or 1. 
⚫ 
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Inclusion criteria 
to be checked at 
 
FGFR 
testing 
Screening 
12. Adequate bone marrow, liver and renal function as assessed by 
laboratory requirements conducted within 7 days of first study drug 
administration: 
• Absolute neutrophil count (ANC) ≥ 1,500/mm3 (without 
granulocyte colony-stimulating factor support within 2 weeks 
before the first study drug administration) 
• Lymphocyte count ≥ 300/ mm3  
• Hemoglobin ≥ 9 g/dL (without transfusion or erythropoietin 
within 4 weeks before the first study drug administration) 
• Platelet count ≥ 100,000/mm3 (without transfusion within 2 
weeks before the first study drug administration) 
• Total bilirubin ≤ 1.5  the upper limit of normal (ULN). Known 
Gilbert syndrome is allowed if total bilirubin is ≤ 3 x ULN. 
• Alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST) ≤ 2.5  ULN (≤ 5 times ULN for patients with liver 
involvement of their cancer) 
• Alkaline phosphatase ≤ 2.5 times ULN (≤ 5  ULN for patients 
with liver or bone involvement of their cancer) 
• Lipase and amylase ≤ 2  ULN 
• Serum albumin ≥ 2.5 g/dL 
• Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m2 according 
to the modification of diet in renal disease (MDRD) abbreviated 
formula. 
• INR ≤ 1.5  ULN and 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 and they are on a stable dose as defined by the local 
standard of care. 
 
⚫ 
13. Negative serum pregnancy test in women of childbearing potential 
(performed within 7 days before the first treatment). Negative results 
must be available before the first study drug administration. 
 
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Inclusion criteria 
to be checked at 
 
FGFR 
testing 
Screening 
14. Women of childbearing potential (WOCBP) and fertile men must 
agree to use adequate contraception when sexually active from 
signing of the ICF for study treatment eligibility until at least 5 
months after the last atezolizumab administration or until at least 
one week after the last rogaratinib intake, whichever is later. 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: 
• Combined (estrogen and progesterone containing: oral, 
intravaginal, transdermal) and progesterone-only (oral, 
injectable, implantable) hormonal contraception associated with 
inhibition of ovulation. 
• Intrauterine device (IUD) or intrauterine hormone-releasing 
system (IUS). 
• Bilateral tubal occlusion or vasectomized partner (provided that 
partner is the sole sexual partner and has received medical 
assessment of the surgical success). 
• Sexual abstinence (reliability to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle 
of the patient).  
o 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 5 months after last atezolizumab 
administration or until at least one week after the last rogaratinib 
intake, whichever is later. 
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 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. 
 
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6.2 
Exclusion criteria 
The following exclusion criteria are applicable for all patients: 
Exclusion criteria 
to be checked at 
 
FGFR 
testing 
Screening 
1. Previous or concurrent cancer except  
• cervical carcinoma in situ 
• treated basal-cell carcinoma or squamous cell skin cancer 
• localized prostate cancer treated with curative intent and known 
absence of prostate-specific antigen (PSA) relapse or incidental 
prostate cancer (T1/T2a, Gleason score ≤ 6, and PSA ≤ 10 
ng/mL undergoing active surveillance and treatment-naïve) 
• any other cancer curatively treated > 3 years before the first 
study drug administration 
 
⚫ 
2. Ongoing or previous treatment with anti-FGFR directed therapies 
(e.g. receptor tyrosine kinase inhibitors including rogaratinib or 
FGFR-specific antibodies). 
⚫ 
 
3. Previous assignment to treatment during this study 
⚫ 
⚫ 
4. Investigational drug treatment outside of this study during or within 
4 weeks before the first study drug administration. 
 
⚫ 
5. 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:  
• evaluable or measurable disease outside the CNS 
• no metastases to midbrain, pons, medulla, cerebellum, or within 
10mm of the optic apparatus (optic nerves and chiasm) 
• no history of intracranial or spinal cord hemorrhage 
• no evidence of significant vasogenic edema 
• no ongoing requirement for dexamethasone as therapy for CNS 
disease; anticonvulsants at stable dose are allowed 
• no stereotactic radiation, whole-brain radiation or neurosurgical 
resection within 4 weeks before the first study drug 
administration 
• radiographic demonstration of interim stability (i.e. no 
progression) between the completion of CNS-directed therapy 
and the screening radiographic study 
• Screening CNS radiographic study ≥ 4 weeks since completion 
of radiotherapy or surgical resection and ≥ 2 weeks since 
discontinuation of corticosteroids 
 
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Exclusion criteria 
to be checked at 
 
FGFR 
testing 
Screening 
6. History or current condition of an uncontrolled cardiovascular 
disease including any of the following conditions: 
• Congestive heart failure (CHF) NYHA Class 2 or greater, 
unstable angina (symptoms of angina at rest) or  
• New-onset angina (within last 3 months before the first study 
drug administration)  
• Myocardial infarction (MI) within past 6 months before the first 
study drug administration 
• Unstable cardiac arrhythmias requiring anti-arrhythmic therapy. 
Patients with arrhythmia not requiring therapy or under control 
with anti-arrhythmic therapy such as beta-blockers or digoxin 
are eligible. 
• Patients with known coronary artery disease, congestive heart 
failure not meeting the above criteria, or known left ventricular 
ejection fraction < 50% must be on a stable medical regimen that 
is optimized in the opinion of the treating physician, in 
consultation with a cardiologist if appropriate.  
 
⚫ 
7. History of autoimmune disease, including but not limited to 
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, 
vascular thrombosis associated with anti-phospholipid syndrome, 
granulomatosis with polyangiitis, Sjögren’s syndrome, Guillain-
Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis 
The following conditions are no reason for exclusion: 
• History of autoimmune-related hypothyroidism clinically stable 
on thyroid replacement hormone  
• Controlled Type-I diabetes mellitus on a stable dose of insulin 
regimen. 
 
⚫ 
8. Uncontrolled pleural effusion, pericardial effusion, or ascites 
requiring recurrent drainage procedures (once monthly or more 
frequently). Patients with indwelling catheters (e.g. PleurX) are 
allowed. 
 
⚫ 
9. History of idiopathic pulmonary fibrosis, organizing pneumonia 
(e.g. bronchiolitis obliterans), drug-induced pneumonitis, idiopathic 
pneumonitis, or evidence of active pneumonitis on screening chest 
CT scan. 
History of radiation pneumonitis in the radiation field (fibrosis) is 
permitted. 
 
⚫ 
10. Known human immunodeficiency virus (HIV) infection 
 
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Exclusion criteria 
to be checked at 
 
FGFR 
testing 
Screening 
11. Active hepatitis B virus (HBV; chronic or acute; defined as having a 
known positive hepatitis B surface antigen [HBsAg] test at the time 
of screening) or hepatitis C infection requiring treatment.  
• Patients with past HBV infection or resolved HBV infection 
(defined as the presence of hepatitis B core antibody [HBcAb] 
and absence of HBsAg) are eligible if HBV DNA is negative. 
• Patients positive for hepatitis C virus (HCV) antibody are 
eligible only if polymerase chain reaction is negative for HCV 
RNA.  
 
⚫ 
12. Active tuberculosis (baseline chest X-ray and CT can be used for 
tuberculosis screening) 
 
⚫ 
13. Clinically active infections (CTCAE v4.03 ≥ Grade 1) within 2 
weeks before the first study drug administration 
 
⚫ 
14. Severe (CTCAE v.4.03 Grade ≥ 3) infections within 4 weeks before 
the first study drug administration, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe 
pneumonia 
 
⚫ 
15. Treatment with therapeutic oral or i.v. antibiotics within 2 weeks 
before the first study drug administration. 
Patients receiving prophylactic antibiotics (e.g. for prevention of a 
urinary tract infection or to prevent chronic obstructive pulmonary 
disease exacerbation) are eligible. 
 
⚫ 
16. Seizure disorder requiring medication 
 
⚫ 
17. History of organ allograft 
 
⚫ 
18. Evidence or history of bleeding diathesis or coagulopathy 
 
⚫ 
19. Any hemorrhage / bleeding event CTCAE v.4.03 ≥ Grade 3 within 
4 weeks before the first study drug administration 
 
⚫ 
20. Serious, non-healing wound, ulcer, or bone fracture 
 
⚫ 
21. Known hypersensitivity to any of the study drugs, study drug 
classes, or excipients in the formulation 
 
⚫ 
22. History of severe allergic, anaphylactic, or other hypersensitivity 
reactions to chimeric or humanized antibodies or fusion proteins 
 
⚫ 
23. Inability to swallow oral tablets 
 
⚫ 
24. Any malabsorption condition 
 
⚫ 
25. Current diagnosis of any retinal disorders including retinal 
detachment, retinal pigment epithelial detachment (RPED), central 
serous retinopathy or retinal vein occlusion. 
 
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Exclusion criteria 
to be checked at 
 
FGFR 
testing 
Screening 
26. Current evidence of endocrine alteration of calcium phosphate 
homeostasis (e.g. parathyroid disorder, history of 
parathyroidectomy, tumor lysis, tumoral calcinosis, paraneoplastic 
hypercalcemia). 
 
⚫ 
27. Concomitant therapies that are known to increase serum calcium or 
phosphate levels (i.e. antacids, phosphate-containing laxatives 
oral/rectal, potassium phosphate) and that cannot be discontinued or 
switched to a different medication before the first study drug 
administration 
 
⚫ 
28. Any condition that is unstable or could jeopardize the safety of the 
patient and their compliance in the study 
 
⚫ 
29. Breast-feeding 
 
⚫ 
30. Treatment with systemic immunostimulatory agents (including but 
not limited to IFNs, TNF [CD137 agonist] and interleukin [IL]-2) 
within 6 weeks or five half-lives of the drug, whichever is shorter, 
before the first study drug administration. 
 
⚫ 
31. Use of strong inhibitors of CYP3A4 and strong inducers of CYP3A4 
(see Appendix 16.1) are not permitted for 2 weeks before the first 
study drug administration.  
 
⚫ 
32. Treatment with systemic corticosteroids or other systemic 
immunosuppressant medications (including but not limited to 
prednisone, dexamethasone, cyclophosphamide, azathioprine, 
methotrexate, thalidomide, and anti-tumor necrosis factor [anti-
TNF] agents) within 2 weeks before the first study drug 
administration, or anticipated requirement for systemic 
immunosuppressive medications during the trial. 
• Patients who have received acute, low-dose, systemic 
immunosuppressant medications (e.g. a one-time dose of 
dexamethasone for nausea) may be enrolled in the study after 
discussion with and approval by the sponsor. 
• The use of inhaled corticosteroids, physiologic replacement 
doses of glucocorticoids (i.e. for adrenal insufficiency), and 
mineralocorticoids (e.g. fludrocortisone for adrenal 
insufficiency) is allowed. 
 
⚫ 
33. Any administration of a live, attenuated, replication competent virus 
vaccine within 28 days before the study start or anticipation that 
such a live, attenuated, replication competent virus vaccine will be 
required during the study. Patients may receive inactivated vaccines. 
 
⚫ 
34. Autologous bone marrow transplant or stem cell rescue within 
4 months before the first study drug administration 
 
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Exclusion criteria 
to be checked at 
 
FGFR 
testing 
Screening 
35. Major surgery, open biopsy or significant traumatic injury within 
4 weeks before the first study drug administration (central line 
surgery is not considered major surgery). 
 
⚫ 
36. Renal failure requiring peritoneal dialysis or hemodialysis 
 
⚫ 
37. Systolic/diastolic blood pressure ≤ 100/60 mmHg and  
concurrent heart rate ≥ 100/min 
 
⚫ 
38. Clinically significant uncontrolled hypertension (systolic blood 
pressure > 150 mmHg or diastolic pressure > 100 mmHg despite 
optimal medical management) 
 
⚫ 
39. Close affiliation with the investigational site; e.g. a close relative of 
the investigator or a dependent person (e.g. employee of or student 
at the investigational site) 
 
⚫ 
40. Substance abuse, medical, psychological or social conditions that 
may interfere with the patient’s participation in the study or 
evaluation of the study results 
 
⚫ 
 
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 receiving study treatment, a withdrawn 
patient is referred to as either “FGFR testing failure” (those that are FGFR test negative 
and/or those that do not meet the inclusion/exclusion criteria for FGFR testing) or “screening 
failure” as specified below: 
FGFR testing failure 
A patient who was tested for FGFR mRNA expression level by FGFR1/3 RNAscope in situ 
hybridization assay and the test result for FGFR1 or 3 mRNA expression levels was not 
RNAscope score of 3+ or 4+ (measurement is part of this protocol) or fails to satisfy the 
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withdrawn from the study and is regarded a “FGFR testing failure”. The “FGFR testing 
failure” will be registered.  
Re-testing is allowed if an unevaluable test result occurs. 
See Section 11.1 for data to be collected for FGFR testing failures (those that are FGFR test 
negative and/or those that do not meet the inclusion/exclusion criteria for FGFR testing). 
Screening failure 
A patient who, for any reason (e.g. failure to satisfy the selection criteria), terminates the 
study before start of study treatment is regarded a “screening failure”. 
See Section 11.1 for data to be collected for screening failures. 
 
6.4.1.2 
Re-screening 
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 inclusion / exclusion criteria preventing the patient’s initial attempt to participate 
have been changed (via protocol amendment). 
Re-screening of patients who have failed screening may only be allowed once after discussion 
with the sponsor’s designated medical representative and after approval by the sponsor. 
Sponsor 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 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.  
 
6.4.1.3 
Withdrawal criteria 
Patients must be withdrawn from the study treatment if any of the following occurs: 
• Consent withdrawal at their own request or at the request of their legally acceptable 


 
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representative. 
o 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.  
• Substantial non-compliance with study procedures 
o Patients requiring a dose interruption of rogaratinib due to toxicity > 21 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. 
o Off study drug (atezolizumab) longer than 42 days from the next intended dose 
▪ 
If, in the judgment of the investigator, the patient is likely to derive clinical 
benefit from resuming atezolizumab after a hold > 42 days, atezolizumab may 
be restarted after sponsor approval. 
▪ 
If patients must be tapered off steroids used to treat adverse events, 
atezolizumab may be held for > 42 days. The acceptable length of interruption 
will depend on agreement between the investigator and the sponsor. (See also 
Section 7.4.3.3 for further details and specific recommendations). 
o Lost to follow-up 
o Use of another non-protocol anti-cancer therapy 
• Unacceptable toxicity 
o If, in the investigator’s opinion, continuation of study would be harmful to the patient’s 
well-being. 
o Any toxicity requiring rogaratinib dose reductions below dose level -2. 
o Any toxicity requiring rogaratinib dose interruption longer than 21 days to resolve to 
Grade 1 or better. 
o Severe (Grade 3 or higher) allergic reactions such as exfoliative erythroderma, 
anaphylaxis, or vascular collapse. 
o Severe (Grade 3 or higher) infusion-related reactions. 
o Any other potential adverse reaction deemed sufficiently serious to warrant 
discontinuation of treatment by the investigator or his designated associate(s). 
o Any decrease in visual acuity, ocular pain or discomfort, or symptomatic retinal 
disorders including retinal detachment / retinal pigment epithelial detachment / central 
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, 
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assessment. 
o Liver toxicity with AST or ALT > 3 x ULN with concomitant bilirubin > 2 x ULN in 
the absence of an alternative explanation for these elevations. 
o ≥ Grade 3 liver toxicity with ALT or AST > 5 x ULN and/or total bilirubin > 3 x ULN 
in the absence of an alternative explanation for these elevations. 
o Any grade myasthenic syndrome/myasthenia gravis, Guillain-Barré or 
meningoencephalitis. 
o Any grade of recurrent symptomatic pancreatitis. 
o Newly diagnosed soft tissue mineralization suspected to be caused by rogaratinib.  
o Grade 4 non-hematological toxicity (laboratory abnormalities of any grade will not be 
considered toxicity unless deemed clinically significant by the investigator).  
o Grade 3 or higher non hematologic toxicity atezolizumab-related and requiring 
treatment discontinuation (see also Section 7.4.3.3). 
o Any Grade 2 or higher non hematologic toxicity atezolizumab-related not resolving at 
Grade 1 or better within 12 weeks despite symptomatic therapy 
• Pregnancy as confirmed by a positive serum beta-HCG test. Pregnancy will be reported 
under the same timelines as a serious adverse event. 
• At specific request of the sponsor. 
 
Patients may be withdrawn from the study treatment if any of the following occurs: 
• If the patient develops conditions which would have prevented his/her entry into the study 
according to the inclusion / exclusion criteria, he/she must be withdrawn immediately if 
safety is concerned; in other cases, the investigator will decide whether there is a conflict 
for the patient to continue.  
• Development of a second malignancy that requires a different treatment. At investigator’s 
discretion study treatment may continue if UC has a poorer prognosis as compared with the 
second malignancy of new onset. 
• Development of any intercurrent illness or situation which may, in the judgment of the 
investigator, affect assessments of clinical status and study endpoints to a relevant degree.  
• Use of illicit drugs or other substances that may, in the opinion of the investigator or his 
designated associate(s), have a reasonable chance of contributing to toxicity or otherwise 
confound the results.  
• Symptomatic deterioration (i.e. uncontrollable pain secondary to disease or unmanageable 
ascites, etc.) attributed to disease progression as determined by the investigator after 
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• Disease progression per RECIST v1.1. At discretion of the investigator, willing patients 
will be permitted to continue study treatment after radiologic progression according to 
RECIST v1.1 if all the following criteria are met: 
o Evidence of clinical benefit (defined as the stabilization or improvement of disease-
related symptoms) as assessed by the investigator. 
o Absence of symptoms and signs indicating unequivocal progression of disease 
(including worsening of laboratory values [e.g. new or worsening hypercalcemia]). 
o No decline in ECOG performance status that can be attributed to disease progression. 
o Absence of tumor progression at critical anatomical sites (e.g. leptomeningeal disease) 
that cannot be managed by protocol-allowed medical interventions. 
In addition, treatment beyond progression should not delay an imminent intervention to 
prevent serious complications of disease progression (e.g. central nervous system [CNS] 
metastases).  
Patients for whom radiographic disease progression is confirmed at a subsequent tumor 
assessment may be considered for continuing study treatment at the discretion of the 
investigator if they still meet the criteria above and in absence of unacceptable toxicity.  
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.  
After permanent treatment discontinuation, a safety assessment visit must be scheduled for all 
patients (refer to Section 5.2.3). After primary completion, follow-up information will not be 
collected after safety assessment visit. 
Withdrawal from active follow-up 
Patients must be withdrawn from active follow-up if any of the following occurs: 
• Radiologically confirmed PD of urothelial carcinoma is observed (investigator 
assessment). (Note: this applies only to the further efficacy assessments during the active 
follow-up period in patients who prematurely discontinued study treatment for reasons 
other than radiological disease progression). 
• Start of subsequent systemic anti-cancer treatment. (Note: this applies only to the further 
efficacy assessments during the active follow-up period in patients who prematurely 
discontinued study treatment for reasons other than radiological disease progression). 
• 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.  
• Development of a malignancy other than urothelial carcinoma 
• Substantial non-compliance with the requirements of the study 


 
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• 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 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 and sites 
are expected to make at least 5 attempts to contact the patient over the course of 3 months. An 
additional contact attempt should be made at the time of the survival sweep. 
 
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. 
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 
Replacement of patients may occur in Part A in order to ensure the necessary number of 
evaluable patients for dose selection (at least 4 patients per tested dose level, a total of 20 
evaluable patients). Patients who are not valid for efficacy assessment may be replaced, to 
ensure at least 26 valid patients for assessment of the RP2D. Patients may be replaced in the 
following circumstances: 
Dose selection: 
• Patients who discontinue or took less than 80% of the per protocol required total dose of 
either study drug (rogaratinib or atezolizumab) during the first cycle due to any reason 


 
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other than a DLT (note: protocol-defined dose reductions will not be considered 
incompliant).  
Efficacy:  
• Patients who took less than 80% of the per protocol required total dose of either study drug 
(rogaratinib or atezolizumab) during the first two cycles or patients without an efficacy 
assessment. 
 
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.  
The patient number is a 9-digit number consisting of: 
Digits 1 to 5  = Unique center number 
Digits 6 to 9 = Current patient number within the center. 
 
7. 
Treatments 
7.1 
Treatments to be administered 
In Part A of the study, patients will receive a combination treatment of rogaratinib (a pan 
FGFR inhibitor) plus atezolizumab (a PD-L1 monoclonal antibody). 
7.2 
Identity of study treatment 
In this protocol, the term “test drug” refers to rogaratinib only. The term “study drug” refers 
to any of protocol-stipulated drugs, i.e. rogaratinib or atezolizumab, and “study treatment” 
refers to the combination of rogaratinib and atezolizumab. 
All study treatment 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, 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 bulk batch 
of the ingredients. Lists linking all numbering levels will be maintained by the sponsor’s 
clinical supplies 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’s study file. 
In case patients are transferred to a roll-over study or any other form of continued study drug 
supply with no cost to the patient, drug formulation and / or dosage might change compared 
to this study depending on the course of the clinical development.  


 
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In addition, the supply of commercially available non-Bayer drugs in a roll-over study or any 
other form of continued study drug supply with no cost to the patient 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. 
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  
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; PP = Polypropylene. 
7.2.2 
Atezolizumab – combination drug 
The study drug atezolizumab serves as the combination drug in this study Part A. 
Atezolizumab received accelerated FDA and full EMA approval for the treatment of 
metastatic urothelial carcinoma who have been previously treated with a platinum-based 
chemotherapy or who are considered ineligible for cisplatin chemotherapy (18, 31). 
Atezolizumab will be sourced centrally by the sponsor. For full details on atezolizumab and 


 
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instructions for dilution, please refer to the current Summary of Product Characteristics 
(SmPC) or the investigator’s brochure. (Note: the SmPC should only be referred to for the 
preparation instructions for atezolizumab. The IB should be the reference for all other 
information about atezolizumab). 
Please also refer to atezolizumab label for guidance when prescribing with other medications. 
Atezolizumab vials should be stored under refrigeration at 2°C to 8°C (36°F to 46°F) in the 
original carton to protect from light. They should not be frozen or shaken. 
7.3 
Treatment assignment 
In Part A, all eligible patients will be assigned to receive the same combination treatment, 
rogaratinib plus atezolizumab. 
7.4 
Dosage and administration 
7.4.1 
Doses, dosing schedule and route of administration 
7.4.1.1 
Rogaratinib – test drug 
Rogaratinib will be administered orally in a stepwise dose selection schedule shown in Table 
7–2 until disease progression, unacceptable toxicity or consent withdrawal. 
Patients will receive their initial dose of 800mg rogaratinib in the morning of Cycle 1 Day 1, 
followed by serial PK blood sampling for 8 hours and a second dose of 800mg rogaratinib in 
the evening. Rogaratinib will be administered continuously twice daily on all 21 days in each 
cycle. 
Special considerations/instructions for rogaratinib 
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.  
It is important to take the medications at the same times each day approximately 12 hours 
apart. For the second dose of rogaratinib on C1D1, a time window of ± 3 hours is permitted. 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, the patient should 
miss the dose and continue with the next dose at the next prescribed interval. 
Rogaratinib and atezolizumab will be dosed at the same time, starting first with the infusion 
and shortly after start (< 5 minutes) the intake of rogaratinib. 
7.4.1.2 
Atezolizumab – combination drug 
A fixed dose of 1200 mg atezolizumab will be administered through intravenous (i.v.) 
infusion on Day 1 of each 21-day cycle until disease progression, unacceptable toxicity or 
consent withdrawal. 


 
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Administration of atezolizumab will be performed in a setting with emergency medical 
facilities and staff who are trained to monitor for and respond to medical emergencies. For 
more detailed information regarding administration, refer to the investigator’s brochure. 
The initial dose of atezolizumab will be delivered over 60 (± 15) minutes. If the first infusion 
in Cycle 1 is tolerated without infusion-associated adverse events, the second infusion in 
Cycle 2 may be delivered over 30 (± 10) minutes. If the 30-minute infusion is well tolerated, 
all infusions in the subsequent cycles may be delivered over 30 (± 10) minutes. For the first 
infusion, the patient’s vital signs (heart rate, respiratory rate and blood pressure) should be 
monitored 60 minutes before, during (every 15 [± 5] minutes), and 30 (± 10) minutes after the 
infusion. For subsequent infusions, vital signs will be collected within 60 minutes before 
infusion and at the end of the infusion. Patients will be informed about the possibility of 
delayed post-infusion symptoms and instructed to contact their study physician if they 
develop such symptoms. 
No pre-medication will be allowed for the first dose of atezolizumab. Pre-medication may be 
administered for Cycles ≥ 2 at the discretion of the treating physician in case of previous 
infusion reaction. Pre-medication should be recorded in eCRF as concomitant medication.  
For the management of infusion-related reactions see the specific section in Section 7.4.3.3. 
Most common adverse reactions (≥ 20%) in patients with locally advanced or metastatic 
urothelial carcinoma were: fatigue, decreased appetite, nausea, urinary tract infection, 
constipation, diarrhea and pyrexia. Atezolizumab has been associated with risks such as the 
following: infusion-related reactions and immune-related hepatitis, pneumonitis, colitis, 
pancreatitis, diabetes mellitus, hypothyroidism, hyperthyroidism, adrenal insufficiency, 
Guillain-Barré syndrome, myasthenic syndrome or myasthenia gravis, myocarditis and 
meningoencephalitis. Immune-related adverse reactions (pneumonitis, hepatitis, colitis, 
endocrinopathies, other immune-related adverse reactions) requiring systemic corticosteroids 
or hormone replacement therapy occurred in < 20% patients. In addition, systemic immune 
activation (described below) is a potential risk associated with atezolizumab when given in 
combination with other immunomodulating agents. 
Any overdose or incorrect administration of combination drug should be noted on the Study 
Drug Administration electronic Case Report Form (eCRF). Adverse events associated with an 
overdose or incorrect administration of study drug should be recorded on the Adverse Event 
eCRF. 
Guidelines for dose modification, treatment interruption or discontinuation and for the 
management of specific adverse events are provided in a specific section in Section 7.4.3.3. 
7.4.2 
Justification of selected doses 
Rogaratinib: rogaratinib dose of 800 mg b.i.d. was chosen for further clinical development 
based on pharmacokinetic, biomarker, safety and anti-tumor activity in the Phase 1 dose 
escalation study 16443. 
 
Atezolizumab: the approved dose of atezolizumab will be used in this study. 


 
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7.4.3 
Dose modifications 
7.4.3.1 
Dose limiting toxicities (DLTs) 
A DLT is defined as any of the following TEAEs occurring during Cycle 1 and regarded by 
the investigators and/or sponsor to be related to rogaratinib or atezolizumab. The CTCAE 
v 4.03 will be used to assess toxicities / adverse events. 
Hematological 
• Absolute neutrophil count (ANC) < 500/mm3 for more than 7 days 
• Febrile neutropenia (a disorder characterized by an ANC < 1,000/mm3 and single 
temperature ≥ 38.3 °C or sustained temperature of ≥ 38.0 °C for more than 1 hour) 
• Platelets < 25,000/mm3  
• Hemoglobin < 8.0 g/dL 
• Grade 3 hemorrhage associated with thrombocytopenia of ≥ Grade 3 
Non-hematological 
• Any non-hematologic Grade 3 or higher toxicity except:  
o Grade 3 nausea, vomiting, and fatigue that resolve within 72 hours with or 
without supportive care. 
o Grade 3 diarrhea will be classified as DLTs if not resolved to Grade ≤ 2 or 
baseline following dose interruption of rogaratinib and/or withholding 
atezolizumab within 3 days with or without supportive care. 
o Laboratory abnormalities of any grade will not be considered toxicity unless 
deemed clinically significant by the investigator. 
o Grade 3 hypothyroidism 
• Any grade myasthenic syndrome/myasthenia gravis, Guillain-Barré or 
meningoencephalitis. 
• Decrease of three lines or more in visual acuity scales, Grade 2 or higher ocular pain 
or discomfort, or symptomatic retinal disorders including retinal detachment, RPED, 
central serous retinopathy or retinal vein occlusions. 
• Grade 2 with AST or ALT >3 x ULN and up to 5 x ULN or total bilirubin greater than 
1.5 and up to 3 x ULN in absence of an alternative explanations for these elevations. 
• Any toxicity not resolving within 21 days at ≤Grade 1 with or without supportive care. 


 
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Miscellaneous 
• In case an unexpected drug-related toxicity is seen more frequently, this toxicity may 
be declared a DLT for the remainder of the study after thorough consultation between 
the investigator and the sponsor. 
• Any rogaratinib-related toxicity that, at the discretion of the investigator, or his 
designated associate(s), is thought to warrant withholding the drug for more than 3 
consecutive days.  
• Such toxicities might be Grade 1 or Grade 2 toxicities which interfere with the 
activities of daily life (e.g. long-lasting fatigue, or anorexia), making a dose reduction 
necessary in order to ensure the patient’s compliance. 
• Inability to start Cycle 2 Day 1 due to clinically relevant toxicity. 
For certain toxicities such as laboratory assessments without a clear clinical correlation (e.g. 
lipase increase without signs of a clinical pancreatitis) or in patients that violated the protocol, 
a discussion between the investigator and the sponsor may take place if that adverse event 
should be regarded as DLT necessitating dose reduction. 
7.4.3.2 
Dose modifications of rogaratinib 
Dose of rogaratinib may be interrupted / delayed or reduced in case of clinically significant 
toxicities that are related to study drug therapy. The intensity of toxicities will be graded using 
the CTCAE v 4.03.  
If a patient experiences a DLT during Cycle 1 (Days 1-21), the next dose of rogaratinib can be 
delayed for up to 21 days. This is permitted also in case of Grade 3 toxicities that are not 
defined as withdrawal criteria and that are persisting ≤ 7 days. 
All patients who are re-treated following a DLT should undergo dose reduction of rogaratinib 
(see Table 7–2). 
If the toxicity resolves within 21 days after the planned treatment date to ≤ Grade 1 re-starting 
rogaratinib at 1 dose level below the current dose can be considered (see Table 7–2). If such 
an improvement is not observed, the study treatment should be permanently discontinued.  
Patients who experience a Grade 4 non-hematological toxicity, and any other toxicity defined 
as withdrawal criteria will be permanently withdrawn from the study treatment. 
If a patient experiences clinically relevant toxicity after Cycle 1, the next dose of rogaratinib 
can be delayed for up to 21 days. This is permitted also in case of Grade 3 toxicities that are 
not defined as withdrawal criteria and that are persisting ≤ 7 days. If the toxicity resolves 
within 21 days after the planned treatment date to ≤ Grade 1 or baseline, reduction of the next 
dosing of rogaratinib by 1 dose level below the current dose (see Table 7–2) can be 
considered.  
Patients requiring dose reduction to less than 400 mg b.i.d. should be permanently withdrawn 
from the study treatment. 


 
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Table 7–2: 
Dose levels of rogaratinib (BAY 1163877) 
Level 
Dose 
Starting level 800 mg b.i.d. 
 
-1 
600 mg b.i.d. 
 
-2 
400 mg b.i.d. 
b.i.d = Twice daily, bis in die. 
Dose modifications will be based on the highest intensity 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, with the exception of dose reduction 
due to liver toxicities, 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 and if toxicity has resolved to baseline. 
• Patients requiring a dose interruption of rogaratinib due to toxicity > 21 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 -2 are needed, patients will be withdrawn 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 of treatment with rogaratinib (interruptions will not 
prolong the duration of a cycle).  
Detailed dose adjustments for toxicities are described in Table 7–3. Patients who experience a 
Grade 4 toxicity must discontinue study drug permanently. 


 
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Table 7–3: 
Guidance for dose modification of rogaratinib due to toxicity (excluding 
hyperphosphatemia, liver toxicity, retinal disorders) 
Grade a 
Dose delay 
Dose modification 
1 – 2 b 
Treat as scheduled 
No change 
3 
Delay c until recovery to  Grade 1 
Decrease by 1 dose level d 
4 
Discontinue study treatment permanently 
Discontinue study treatment permanently 
a: Excludes alopecia, fatigue, nausea/vomiting if adequately controlled by antiemetic treatments. Laboratory abnormalities of 
any grade will not be considered toxicity unless deemed clinically significant by the investigator. In addition, specific dose 
modification rules for hyperphosphatemia, liver toxicity and retinal disorders are given in the following sections. 
b: In case of Grade 2 diarrhea with no signs or symptoms of colitis and that does not resolve within 72 hours with or without 
supportive care, rogaratinib dosing has to be interrupted until resolution to Grade ≤ 1. No dose reduction is required. 
c: If not recovered within 21 days, the study treatment will be permanently discontinued. 
d: If dose reductions by more than 2 levels are required, the study treatment will be permanently discontinued. 
 
7.4.3.2.1 Hyperphosphatemia 
Dose modifications of rogaratinib for elevated serum phosphate levels (≥ 7 mg/dL) and 
management guidance for hyperphosphatemia are presented in Table 7–4. 
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 chelators are not tolerated, low-phosphorus 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 the day of detection of hypocalcemia and should be repeated as clinically 
indicated. 


 
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7.4.3.2.2 Liver toxicity 
Dose modifications of rogaratinib for liver toxicity are presented in Table 7–5 and have been 
adapted based on criteria established for liver toxicity due to atezolizumab concomitant 
administration. Immune-related hepatitis has been associated with the administration of 
atezolizumab. Refer to the latest available versions of rogaratinib and atezolizumab IBs for 
further details. Eligible patients must have adequate liver function, as manifested by 
measurement of hepatic transaminases and total bilirubin, and liver function will be monitored 
throughout study treatment. Liver toxicity refers to ALT and/or AST and/or bilirubin 
increases and graded according to CTCAE v.4.03. 


 
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Table 7–5: 
Dose modifications of rogaratinib and atezolizumab for liver toxicity 
Toxicity 
Modification schedule 
Hepatic event, Grade 1 
 
No modifications. Treat as scheduled and check AST, ALT and 
bilirubin weekly for at least 4 weeks a or until values resolve to 
within normal limits 
Hepatic event, Grade 2 
with AST or ALT > 3 x ULN and up to 
5 x ULN or total bilirubin greater than 1.5 and 
up to 3 x ULN in absence of an alternative 
explanation for these elevations 
All events: 
No modification. Check AST, ALT and bilirubin level more 
frequently until return to baseline value 
Events of > 5 days’ duration: 
1. 
STOP rogaratinib 
2. 
STOP atezolizumab 
3. 
Initiate treatment with 1-2 mg/kg/day oral prednisone 
or equivalent 
4. 
Check AST, ALT and bilirubin level weekly or more 
frequently till recovery to Grade 0-1 a 
5. 
After recovery to Grade 0-1 re-start with rogaratinib    
-1 DL b and atezolizumab  
6. 
Permanently discontinue atezolizumab and 
rogaratinib, and contact sponsor if event does not 
resolve to Grade 0-1 within 12 weeks 
Hepatic event, Grade 3  
with AST or ALT > 3 x ULN with concomitant 
bilirubin > 2 x ULN in absence of an 
alternative explanation for these elevations 
or 
with AST or AST > 5 x ULN and/or total 
bilirubin > 3 x ULN in absence of an 
alternative explanation for these elevations 
Withdraw patient from study treatment permanently a, c, d and 
contact sponsor 
Consider patient referral to gastrointestinal specialist for 
evaluation and liver biopsy to establish etiology of hepatic 
injury 
Initiate treatment with 1-2 mg/kg/day oral prednisone or 
equivalent 
If event does not improve within 48 hours after initiating 
corticosteroids, considering adding an immunosuppressive 
agent. 
If event resolves to Grade 1 or better, taper corticosteroids 
over ≥ 1 months 
Hepatic event, Grade 4 
Withdraw patient from study treatment permanently a, c 
ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; DL = Dose level; ULN = Upper limit of normal. 
a: In case of interruption/discontinuation, check AST, ALT, and bilirubin weekly or more frequently according to local 
standard of care, until recovery to Grade 0-1 or to baseline.  
b: Dose will not be re-escalated to original dose after dose reduction for toxicity. If more than 2 dose level reductions are 
required, treatment will be permanently discontinued. 
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 per investigator’ judgment the Grade 3 hepatic event is unrelated to study treatment and reversible, the treatment may 
be restarted after resolution to Grade 0 or 1 or to baseline. 
 


 
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Patients with right upper-quadrant abdominal pain and/or unexplained nausea or vomiting 
should have liver function tests (LFTs) performed immediately and reviewed before 
administration of the next dose of study drug. 
For patients with elevated liver function tests, concurrent medication, viral hepatitis, and toxic 
or neoplastic etiologies should be considered and addressed, as appropriate. 
 
7.4.3.2.3 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 (RPED) 
/ central 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 / central 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 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 judgement 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. 
 
7.4.3.3 
Dose modifications of atezolizumab  
There will be no dose reduction for atezolizumab in this study.  
Patients may temporarily suspend study treatment if they experience toxicity that is 
considered related to study drug and requires a dose to be held.  
If atezolizumab is held because of related adverse events for > 42 days beyond the next 
scheduled dosing, the patient will be discontinued from atezolizumab and will be followed for 
safety and efficacy as specified in Section 9.2.3. 
If, in the judgment of the investigator, the patient is likely to derive clinical benefit from 
resuming atezolizumab after a hold > 42 days, atezolizumab may be restarted with the 
approval of the sponsor.  
If patients must be tapered off steroids used to treat adverse events, atezolizumab may be held 
for > 42 days. The acceptable length of interruption will depend on agreement between the 
investigator and the sponsor. During steroid taper and if toxicity has resolved to Grade ≤ 1, 
rogaratinib may continue as monotherapy. 


 
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Infusion-related reactions 
Severe infusion reactions have occurred in patients in clinical trials of atezolizumab. Refer to 
the latest available version of atezolizumab IB for further details. Immediately interrupt 
infusion in patients with mild or moderate infusion-related reactions (Grade 1 and 2). 
Permanently discontinue atezolizumab in patients with Grade 3 or 4 infusion-related 
reactions. 
The management of infusion-related reactions will be according to severity as follows: 
In the event that a patient experiences a mild (NCI CTCAE Grade 1) infusion-related event, 
the infusion rate should be immediately interrupted at the time of event onset. Once the event 
has resolved, the investigator should wait for 30 minutes and then restart the infusion at half 
the rate been given at time of event onset. If tolerated at the reduced rate for 30 minutes, the 
infusion rate may then be increased to the original rate. If the symptoms recur, discontinue 
infusion of this dose. 
In the event that a patient experiences a moderate infusion-related event (NCI CTCAE Grade 
2) or flushing, fever, or throat pain, the patient should have his or her infusion immediately 
interrupted and should receive aggressive symptomatic treatment (e.g. oral or i.v. 
antihistamine, anti-pyretic, glucocorticoids, epinephrine, bronchodilators, oxygen). The 
infusion should be restarted only after the symptoms have adequately resolved to baseline 
grade. The infusion rate at restart should be half of the infusion rate that was in progress at the 
time of the onset of the infusion-related event. For the subsequent infusion, administer oral 
premedication with antihistamine and anti-pyretic and monitor closely for infusion-related 
reactions. 
For severe or life-threatening infusion-related events (NCI CTCAE Grade 3 or 4), the infusion 
should be stopped immediately, and aggressive resuscitation and supportive measures should 
be initiated (administer aggressive symptomatic treatment e.g. oral or i.v. antihistamine, anti-
pyretic, glucocorticoids, epinephrine, bronchodilators, oxygen). Patients experiencing severe 
or life-threatening infusion-related events will not receive further infusion and will be further 
managed as clinically indicated until the event resolves. 
 
As per the IB withhold atezolizumab for any of the following:  
• Grade 2 pneumonitis 
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 3 
and up to 5 times upper limit of normal (ULN) or total bilirubin greater than 1.5 and 
up to 3 times ULN  
• Grade 2 or 3 diarrhea or colitis 
• Grade 2 or 3 hypophysitis 
• Symptomatic adrenal insufficiency,  
• Grade 3 or 4 hypothyroidism or hyperthyroidism 


 
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• Grade 3 or 4 hyperglycemia  
• Suspected Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) 
• Grade 2 immune-mediated neuropathy, including facial paresis 
• Grade 2 ocular inflammatory toxicity 
• Grade 2 or 3 pancreatitis, or Grade 3 or 4 increases in amylase or lipase levels (greater 
than 2.0 times ULN)  
• Grade 3 or 4 infection  
• Grade 2 infusion-related reactions 
• Grade 3 rash 
• Grade 1 immune-mediated pericarditis 
• Grade 2 immune-related nephritis 
• Grade 2 or 3 immune-related myositis 
Atezolizumab may be resumed in patients whose adverse reactions recover to Grade 0–1 
(except for Grade 1 immune-mediated pericarditis). 
 
Permanently discontinue atezolizumab for any of the following:  
• Grade 3 or 4 pneumonitis  
• AST or ALT greater than 5 times ULN or total bilirubin greater than 3 times ULN in 
the absence of an alternative explanation for these elevations 
• Grade 4 diarrhea or colitis  
• Grade 4 hypophysitis 
• Grade 4 immune-mediated hypothyroidism or hyperthyroidism 
• Any grade confirmed SJS or TEN 
• Grade 3 or 4 immune-mediated neuropathy, including facial paresis 
• Any grade myasthenic syndrome/myasthenia gravis, Guillain-Barré or 
meningoencephalitis  
• Grade 2–4 immune-mediated myelitis 
• Grade 3 or 4 ocular inflammatory toxicity  
• Grade 4 or any grade of recurrent symptomatic pancreatitis 
• Grade 2–4 immune-mediated myocarditis or immune-mediated pericardial disorders 
• Grade 3 or 4 immune-related nephritis  
• Grade 3 or 4 infusion-related reactions 


 
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• Grade 4 rash 
• Grade 4 immune-related myositis 
 
Management of specific adverse events 
Toxicities associated or possibly associated with atezolizumab treatment should be managed 
according to standard medical practice. Additional tests, such as autoimmune serology or 
biopsies, should be used to determine a possible immunogenic etiology. 
Although most immune-mediated adverse events observed with immunomodulatory agents 
have been mild and self-limiting, such events should be recognized early and treated promptly 
to avoid potential major complications. Discontinuation of atezolizumab may not have an 
immediate therapeutic effect, and there is no available antidote for atezolizumab. In severe 
cases, immune-mediated toxicities may be acutely managed with topical corticosteroids, 
systemic corticosteroids, mycophenolate, or TNF-α inhibitors. 
The primary approach to Grade 1−2 immune-mediated adverse events is supportive and 
symptomatic care; for higher grade immune-mediated adverse events, oral or parenteral 
steroids are given, and either skipping a dose or stopping therapy is appropriate. 
If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.  
Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for 
corticosteroids to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The acceptable 
length of the extended period of time must be agreed upon by the investigator and the 
sponsor. Recurrent Grade 2 immune-mediated adverse events may also mandate skipping a 
dose of atezolizumab or the use of steroids. Consideration for benefit-risk balance should be 
made by the investigator, with consideration of the totality of information as it pertains to the 
nature of the toxicity and the degree of clinical benefit a given patient may be experiencing 
prior to further administration of atezolizumab.  
Atezolizumab should be permanently discontinued in patients with life-threatening immune-
mediated adverse events. However, resumption of atezolizumab may be considered in patients 
who are deriving benefit and have fully recovered from the immune-related event. Patients 
can be rechallenged with atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the sponsor. 
 
Management of immune-mediated AEs 
For further details, please also refer to the latest version of the investigator’s brochure of 
atezolizumab. 
Immune-mediated pneumonitis or interstitial lung disease 
Immune-mediated pneumonitis or interstitial lung disease, defined as requiring use of 
corticosteroids and with no clear alternate etiology, might occur during treatment with 
atezolizumab. Refer to the latest available version of atezolizumab IB for further details. It is 


 
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recommended to monitor patients for signs or symptoms of pneumonitis (dyspnea, cough, 
fatigue, hypoxia) with radiographic imaging.  
All pulmonary events should be thoroughly evaluated for other commonly reported etiologies 
such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary embolism, 
heart failure, chronic obstructive pulmonary disease, or pulmonary hypertension. COVID-19 
evaluation should be performed per institutional guidelines where relevant.   
The management of immune-mediated pneumonitis will be according to the severity (Table 
7–6). 
 
Table 7–6:  
Management guidelines for pulmonary events, including pneumonitis 
Event 
CTCAE Grade 1 
CTCAE Grade 2 
CTCAE Grade 3 or 4 
Pulmonary 
event 
Continue atezolizumab and 
monitor closely 
 
Re-evaluate on serial 
imaging 
 
Consider patient referral to 
pulmonary specialist 
 
For recurrent events, treat 
as a Grade 3 or 4 event 
 
Withhold atezolizumab until 
resolution  
 
Refer patient to pulmonary 
and infectious disease 
specialist and consider 
bronchoscopy or BAL with or 
without transbronchial biopsy 
 
Initiate treatment with 
1−2 mg/kg/day oral 
prednisone or equivalent 
 
Resume atezolizumab if 
event resolves to ≤ Grade 1 
within 12 weeks 
  
Permanently discontinue 
atezolizumab if event does 
not resolve to ≤ Grade 1 
within 12 weeks and contact 
the sponsor a, b, c, d 
 
For recurrent events or 
events with no improvement 
after 48–72 hours of 
corticosteroids, treat as a 
Grade 3 or 4 event 
Permanently discontinue 
atezolizumab and contact 
sponsor c 
 
Oral or i.v. broad-spectrum 
antibiotics should be 
administered in parallel to the 
immunosuppressive 
treatment  
 
Bronchoscopy or BAL with or 
without transbronchial biopsy 
is recommended 
  
Initiate treatment with 
1−2 mg/kg/day i.v. 
methylprednisone  
 
If event does not improve 
within 48 hours after initiating 
corticosteroids, consider 
adding an 
immunosuppressive agent  
 
If event resolves to Grade 1 
or better, taper 
corticosteroids over 
≥ 1 month  
BAL = bronchoscopic alveolar lavage; CTCAE = Common Terminology Criteria for Adverse Events; i.v. = 
intravenous. 
a: If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed.  
b: Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for corticosteroids to be 
reduced to ≤ 10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of 
time must be agreed upon by the investigator and the sponsor.  
c: Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event. Patients can be rechallenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the sponsor. 
d: In case of pneumonitis, atezolizumab should not be resumed after permanent discontinuation. 
 


 
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Immune-mediated hepatitis 
Immune-mediated hepatitis, defined as requiring use of corticosteroids and with no clear 
alternate etiology, occurred in patients receiving atezolizumab treatment. Liver test 
abnormalities occurred in patients who received atezolizumab. Refer to the latest available 
version of atezolizumab IB for further details. For management of liver toxicity, refer to the 
Section 7.4.3.2.2 and Table 7–5. 
 
Immune-mediated colitis or diarrhea 
Immune-mediated colitis or diarrhea, defined as requiring use of corticosteroids and with no 
clear alternate etiology, occurred in patients receiving atezolizumab. Refer to the latest 
available version of atezolizumab IB for further details. It is recommended to monitor patients 
for signs and symptoms of diarrhea or colitis.  
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies including rogaratinib-related gastrointestinal toxicities. For events of significant 
duration or magnitude or associated with signs of systemic inflammation or acute-phase 
reactants (e.g., increased CRP, platelet count, or bandemia): perform sigmoidoscopy (or 
colonoscopy, if appropriate) with colonic biopsy, with three to five specimens for standard 
paraffin block to check for inflammation and lymphocytic infiltrates to confirm colitis 
diagnosis. 
Management of immune-related colitis will be according to its severity (Table 7–7). 
 


 
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Table 7–7:  
Management guidelines for immune-mediated gastrointestinal events 
(diarrhea or colitis) 
Event 
CTCAE Grade 1 
CTCAE Grade 2 
CTCAE Grade 3 or 4 
Diarrhea or  
colitis 
Continue atezolizumab. 
 
Initiate symptomatic 
treatment (oral fluids,  
loperamide, avoid high 
fiber/lactose diet). 
 
Endoscopy is 
recommended if 
symptoms persist 
for >7 days. 
 
Monitor closely. 
 
Withhold atezolizumab  
 
Initiate symptomatic treatment. 
 
If strong clinical suspicion for 
immune-mediated colitis, start 
empiric i.v. steroids while 
waiting for definitive diagnosis. 
 
Patient referral to 
gastrointestinal specialist is 
recommended. 
 
For recurrent event or for 
events that persist >5 days, 
initiate treatment with 
1-2 mg/kg/day oral prednisone 
or equivalent. If the event does 
not improve within 48 hours 
after initiating corticosteroids, 
consider adding an 
immunosuppressive agent. 
 
Resume atezolizumab if event 
resolves to ≤ Grade 1 within 
12 weeks. a,b 
 
Permanently discontinue 
atezolizumab if event does not 
resolve to ≤ Grade 1 within 
12 weeks and contact the 
sponsor. a, b, c 
 
Grade 3 
Withhold atezolizumab 
 
Refer patients to gastrointestinal 
specialist for evaluation and 
confirmatory biopsy.  
 
Initiate treatment with 
1−2 mg/kg/day intravenous 
methylprednisolone or equivalent 
and convert to 1-2 mg/kg/day 
oral prednisone or equivalent 
upon improvement. If event does 
not improve within 48 hours after 
initiating corticosteroids, consider 
adding an immunosuppressive 
agent.  
 
Resume atezolizumab if event 
resolves to ≤ Grade 1 within 
12 weeks. a,b 
 
Permanently discontinue 
atezolizumab if event does not 
resolve to ≤ Grade 1 within 
12 weeks and contact the 
sponsor. a, b, c 
 
Grade 4 
Permanently discontinue 
atezolizumab and contact 
sponsor. c  
 
Refer patient to gastrointestinal 
specialist for evaluation and 
confirmation biopsy.  
 
Initiate treatment with 
1−2 mg/kg/day intravenous 
methylprednisolone or equivalent 
and convert to 1−2 mg/kg/day 
oral prednisone or equivalent 
upon improvement.  
• If event does not improve within 
48 hours after initiating 
corticosteroids, consider adding 
an immunosuppressive agent.  
• If event resolves to Grade 1 or 
better, taper corticosteroids over 
≥ 1 month.  


 
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CTCAE = Common Terminology Criteria for Adverse Events; i.v. = intravenous. 
a: If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent 
before atezolizumab can be resumed.  
b: Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for corticosteroids to be reduced to 
≤ 10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of time must be agreed upon 
by the investigator and the sponsor.  
c: Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-related event. Patients can be rechallenged with atezolizumab only after approval has been documented by 
both the investigator (or an appropriate delegate) and the sponsor. 
 
 
Immune-related endocrinopathies 
Immune-related hypophysitis, thyroid disorders, adrenal insufficiency, and type 1 diabetes 
mellitus, including diabetic ketoacidosis, have occurred in patients receiving atezolizumab. 
Refer to the latest available version of atezolizumab IB for further details. Monitor patients 
for clinical signs and symptoms of endocrinopathies.  
For management guidelines of endocrine events, see Table 7–8 below. 
Table 7–8: 
Management guidelines for endocrine events 
Event 
Management 
Hypophysitis 
(pan-hypopituitarism), Grade 2 
or 3  
 
 
 
 
 
 
 
 
 
Withhold atezolizumab for up to 12 weeks after event onset a 
Refer patient to endocrinologist 
Perform brain MRI (pituitary protocol) 
Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day i.v. 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement 
Initiate hormone replacement if clinically indicated 
If event resolves to Grade 1 or better, resume atezolizumab b 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact the 
sponsor c 
For recurrent hypophysitis, treat as a Grade 4 event 
Hypophysitis 
(pan-hypopituitarism), Grade 4  
Permanently discontinue atezolizumab and contact the sponsor c 
Refer patient to endocrinologist 
Perform brain MRI (pituitary protocol) 
Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day i.v. 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement 
Initiate hormone replacement if clinically indicated 
Grade 1 hypothyroidism  
 
Continue atezolizumab 
Initiate treatment with thyroid replacement hormone 
Monitor TSH weekly 


 
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Table 7–8: 
Management guidelines for endocrine events 
Event 
Management 
Grade 2 hypothyroidism 
Consider withholding atezolizumab 
Initiate treatment with thyroid replacement hormone 
Monitor TSH closely 
Consider patient referral to endocrinologist 
Resume atezolizumab when symptoms are controlled and thyroid function 
is improving 
Grade 3 and 4 hypothyroidism 
 
 
Withhold atezolizumab 
Initiate treatment with thyroid replacement hormone 
Monitor TSH closely 
Refer to an endocrinologist 
If patient develops myxedema (bradycardia, hypothermia and altered 
mental status), admit to hospital 
Resume atezolizumab when symptoms are controlled and thyroid function 
is improving 
In case of Grade 4 immune-mediated hypothyroidism, permanently 
discontinue atezolizumab and contact the sponsor c 
Grade 1 hyperthyroidism 
Consider patient referral to endocrinologist 
TSH ≥ 0.1 mIU/L and < 0.5 mIU/L:  
Continue atezolizumab  
Monitor TSH every 4 weeks  
TSH < 0.1 mIU/L:  
Follow guidelines for Grade 2 hyperthyroidism  
Grade 2 hyperthyroidism 
Consider withholding atezolizumab 
Initiate treatment with anti-thyroid drug such as methimazole or carbimazole 
as needed 
Consider patient referral to endocrinologist  
Resume atezolizumab when symptoms are controlled and thyroid function 
is improving 
Grade 3 and 4 hyperthyroidism 
Withhold atezolizumab 
Initiate treatment with anti-thyroid drugs such as methimazole or 
carbimazole as needed 
Refer to endocrinologist 
Resume atezolizumab when symptoms are controlled and thyroid function 
is improving 
In case of Grade 4 immune-mediated hyperthyroidism, permanently 
discontinue atezolizumab and contact the sponsor c 


 
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Table 7–8: 
Management guidelines for endocrine events 
Event 
Management 
Symptomatic adrenal 
insufficiency Grade 2-4 
Withhold atezolizumab a  
Refer patient to endocrinologist  
Perform appropriate imaging  
Initiate treatment with 1−2 mg/kg/day intravenous methylprednisolone or 
equivalent and convert to 1−2 mg/kg/day oral prednisone or equivalent 
upon improvement  
Resume atezolizumab if event resolves to Grade 1 or better and patient is 
stable on replacement therapy (if required) within 12 weeks a, b  
Permanently discontinue atezolizumab and contact sponsor if event does 
not resolve to Grade 1 or better or patient is not stable on replacement 
therapy within 12 weeks a, b, c  
Hyperglycemia, Grade 1 or 2 
Continue atezolizumab  
Initiate treatment with insulin if needed  
Monitor for glucose control 
Hyperglycemia, Grade 3 or 4 
Withhold atezolizumab  
Initiate treatment with insulin  
Monitor for glucose control  
Resume atezolizumab when symptoms resolve and glucose levels are 
stable  
i.v. = intravenous; mIU = Milli international unit; MRI = magnetic resonance imaging; TSH = thyroid-stimulating hormone.  
a: If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent 
before atezolizumab can be resumed.  
b: Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for corticosteroids to be reduced to 
≤ 10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of time must be agreed upon 
by the investigator and the sponsor.  
c: Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-related event. Patients can be rechallenged with atezolizumab only after approval has been documented by 
both the investigator (or an appropriate delegate) and the sponsor. 
 
Severe cutaneous adverse reactions 
Severe cutaneous adverse reactions are an identified risk of atezolizumab. Severe cutaneous 
adverse reactions are a heterogeneous group of immunologically mediated drug eruptions 
frequently associated with drug use including immune checkpoint inhibitors as a class. 
Although rare, these events are potentially fatal, and mainly constituted by erythema 
multiforme, acute generalised exanthematous pustulosis, SJS, TEN, and drug rash with 
eosinophilia and systemic symptoms. 
The management of severe cutaneous adverse reactions will be as follows: 
• For suspected severe cutaneous adverse reactions, refer patients to a dermatologist for 
further diagnosis and management 


 
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• Withhold atezolizumab for patients with suspected SJS or TEN 
• Withdraw atezolizumab permanently for any grade confirmed SJS or TEN 
• Use caution when considering the use of atezolizumab in a patient who has previously 
experienced a severe or life-threatening skin adverse reaction on prior treatment with 
other immune-stimulatory anticancer agents. 
 
Other immune-related adverse reactions 
For further details, refer to the latest version of the investigator’s brochure of atezolizumab. 
Other immune-related adverse reactions including meningoencephalitis, myasthenic 
syndrome/myasthenia gravis, Guillain-Barré, myocarditis, ocular inflammatory toxicity, 
pancreatitis, including increases in serum amylase and lipase levels, and myositis have 
occurred in patients treated with atezolizumab. For management guidelines of ocular toxicity, 
refer to Section 7.4.3.2.3. 
Meningitis / encephalitis 
Monitor patients for clinical signs and symptoms of meningitis or encephalitis.  
Permanently discontinue atezolizumab for any grade of meningitis or encephalitis. Treat with 
i.v. steroids (1–2 mg/kg/day methylprednisolone or equivalent) and convert to oral steroids 
(prednisone 60 mg/day or equivalent) once the patient has improved. When symptoms 
improve to ≤ Grade 1, taper steroids over ≥ 1 month. 
Motor and sensory neuropathy 
Monitor patients for symptoms of motor and sensory neuropathy. Management guidelines for 
neurologic disorders are presented in Table 7–9. 
 
Table 7–9: 
Management guidelines for neurologic disorders 
Event  
Management 
Immune-mediated 
neuropathy, Grade 1 
Continue atezolizumab. 
Investigate etiology. 
Any cranial nerve disorder (including facial paresis) should be managed as per 
Grade 2 management guidelines below. 


 
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Table 7–9: 
Management guidelines for neurologic disorders 
Event  
Management 
Immune-mediated 
neuropathy, including 
facial paresis, Grade 2  
Withhold atezolizumab for up to 12 weeks after event onset. a 
Investigate etiology and refer patient to neurologist. 
Initiate treatment as per institutional guidelines. 
For general immune-mediated neuropathy: 
If event resolves to Grade 1 or better, resume atezolizumab. b 
If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact the sponsor. c 
For facial paresis: 
If event resolves fully, resume atezolizumab b 
If event does not resolve fully while withholding atezolizumab, permanently 
discontinue atezolizumab and contact the sponsor. c 
Immune-mediated 
neuropathy, including 
facial paresis, Grade 3 
or 4 
Permanently discontinue atezolizumab and contact the sponsor. c 
Refer patient to neurologist. 
Initiate treatment as per institutional guidelines. 
Myasthenia gravis and 
Guillain-Barré 
syndrome (any grade) 
Permanently discontinue atezolizumab and contact the sponsor. 
Refer patient to neurologist. 
Initiate treatment as per institutional guidelines. 
Consider initiation of corticosteroids equivalent to 1–2 mg/kg/day oral or i.v. 
prednisone. 
Immune-mediated 
myelitis, Grade 1 
Continue atezolizumab unless symptoms worsen or do not improve. 
Investigate etiology and refer patient to a neurologist. 
Immune-mediated 
myelitis, Grade 2 
Permanently discontinue atezolizumab and contact the sponsor.  
Investigate etiology and refer patient to a neurologist. 
Rule out infection. 
Initiate treatment with corticosteroids equivalent to 1–2 mg/kg/day oral prednisone. 
Immune-mediated 
myelitis, Grade 3 or 4 
Permanently discontinue atezolizumab and contact the sponsor 
Refer patient to a neurologist. 
Initiate treatment as per institutional guidelines. 
a 
Atezolizumab may be withheld for a longer time (i.e., >12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to the equivalent of ≤10 mg/day oral prednisone. The acceptable length of the extended time 
must be based on the investigator’s benefit-risk assessment and in alignment with the protocol requirement for duration 
of treatment and documented by the investigator. The sponsor is available to advise as needed. 
b 
If corticosteroids have been initiated, they must be tapered over ≥1 month to the equivalent of ≤10 mg/day oral 
prednisone before atezolizumab can be resumed. 
c 
Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-mediated event. The decision to rechallenge patients with atezolizumab should be based on the investigator’s 
benefit-risk assessment and documented by the investigator. The sponsor is available to advise as needed. 


 
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Infections 
Severe infections, including sepsis, herpes encephalitis, and mycobacterial infection leading 
to retroperitoneal hemorrhage occurred in patients receiving atezolizumab. Monitor patients 
for signs and symptoms of infection and treat with antibiotics for suspected or confirmed 
bacterial infections. Withhold atezolizumab for ≥ Grade 3 infection. 
Pancreatitis 
Symptomatic pancreatitis without an alternative etiology occurred in clinical trials of 
atezolizumab. Monitor patients for signs and symptoms of acute pancreatitis. 
The differential diagnosis of acute abdominal pain should include pancreatitis. Appropriate 
work-up should include an evaluation for ductal obstruction, as well as serum amylases and 
lipase tests. 
See Table 7–10 for management guidelines for pancreatic events, including pancreatitis. 
 
Table 7–10: 
Management guidelines for pancreatic events, including pancreatitis 
Event  
Management 
Amylase and/or lipase 
elevation, Grade 2 
1.5−2.0  ULN 
 
Continue atezolizumab.  
Monitor amylase and lipase weekly.  
For prolonged elevation (e.g., > 3 weeks), consider treatment with 10 mg/day oral 
prednisone or equivalent.  
Amylase and/or lipase 
elevation, Grade 2 
 2.0−5.0  ULN, 
Grade 3 or 4  
 
Withhold atezolizumab.  
Refer patient to gastrointestinal specialist.  
Monitor amylase and lipase every other day.  
If no improvement, consider treatment with 1−2 mg/kg/day oral prednisone or 
equivalent.  
Resume atezolizumab if event resolves to Grade 1 or better within 12 weeks. a, b  
Permanently discontinue atezolizumab and contact sponsor if event does not 
resolve to Grade 1 or better within 12 weeks. a, b, c  
For recurrent events, permanently discontinue atezolizumab and contact sponsor. c  
Immune-related 
pancreatitis, 
Grade 2 or 3  
 
Withhold atezolizumab.  
Refer patient to gastrointestinal specialist.  
Initiate treatment with 1−2 mg/kg/day intravenous methylprednisolone or equivalent 
and convert to 1−2 mg/kg/day oral prednisone or equivalent upon improvement.  
Resume atezolizumab if event resolves to Grade 1 or better within 12 weeks. a, b  
Permanently discontinue atezolizumab and contact sponsor if event does not 
resolve to Grade 1 or better within 12 weeks. a, b, c  
For recurrent events, permanently discontinue atezolizumab and contact sponsor. c  


 
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Table 7–10: 
Management guidelines for pancreatic events, including pancreatitis 
Event  
Management 
Immune-related 
pancreatitis, Grade 4  
 
Permanently discontinue atezolizumab and contact sponsor. c  
Refer patient to gastrointestinal specialist.  
Initiate treatment with 1−2 mg/kg/day intravenous methylprednisolone or equivalent 
and convert to 1−2 mg/kg/day oral prednisone or equivalent upon improvement.  
If event does not improve within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent.  
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 
ULN = upper limit of normal 
a: If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent 
before atezolizumab can be resumed.  
b: Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for corticosteroids to be reduced to 
≤ 10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of time must be agreed upon 
by the investigator and the sponsor.  
c: Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-related event. Patients can be rechallenged with atezolizumab only after approval has been documented by 
both the investigator (or an appropriate delegate) and the sponsor.  
 
Immune-mediated cardiac events 
Immune-mediated cardiac events include immune-mediated myocarditis and immune-
mediated pericardial disorders. 
Immune-mediated myocarditis 
Immune-mediated myocarditis is an important identified risk associated with the 
administration of atezolizumab. Immune-mediated myocarditis should be suspected in any 
patient presenting with signs or symptoms suggestive of myocarditis, including, but not 
limited to, dyspnea, chest pain, palpitations, fatigue, decreased exercise tolerance, or syncope. 
Immune-mediated myocarditis needs to be distinguished from myocarditis resulting from 
infection (commonly viral, e.g. patient may recall a recent history of gastrointestinal illness), 
ischemic events, underlying arrhythmias, exacerbation of pre-existing cardiac conditions, or 
progression of malignancy. 
All patients suspected for possible myocarditis should be urgently evaluated with cardiac 
enzymes, ECG, chest X-ray, echocardiogram, and cardiac MRI as appropriate per institutional 
guidelines. A cardiologist should be consulted. An endomyocardial biopsy may be considered 
for definitive diagnosis and appropriate treatment, if clinically indicated. 
Patients with signs and symptoms of myocarditis, in the absence of an identified alternate 
etiology, should be treated according to guidelines in the Table 7–11. 
Immune-mediated pericardial disorders 
Immune-mediated pericarditis should be suspected in any patient presenting with chest pain 
and may be associated with immune-mediated myocarditis. Immune-mediated pericardial 
effusion and cardiac tamponade should be suspected in any patient presenting with chest pain 
associated with dyspnea or hemodynamic instability. Patients should be evaluated for other 


 
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causes of pericardial disorders such as infection (commonly viral), cancer related (metastatic 
disease or chest radiotherapy), cardiac injury related (post myocardial infarction or 
iatrogenic), and autoimmune disorders, and should be managed accordingly. 
All patients with suspected pericardial disorders should be urgently evaluated by performing 
an ECG, chest X-ray, transthoracic echocardiogram, and cardiac MRI as appropriate per 
institutional guidelines. A cardiologist should be consulted. Pericardiocentesis should be 
considered for diagnostic or therapeutic purposes, if clinically indicated. 
Patients with signs and symptoms of pericarditis, pericardial effusion, or cardiac tamponade, 
in the absence of an identified alternate etiology, should be treated according to the guidelines 
in Table 7–11. Withhold treatment with atezolizumab for Grade 1 pericarditis and conduct a 
detailed cardiac evaluation to determine the etiology and manage accordingly. 
 
Table 7–11: 
Management guidelines for immune-mediated cardiac events 
Event 
Management 
Immune-mediated 
myocarditis, Grades 2–4 
and immune-mediated 
pericardial disorders, 
Grades 2–4 
Permanently discontinue atezolizumab and contact sponsor. c 
Refer patient to cardiologist; initiate treatment as per institutional guidelines and, 
as needed, consider antiarrhythmic drugs, temporary pacemaker, ECMO, VAD or 
pericardiocentesis as appropriate. 
Initiate treatment with 1−2 mg/kg/day i.v. methylprednisolone or equivalent and 
convert to 1−2 mg/kg/day oral prednisone or equivalent upon improvement. a,b 
If event does not improve within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent. 
If event resolves to Grade 1 or better, taper corticosteroids over  1 month. 
ECMO = Extracorporeal membrane oxygenation; i.v. = Intravenous(ly); VAD = Ventricular assist device. 
 
Immune-related nephritis 
Immune-related nephritis has been associated with the administration of atezolizumab.  Eligible 
patients must have adequate renal function, and renal function, including serum creatinine, 
should be monitored throughout study treatment. Patients with abnormal renal function should 
be evaluated and treated for other more common etiologies (including prerenal and postrenal 
causes, and concomitant medications such as non-steroidal anti-inflammatory drugs). Refer the 
patient to a renal specialist if clinically indicated. A renal biopsy may be required to enable a 
definitive diagnosis and appropriate treatment. 
Patients with signs and symptoms of nephritis, in the absence of an identified alternate etiology, 
should be treated according to the guidelines in Table 7–12. 


 
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Table 7–12: 
Management guidelines for renal events  
Event 
Management 
Renal event, 
Grade 1 
Continue atezolizumab. 
Monitor kidney function, including creatinine, closely until values resolve to within normal 
limits or to baseline values.  
Renal event, 
Grade 2 
Withhold atezolizumab for up to 12 weeks after event onset. a 
Refer patient to renal specialist. 
Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral prednisone. 
If event resolves to Grade 1 or better, resume atezolizumab. b 
If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact sponsor. c 
Renal event, 
Grade 3 or 4 
Permanently discontinue atezolizumab and contact sponsor.  
Refer patient to renal specialist and consider renal biopsy. 
Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral prednisone. 
If event does not improve within 48 hours after initiating corticosteroids, consider adding 
an immunosuppressive agent. 
If event resolves to Grade 1 or better, taper corticosteroids over  1 month. 
a 
Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to allow for corticosteroids 
(if initiated) to be reduced to the equivalent of  10 mg/day oral prednisone. The acceptable length of the extended 
period of time must be agreed upon by the investigator and the sponsor. 
b 
If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of  10 mg/day oral 
prednisone before atezolizumab can be resumed. 
c 
Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-related event. Patients can be re-challenged with atezolizumab only after approval has been documented by 
both the investigator (or an appropriate delegate) and the sponsor. 
 
Immune-related myositis 
Immune-related myositis is an important identified risk associated with the use of 
atezolizumab. Myositis or inflammatory myopathies are a group of disorders sharing the 
common feature of inflammatory muscle injury; dermatomyositis and polymyositis are among 
the most common disorders. Initial diagnosis is based on clinical (muscle weakness, muscle 
pain, skin rash in dermatomyositis), biochemical (serum creatine-kinase increase), and 
imaging (electromyography/MRI) features, and is confirmed with a muscle-biopsy. One 
etiology of myositis is immune-mediated, which is the current concern with atezolizumab.  
Refer to Table 7–13 for detailed management guidelines of immune-mediated myositis.  
 


 
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Table 7–13: 
Management guidelines for immune-related myositis 
Event  
Management 
Immune-related 
myositis, Grade 1 
Continue atezolizumab 
Refer patient to rheumatologist or neurologist. 
Initiate treatment as per institutional guidelines. 
Immune-related 
myositis, Grade 2  
Withhold atezolizumab for up to 12 weeks after event onset a and contact sponsor. 
Refer patient to rheumatologist or neurologist. 
Initiate treatment as per institutional guidelines. 
Consider treatment with corticosteroid equivalent to 1-2 mg/kg/day i.v. 
methylprednisolone and convert to 1-2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
If corticosteroids are initiated and event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
If event resolves to Grade 1 or better, resume atezolizumab. b 
If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact sponsor. c 
Immune-related 
myositis, Grade 3  
Withhold atezolizumab for up to 1 weeks after event onset a and contact sponsor. 
Refer patient to rheumatologist or neurologist. 
Initiate treatment as per institutional guidelines. 
Respiratory support may be required in more severe cases. 
Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day i.v. 
methylprednisolone or higher-dose bolus if patient is severely compromised (e.g. 
cardiac or respiratory symptoms, dysphagia, or weakness that severely limits mobility); 
convert to 1-2 mg/kg/day oral prednisolone or equivalent upon improvement. 
If event does not improve within 48 hours after initiating corticosteroids, consider adding 
an immunosuppressive agent. 
If event resolves to Grade 1 or better, resume atezolizumab. b 
If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact sponsor. c 
For recurrent events, treat as a Grade 4 event. 
Immune-related 
myositis, Grade 4  
Permanently discontinue atezolizumab and contact sponsor. c  
Refer patient to rheumatologist or neurologist. 
Initiate treatment as per institutional guidelines. Respiratory support may be required in 
more severe cases. 
Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day i.v. 
methylprednisolone or higher-dose bolus if patient is severely compromised (e.g. 
cardiac or respiratory symptoms, dysphagia, or weakness that severely limiting 
mobility); convert to 1-2 mg/kg/day oral prednisone or equivalent upon improvement. 
If event does not improve within 48 hours after initiating corticosteroids, consider adding 
an immunosuppressive agent. 


 
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Table 7–13: 
Management guidelines for immune-related myositis 
Event  
Management 
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 
i.v. = intravenous 
a: Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for corticosteroids 
(if initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The acceptable length of the extended period 
of time must be agreed upon by the investigator and the sponsor.  
b: If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent 
before atezolizumab can be resumed.  
c: Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-related event. Patients can be re-challenged with atezolizumab only after approval has been documented by 
both the investigator (or an appropriate delegate) and the sponsor. 
 
Systemic immune activation 
Systemic immune activation (SIA) is a rare condition characterized by an excessive immune 
response. Given the mechanism of action of atezolizumab, SIA is considered a potential risk 
when given in combination with other immunomodulating agents. SIA should be included in 
the differential diagnosis for patients who, in absence of an alternate etiology, develop a 
sepsis-like syndrome after administration of atezolizumab. 
Recommendations regarding early identification of SIA are provided below. In event of 
suspected SIA, the sponsor should be contacted immediately for additional guidance and 
study treatment should be interrupted. Atezolizumab should be permanently discontinued in 
patients with life-threatening immune-mediated adverse events. 
Early disease recognition is critical, and the clinician should consider SIA if, in absence of 
alternative etiologies, ≥ 2 of the following are present: 
• Hypotension refractory to aggressive i.v. fluid challenge. May/can require vasopressin 
support 
• Respiratory distress requiring aggressive supportive care. Supplemental oxygen, 
possible intubation. 
• Fever greater than 38.5°C 
• Acute renal or hepatic failure 
• Bleeding from coagulopathy 
• Unexplained laboratory abnormalities (change from baseline): 
• Cytopenia (≥ Grade 2 in two or more lineage), significant transaminitis, coagulopathy, 
elevated creatinine. 
Initial evaluation should include CBC with peripheral smear, PT, PTT, fibrinogen, D-dimer, 
ferritin, triglyceride, AST/ALT, total bilirubin, LDH, and a complete neurologic and 
abdominal examination (assess for hepatosplenomegaly). 


 
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If cytopenia (≥ 2 lineages and change from baseline) are present or ferritin is ≥ 3000 ng/mL, 
the following evaluations should also be performed: 
• Bone marrow biopsy/aspirate (assess for evidence of hemophagocytosis) 
• sCD25 (soluble IL-2 receptor) 
• Natural killer cell activity 
• Cytomegalovirus, Epstein-Barr virus and herpes-simplex virus evaluation (evaluate 
for reactivated or active disease) 
SIA is a clinical syndrome characterized by the following: 
• Onset greater than 24 hours after exposure to drug, and 
• Progressive clinical deterioration in an acutely ill patient (in absence of an alternate 
etiology), and 
• Involving multiple organs (≥ 2), and 
• Demonstrating specific laboratory abnormalities. 
Diagnosis of SIA should only be made in patients who present with a constellation of clinical 
findings as outlined above and who fulfill the following established diagnostic criteria in the 
absence of an alternate etiology. 
7.4.4 
Treatment duration 
Patients will continue dosing of both study drugs (rogaratinib and atezolizumab) until any of 
the following occurs: 
• Radiological disease progression according to RECIST v1.1 
o At the investigator discretion, study treatment may continue beyond 
radiological progression as defined by RECIST v1.1 (e.g. in case of suspected 
pseudoprogression) 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 
• Consent withdrawal 
• 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. 
 


 
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7.5 
Blinding 
Not applicable – Part A will be conducted in an open-label fashion.  
 
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 study file; 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 drugs via the IxRS. The personnel will use the study drugs only within the 
framework of this clinical study and in accordance with this protocol. Receipt, distribution, 
return and destruction (if any) of the study drugs 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. 
If performing drug accountability implies a potential risk of contamination, a safety process/ 
guidance for handling returned drug will be provided. 
7.7 
Treatment compliance 
For treatment compliance oral administration of the morning dose of rogaratinib on Cycle 1 
Days 1, 2, 8 and 15, and on Day 1 of subsequent cycles and every administration of 
atezolizumab will be done under supervision of site staff. This person will ascertain and 
document that the patient receives the treatment as planned. The information of each 
administration, such as dosing date, time and the administered dose, will be recorded in the 
eCRF. Patient compliance includes a willingness to comply with all aspects of the protocol, 
and to have blood collected for all safety and pharmacokinetic evaluations. Furthermore, 
patients need to agree with analysis of FGFR1/3 mRNA expression obtained from their own 
fresh or archival tumor tissue. Providing a fresh or archival tumor biopsy at FGFR testing is 
mandatory. Patients may be discontinued from the study for non-compliance with study 
procedures, at the discretion of the investigator or sponsor. 
All reasons for non-compliance should be clearly documented in the patients’ records and the 
eCRF. 
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. 
The preparation and administration of atezolizumab will be performed by members of the 
investigator team during hospitalization and site visits.  


 
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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. 
Every interruption/delay or reduction of the study treatment, regardless of the duration needs 
to be recorded.  
Any discrepancies between actual and expected amount of returned study drug must be 
discussed with the patient at the time of the visit, and any explanation must be documented in 
the source records. 
8. 
Non-study therapy 
8.1 
Prior and concomitant therapy 
All therapies specified as exclusion criteria (Section 6.2), except antibiotics, are also 
prohibited throughout the entire course of the study.  
Therapeutic monitoring should be performed consistent with the local clinical standard of care 
following dose modification of study treatment. In general, patients should be closely 
monitored for side effects of all concomitant medications regardless of path of elimination. 
All concomitant medications (including start / stop dates, total daily dose, and indication) 
must be recorded in the patient’s source documentation and in the eCRF. Concomitant use of 
contrast media need not be recorded unless the patient experiences an AE and there is a 
reasonable possibility that the event might have been caused by exposure to contrast media. 
Please refer also to atezolizumab label for guidance when prescribing with other medications. 
 
Prohibited and discouraged concomitant therapy  
Concomitant therapy with the following medication is prohibited: 
• Concomitant use of strong inhibitors of CYP3A4 and strong inducers of CYP3A4 
(listed in Appendix 16.1) are not permitted for 2 weeks prior to start of study treatment 
or during the study. 
• Concomitant use of herbal preparations containing CYP3A4 inducers (e.g. St John’s 
Wort) are not permitted during the study. 
• Grapefruit and grapefruit juice (CYP3A4 inhibitor) consumption is not permitted 
during the study. 
• 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 (34).  
• Please refer atezolizumab package insert for guidance on prohibited concomitant 
medications. 


 
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Concomitant therapy with the following medication is discouraged: 
• Patients (including those who discontinue the study early) should not receive other 
immunostimulatory agents for 10 weeks after the last dose of atezolizumab. 
• Initiation or increased dose of granulocyte colony-stimulating factors (e.g. granulocyte 
colony-stimulating factor, granulocyte/macrophage colony-stimulating factor, and/or 
pegfilgrastim) should be avoided. However use of granulocyte colony-stimulating 
factors is allowed for therapeutic intent at the discretion of the investigator and 
according to international guidelines and /or local standard of care. 
• 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. 
• Fluconazole is considered a moderate to strong inhibitor of CYP2C9 and should be 
avoided, if possible. 
Permitted concomitant therapy 
Concomitant therapy with the following medication is allowed: 
• Supportive care for any underlying illness or for treatment-related toxicity (e.g. blood 
transfusion, platelet transfusion), if clinically indicated or at the investigator’s 
discretion. 
• All medication and therapies which are considered necessary for the patient’s welfare, 
and which are not expected to interfere with the evaluation of the study drug, 
including antibiotics, may be given at the discretion of the investigator. 
• Additional concomitant medications such as low dose heparin, gonadotropin releasing 
hormone agonist or antagonist, antihistamines and intravenous fluid supply, if 
clinically indicated 
• Patients who experience infusion-associated symptoms may be treated 
symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or famotidine 
or another H2 receptor antagonist, as per standard practice (for sites outside the United 
States, equivalent medications may be substituted per local practice). Serious infusion-
associated events manifested by dyspnea, hypotension, wheezing, bronchospasm, 
tachycardia, reduced oxygen saturation, or respiratory distress should be managed 
with supportive therapies as clinically indicated (e.g., supplemental oxygen and β2-
adrenergic agonists). 
• Systemic corticosteroids and TNF-α inhibitors may attenuate potential beneficial 
immunological effects of treatment with atezolizumab but may be administered at the 
discretion of the treating physician after consultation with the sponsor. If feasible, 
alternatives to corticosteroids should be considered. Pre-medication may be 
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consultation with the sponsor. The use of inhaled corticosteroids, physiologic 
replacement doses of glucocorticoids and mineralocorticoids (e.g. fludrocortisone) for 
patients with orthostatic hypotension or adrenocortical insufficiency is allowed. 
Megestrol administered as an appetite stimulant is acceptable while the patient is 
enrolled in the study. 
• Influenza vaccination should be given during influenza season only (approximately 
October to March in most regions). Patients must not receive live, attenuated influenza 
vaccine within 28 days prior to start of study treatment, during treatment, or within 
90 days following the last dose of atezolizumab. Patients may receive inactivated 
vaccines. 
• COVID-19 vaccines are allowed during study treatment. Vaccines based on mRNA 
technology are preferred, but also live, attenuated vaccines can be allowed if deemed 
appropriate for cancer patients. 
• Patients taking narrow therapeutic index medications should be monitored proactively 
as per local standard of care. 
• Antiemetic therapy is allowed. 
• Bisphosphonates or denosumab with supplement of calcium and vitamin D.  
• Treatment with “non-conventional therapies” (such as acupuncture), and vitamin / 
mineral supplements are permitted provided that they do not interfere with the study 
endpoints, in the opinion of the investigator (to be documented in the source notes and 
in the eCRF). 
• Palliative radiotherapy for pain control (e.g. treatment of known bony metastases). 
Radiotherapy to target lesions is not allowed. 
 
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 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. 
In the event a roll-over study or any other form of continued study drug supply with no cost to 
the patient is established, the present study will end when all patients have transitioned into 
the roll-over study or any other form of continued study drug supply with no cost to the 
patient, 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. 


 
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9. 
Procedures and variables 
In the event of a significant trial-continuity issue (e.g. caused by a pandemic), alternate 
strategies for participant visits, assessments, medication distribution and monitoring may be 
implemented by the sponsor or the investigator, as per local health authority / ethics 
requirements. 
9.1 
Tabular schedule of evaluations 
Tabular schedule of pre-treatment activities is presented in Table 9–1. 
Tabular schedule of treatment and follow-up activities is presented in Table 9–2. 


 
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Table 9–1: 
Schedule of evaluations: Pre-treatment period (FGFR testing and screening) 
Measures / actions 
Pre-treatment 
 
FGFR testing 
Screening 
 
 
Relative to first study drug administration 
 
 
Within 28 days 
before* 
Within 7 days 
before* 
Signed informed consent 
   ●a1 
   ●a2 
 
Inclusion / exclusion criteria 
 ●b 
● 
● 
Tumor material for FGFR testing and additional 
biomarkers analyses (archival tissue sample or 
fresh biopsy)c 
● 
 
 
Demographic data 
● 
 
 
Complete medical / oncological history 
 
● 
 
Baseline characteristicsd, including: 
 
 
 
Documentation of primary diagnosis (refractory, 
locally advanced or metastatic solid tumor) using 
complete pathological report 
● 
 
 
Prior anti-cancer therapye 
● 
● 
 
TNM classification (AJCC 8th edition) 
● 
● 
 
Existence of liver metastases (absence vs. 
presence) 
 
● 
 
Existence of visceral metastases (absence vs. 
presence) 
 
● 
 
Alcohol and smoking history/habits 
 
● 
 
Karnofsky performance status 
 
● 
 
Physical examinations  
 
● 
 
Body height 
 
● 
 
Body weight 
 
● 
 
12-lead ECGf 
 
● 
 
Vital signs (incl. body temperature, heart rate, RR, BP) 
 
● 
 
ECOG performance status 
● 
● 
 
Ophthalmologic examination 
 
● 
 
Chest X-rayg 
 
● 
 
Blood / urine collection for safety laboratory testsh 
 
 
● 
Hormone panel (thyroid function tests [TSH, free T3 
and free T4]) 
 
 
● 
Calculation of eGFR (MDRD abbreviated formula) 
 
 
● 
Serum pregnancy test (in females with childbearing 
potential) 
 
 
● 
Blood sampling for plasma-based biomarker analysesi 
 
 
● 
Tumor assessment (CT / MRI scans)j  
 
● 
 


 
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Table 9–1: 
Schedule of evaluations: Pre-treatment period (FGFR testing and screening) 
Measures / actions 
Pre-treatment 
 
FGFR testing 
Screening 
 
 
Relative to first study drug administration 
 
 
Within 28 days 
before* 
Within 7 days 
before* 
Concomitant medicationk 
 
● 
● 
Toxicity / AE assessmentl 
● 
 
● 
PRO questionnaire (EORTC QLQ-C30) 
 
● 
 
AE = Adverse event; AJCC = American Joint Committee on Cancer; BP = Blood pressure; CT = Computed tomography; ECG = 
Electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = Electronic case report form; eGFR = 
Estimated glomerular filtration rate; EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer 30 
item Quality of Life Questionnaire; FGFR = Fibroblast growth factor receptor; iRECIST = RECIST modified for immune-
based therapeutics; MDRD = Modification of Diet in Renal Disease; MRI = Magnetic resonance imaging; PI/ICF = Patient 
information/informed consent form; PRO = Patient reported outcomes; RECIST = Response Evaluation Criteria In Solid 
Tumors; RR = Respiratory rate; SAE = Serious adverse event; T3 = Triiodothyronine; T4 = Thyroxine; TNM = 
Classification of malignant tumors (Tumor, lymph nodes, metastasis); TSH = Thyroid-stimulating hormone. 
* Pre-study examinations may require hospitalization for 1-2 days. 
a1: Informed consent for FGFR testing (including consent for exploratory biomarker analyses).  
a2: Informed consent for study treatment eligibility must be signed before the 28-day screening phase. 
b:  Selected inclusion and exclusion criteria are to be checked prior to FGFR testing. See Sections 6.1 and 6.2. 
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 and exploratory tumor-based biomarker analyses in all enrolled patients. 
d: 
Refer to Section 9.3.3 for the baseline characteristics to be collected. 
e:  At FGFR testing, prior therapies for the study indication are collected. At screening, study disease 
characteristics and prior therapies for the study indication are updated if applicable, and non-study-
indication-related medications collected. 
f: 
At screening, ECG readings (in the supine position) should be performed in triplicate in close sequence and 
not more than 2 minutes apart.  
g: 
The screening chest X-ray may be substituted with a chest X-ray that had been performed as part of the 
patient’s previous routine care in the 3 months before start of study treatment. 
h:  Safety laboratory tests include clinical chemistry panel, hematology panel, coagulation panel, and urinalysis. 
Please refer to Section 9.6.3.1 for more detailed information of the tests to be collected. 
i:  
The blood samples are intended for isolation of plasma to study tumor markers circulating in blood (see 
Section 9.7.1). 
j:  
The radiological evaluation must include computed tomography (CT) or magnetic resonance imaging (MRI) 
of the brain, chest, abdomen and pelvis with contrast media. A CT scan or MRI of the brain is required at 
screening to rule out brain metastases. Further CT scan or MRI of the brain only need to be repeated if 
metastases or symptoms are present. Pre-study CT/MRI may be acceptable as a baseline scan if done 
within 28 days before start of study treatment and performed according to the Imaging Manual. Formal 
efficacy assessment will be done according to RECIST v1.1. iRECIST will be assessed as exploratory 
endpoint. 
k:  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. 
l:  
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. Any new finding or worsening of any ongoing medical 
history condition after the patient has signed the informed consent for study treatment eligibility must be 
recorded as an AE/SAE. 


 
 
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Table 9–2: 
Schedule of evaluations: Treatment and follow-up periods 
 
Treatment 
Follow-upx 
 
Cycle 1 
21 days 
Cycle 2-4 
21 days  
per cycle 
Cycle ≥ 5 
21 days 
per cycle 
EOT 
Within 14 
days after 
permanent 
discon-
tinuation of 
treatmentv 
Active FU visit 
 
Long-term FU 
(phone call) 
Day (D) 
D1 
D2 
D8 
D15 
D1a 
D8 
D15 
D1 
At least 30 days 
after last dosev 
Every 3 months 
Time window (days) 
 
 
±1 
±1 
±2 
±2 
±2 
±2 
 
+7 
±14 
Safety 
Toxicities / AE assessmentb 
● 
● 
● 
● 
● 
● 
● 
● 
● 
  ●w 
 
Physical examinations 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
Body weight 
● 
 
 
● 
● 
 
 
● 
● 
 
 
12-lead ECGc 
● 
● 
 
● 
● 
 
 
●c 
●c 
 
 
Vital signs (incl. body 
temperature, heart rate, RR, 
BP)d 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
ECOG performance status 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
 
Changes in visione 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
Ophthalmologic examinationf 
 
 
 
 
● 
 
 
● 
● 
 
 
Blood samples for safety 
laboratory testsg 
● 
 
● 
● 
● 
● 
● 
● 
● 
● 
 
Hormone panel (thyroid 
function tests [TSH, 
free T3 and free T4])h 
● 
 
 
 
● 
 
 
● 
● 
 
 
Dipstick urinalysisi 
● 
 
 
 
● 
 
 
 
 
 
 


 
 
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Table 9–2: 
Schedule of evaluations: Treatment and follow-up periods 
 
Treatment 
Follow-upx 
 
Cycle 1 
21 days 
Cycle 2-4 
21 days  
per cycle 
Cycle ≥ 5 
21 days 
per cycle 
EOT 
Within 14 
days after 
permanent 
discon-
tinuation of 
treatmentv 
Active FU visit 
 
Long-term FU 
(phone call) 
Day (D) 
D1 
D2 
D8 
D15 
D1a 
D8 
D15 
D1 
At least 30 days 
after last dosev 
Every 3 months 
Time window (days) 
 
 
±1 
±1 
±2 
±2 
±2 
±2 
 
+7 
±14 
 
 
 
 
 
 
 
 
 
 
 
 
Calculation of eGFR (MDRD 
abbreviated formula) 
● 
 
● 
● 
● 
● 
● 
● 
● 
 
 
Urine pregnancy test (in 
females with childbearing 
potential)j 
● 
 
 
 
● 
 
 
 
 
 
 
Pharmacokinetics 
Blood samples for rogaratinib 
PKk 
●→ 
 
 
 
● 
 
 
● 
 
 
 
Blood samples for 
atezolizumab PKl 
●→ 
 
 
● 
 
 
 
 
 
 
 
Medication 
Concomitant medicationm 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
Drug accountabilityn 
 
 
 
 
● 
 
 
● 
 
 
 
Dispense/return of rogaratinib 
and diaryn 
● 
 
 
 
● 
 
 
● 
● 
 
 
Administration of rogaratinibo 
Continuously twice daily until EOT 
 
 
 
Administration of atezolizumab 
● 
 
 
 
● 
 
 
● 
 
 
 


 
 
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Table 9–2: 
Schedule of evaluations: Treatment and follow-up periods 
 
Treatment 
Follow-upx 
 
Cycle 1 
21 days 
Cycle 2-4 
21 days  
per cycle 
Cycle ≥ 5 
21 days 
per cycle 
EOT 
Within 14 
days after 
permanent 
discon-
tinuation of 
treatmentv 
Active FU visit 
 
Long-term FU 
(phone call) 
Day (D) 
D1 
D2 
D8 
D15 
D1a 
D8 
D15 
D1 
At least 30 days 
after last dosev 
Every 3 months 
Time window (days) 
 
 
±1 
±1 
±2 
±2 
±2 
±2 
 
+7 
±14 
Efficacy 
Tumor assessment (CT/MRI 
scans)p 
Every 14 weeks (± 14 days) 
●q 
Every 14 weeksr 
applies only to patients 
who discontinued without 
progressive disease 
 
Others 
PRO questionnaire (EORTC 
QLQ-C30)s 
● 
 
 
 
● 
 
 
 
 
 
 
Blood sampling for plasma-
based biomarker 
analysest 
● 
 
 
 
● 
 
 
 
● 
 
 
Additional tumor biopsy 
(optional)u 
During Cycle 2 or later and/or at the time of radiological progression 
 
Subsequent systemic anti-
cancer therapy 
 
 
 
 
 
 
 
 
 
● 
● 
Survival status 
 
 
 
 
 
 
 
 
 
 
● 
 
 
 


 
 
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Table 9–2: 
Schedule of evaluations: Treatment and follow-up periods 
AE = Adverse event; AESI = Adverse event of special interest; BP = Blood pressure; CT = Computed tomography; D = Day; ECG = Electrocardiogram; ECOG = Eastern Cooperative 
Oncology Group; eCRF = Electronic case report form; eGFR = Estimated glomerular filtration rate; EOI = End of infusion; EORTC QLQ-C30 = European Organization for 
Research and Treatment of Cancer 30 item Quality of Life Questionnaire; EOT = End of treatment; FU = Follow-up; iRECIST = RECIST modified for immune-based 
therapeutics; MDRD = Modification of Diet in Renal Disease; MRI = Magnetic resonance imaging; PI/ICF = Patient information/informed consent form; PK = Pharmacokinetics; 
PRO = Patient reported outcomes; RECIST = Response Evaluation Criteria In Solid Tumors; RPED = Retinal pigment epithelial detachment; RR = Respiratory rate; SAE = 
Serious adverse event; T3 = Triiodothyronine; T4 = Thyroxine; TSH = Thyroid-stimulating hormone; → = several samplings during the day. 
a: 
Only in Cycle 2, time window should be +1. 
b: 
Chest X-ray should be done in case the patient shows symptoms of pulmonary toxicity. 
c:  During the treatment period, ECGs are to be performed according to the following schedule: on Cycle 1 Day 1 before study drug administration and 2, 3, and 
24 hours after the first dose (i.e. before Cycle 1 Day 2 morning dose), on Cycle 1 Day 15 before morning dose and 2 and 3 hours thereafter, on Cycle ≥ 2 
Day 1 up to 1 hour after morning dose. See also Section 9.6.3.4. After primary completion, C ≥5 and EOT evaluations are optional and at the investigator’s 
discretion. 
d: 
Refer to Section 9.6.3.5 for specific instructions on vital signs measurements. 
e: 
Ask patient for changes in vision. If change in vision is reported, an ophthalmological examination must be performed (see Section 9.6.3.7). 
f: 
Ophthalmologic examination will be performed on Day 1 of every 4th cycle, starting at Cycle 2.  At the EOT visit, ophthalmologic examination will be done 
only in case the patient reports changes in vision. A time window of -7 days is allowed. Patients who experience any decrease in visual acuity, ocular pain or 
discomfort, or any retinal disorders including retinal detachment / RPED / central serous retinopathy / retinal vein occlusion have to undergo ophthalmologic 
examinations on Day 1 of every cycle. See Section 9.6.3.7 for more guidance on ophthalmological examinations, Section 7.4.3.2.3 for dose modification of 
rogaratinib in case of retinal disorders, and Section 9.6.1.6 for AESI reporting. 
g: 
Safety laboratory tests include clinical chemistry panel, hematology panel and coagulation panel. Please refer to Section 9.6.3.1 for more detailed information 
of the tests to be collected. Safety laboratory tests can be collected up to 2 days prior to drug administration. In patients with an elevated serum phosphate 
levels (≥ 7 mg/dL) phosphate levels should be evaluated weekly until resolution (serum phosphate < 7 mg/dL). 
h: 
Hormone panel (thyroid function test) is to be performed on Cycle 1 Day 1 and thereafter on Day 1 of every 3rd cycle (i.e. Cycles 4, 7, 10, 13 etc.), prior to 
atezolizumab infusion. Hormone panel can be collected up to 2 days prior to drug administration. After primary completion, hormone panel (thyroid function 
test) should be done periodically, according to local standard of care.  
i: 
Dipstick urinalysis can be collected up to 2 days prior to drug administration. Additional microscopic examinations will be performed if clinically indicated. 
j:  
Urinary pregnancy tests will be performed on Day 1 of each cycle during treatment. Pregnancy test to be repeated as frequently as required by local 
regulations. A serum pregnancy test must be performed if the urine pregnancy test is positive. After primary completion, pregnancy tests will no longer be 
required if there are no active patients of child-bearing potential. 
k: 
Rogaratinib PK samples will be collected on Cycle 1 Day 1 (Single dose PK): Pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post-dose (to be taken before the 
evening dose of rogaratinib), and on Cycles 2 to 5, Day 1 (exposure-response modeling): pre-dose (before supervised dose administration), and 1 (± 0.5) 
hour post-dose. 
l: 
For monitoring purposes of atezolizumab, blood (plasma) samples will be collected at the following time points: at Cycle 1 Day 1: pre-dose, 1 (EOI), 4 and 8 


 
 
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Table 9–2: 
Schedule of evaluations: Treatment and follow-up periods 
hours post-dose; and at Cycle 1 Day 15: approximately 336 hours post-dose. 
m: 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. 
n: 
To have complete control over the distribution and use of the study drug, the drug accountability must be performed before new medication is handed out to 
the patient. Return of rogaratinib and diary at EOT visit.  
o: 
Patients will receive their initial single-dose of 800 mg rogaratinib in the morning of Cycle 1 Day 1, followed by serial PK blood sampling for 8 hours and a 
second dose of 800 mg rogaratinib in the evening. Rogaratinib will be administered continuously twice daily on all 21 days in each cycle. Oral administration 
of the morning dose of rogaratinib on Cycle 1, Days 1, 2, 8 and 15, and on Day 1 of subsequent cycles will be done with a member of the site. 
p: 
The radiological evaluation must include computed tomography (CT) or magnetic resonance imaging (MRI) of the chest, abdomen and pelvis with contrast 
media. Tumor assessments (CT or MRI) are to be done every 9 weeks (± 7 days) starting from Cycle 1 Day 1 until confirmed radiological disease 
progression or end of the study. After primary completion, scans will be performed every 14 weeks (±14 days). A minimum of at least 9 weeks from start of 
treatment is mandatory for the 1st “on treatment” tumor assessment. Formal efficacy assessment will be done according to RECIST v1.1. iRECIST will be 
assessed as exploratory endpoint. 
q: 
Radiological tumor evaluation (within 14 days after permanent discontinuation of 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). 
r: 
For patients who discontinue study treatment without confirmed radiological 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 every 14 weeks ± 14 days (from the previous scan date). 
s: 
Questionnaire is to be completed before the patient meets with a clinician and before any examination or test is performed on that day. Questionnaire is to be 
completed at screening and before primary completion on Day 1 of every cycle, at the EOT visit, and at the safety assessment visit of the active follow-up. 
After primary completion, questionnaire will not be done. 
t:  
The blood samples are intended for isolation of plasma to study tumor markers circulating in blood (see Section 9.7.1). Until primary completion, during the 
treatment cycles, plasma samples are to be collected on Day 1 of each cycle before administration of study drugs, and at the EOT visit. After primary 
completion, blood sampling for plasma-based biomarker analyses will not be done except at the EOT visit. 
u:  An optional tumor biopsy is highly encouraged to be taken during Cycle 2 or later and/or at the time of disease progression or recurrence as per 
investigator’s decision, if technically feasible (see Section 9.7.1). 
v:  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. 
w:  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. In addition, any AEs after the active follow-up visit qualifying 
as SAEs or AESIs with an onset up to 90 days after last atezolizumab dosing that are reported to the sites need to be documented unless a new anti-cancer 
therapy has been initiated. 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. 
x:  After primary completion, follow-up information will not be collected after the safety assessment visit. 


 
 
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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 as part of the standard of practice at any time during the course of their disease 
prior to the informed consent date and time, may also be used.  
9.2.1.1 
FGFR testing 
FGFR testing of patients will be performed at the investigator’s discretion prior to start of 
screening (signing of informed consent for study treatment eligibility). Investigators should 
ensure all patients will be eligible in terms of clinical condition, disease status and lines of 
treatment. 
The following procedures will be performed prior to FGFR testing: 
• Signed PI/ICF for FGFR testing (including consent for exploratory biomarker analyses) 
(see Section 13.4.1). 
• Register patient (a unique patient identifier will be assigned) 
• Check inclusion and exclusion criteria for FGFR testing (see Section 6.1 for inclusion 
criteria and Section 6.2 for exclusion criteria). 
o If a patient does not meet the selection criteria for FGFR testing, register the 
patient as a ‘FGFR testing failure’ (those that are FGFR test negative and/or those 
that do not meet the inclusion/exclusion criteria for FGFR testing) 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 tissue for FGFR testing 
o Patients who submit TURBT specimens will be required to submit specimens 
containing muscle invasive component of the bladder tumor as verified by 
pathology review. If the TURBT specimens do not contain a muscle invasive 
component (i.e. T2 or greater), the specimens obtained at the time of 
cystectomy/nephroureterectomy or metastatic spread (i.e. sample from a metastatic 
lesion) will be required. An archival specimen, if available, should also be 
submitted. 
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. The tumor material should be derived by a biopsy procedure associated 
with a non-significant risk. See more details in Section 9.7.1. 
o Tissue will be used for central FGFR testing and exploratory tumor-based 
biomarker analyses in all enrolled patients (see Section 9.7.1). 


 
 
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• Document study disease characteristics (including TNM classification) 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 
9.6.3.6) 
• Toxicity/AE assessment  
o 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. 
The following procedure will be performed after FGFR testing: 
• For patients not meeting the eligibility criterion “high FGFR expression level” following 
confirmation by the central lab: record the patient as a ‘FGFR testing failure’ (those that 
are FGFR test negative and/or those that do not meet the inclusion/exclusion criteria for 
FGFR testing). 
 
9.2.1.2 
Screening 
After confirmation of high FGFR1 or 3 mRNA expression level (RNA scope score of 3+ or 
4+; measurement is part of this protocol) 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 PI/ICF for study treatment eligibility 
(Section 13.4.2). Note: Pre-study examinations may require hospitalization for 1-2 days. 
The following screening procedures will be performed within 28 days before first study 
drug administration: 
• Signed PI/ICF for study treatment eligibility (see Section 13.4.2) 
• Register confirmation that PI/ICF for study treatment eligibility has been signed and that 
the patient has started screening. 
• Check 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 the selection criteria for study treatment eligibility, 
register the patient as a ‘screening failure’ and additionally provide the reason, if 
applicable in the eCRF. 
• PRO questionnaire (EORTC QLQ-C30) (see Section 9.7.2) 
o Questionnaire is to be completed before the patient meets with a clinician and 
before any examination or test is performed on that day. 
• Update study disease characteristics (including TNM classification and existence of liver 
and visceral metastases), determine Karnofsky performance status (see Section 9.6.3.6), 


 
 
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and document previous therapy for urothelial carcinoma including outcome, and alcohol 
and smoking history/habits (see Section 9.3.3). 
• Document medical history (see Section 9.3.2) and non-study-indication-related 
medications (see Section 9.3.3). 
• Tumor assessment (CT or MRI) according to RECIST v1.1 and iRECIST (see Section 
9.4). 
o Note: Screening assessment includes imaging of the brain. 
• Send patient for ophthalmological examination (see Section 9.6.3.7) 
o In case of any findings, see Section 9.6.3.7. 
• 12-lead ECG (see Section 9.6.3.4) 
o At screening, ECG readings (in the supine position) should be performed in 
triplicate in close sequence and not more than 2 minutes apart. 
• Measure body height, weight. Additionally, BMI will be derived by the sponsor. See 
Section 9.6.3.3. 
• Perform physical examinations (see Section 9.6.3.2) including cardiovascular, respiratory, 
and abdominal system, a complete review of body systems, neurological examination and 
assessment of skin status. Orientating tests of neurological function will be included. 
• ECOG PS (see Section 9.6.3.6) 
• Measure vital signs, including blood pressure, heart rate, respiratory rate and body 
temperature (see Section 9.6.3.5) 
• Perform chest X-ray (see Section 9.6.3.8) 
o Note: the screening chest X-ray may be substituted with a chest X-ray that had 
been performed as part of the patient’s previous routine care in the 3 months 
before start of study treatment. 
• Record concomitant medications (see Section 8.1) 
o Note: 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. 
 
The following screening procedures will be performed within 7 days before first study drug 
administration: 
• Check the inclusion and exclusion criteria for study treatment eligibility (see Section 6.1 
for inclusion criteria and Section 6.2 for exclusion criteria).  


 
 
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o If a patient does not meet the selection criteria for study treatment eligibility, 
register the patient as a ‘screening failure’ and additionally provide the reason, if 
applicable in the eCRF. 
• Collect blood/urine for safety laboratory tests including clinical chemistry, hematology 
and coagulation panels and urinalysis (see Section 9.6.3.1). 
• Collect blood for hormone panel (thyroid function tests) (see Section 9.6.3.1). 
• Blood sampling for plasma-based biomarker analyses.  
o Note: the blood samples are intended for isolation of plasma to study tumor 
markers circulating in blood (see Section 9.7.1).  
• 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. 
• 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). 
o Note: Chest X-ray should be done in case the patient shows symptoms of 
pulmonary toxicity. 
• Record concomitant medications (see Section 8.1) 
o Note: 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. 
9.2.2 
Treatment period 
For tumor assessments to be performed during the treatment period, see Section 9.2.2.4. 
An optional tumor biopsy is highly encouraged to be taken during Cycle 2 or later and/or at 
the time of disease progression or recurrence as per investigator’s decision, if technically 
feasible (see Section 9.7.1). 


 
 
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9.2.2.1 
Cycle 1 
Day 1 of Cycle 1 
• PRO questionnaire (EORTC QLQ-C30) (see Section 9.7.2) 
o Questionnaire is to be completed before the patient meets with a clinician and 
before any examination or test is performed on that day. 
• ECOG PS (see Section 9.6.3.6) 
• Measure vital signs (see Section 9.6.3.5): 
o BP, HR and RR: 60 minutes before, every 15 (±5) minutes during, and 30 (±10) 
minutes after atezolizumab infusion. 
o Body temperature 
• Measure body weight 
• Perform physical examinations (see Section 9.6.3.2) including cardiovascular, respiratory, 
and abdominal system, a complete review of body systems, neurological examination and 
assessment of skin status. Orientating tests of neurological function will be included. 
• Collect blood/urine for safety laboratory tests including clinical chemistry, hematology 
and coagulation panels and urinalysis (see Section 9.6.3.1). 
o In patients with an elevated serum phosphate level (≥ 7 mg/dL), phosphate levels 
should be evaluated weekly until resolution (serum phosphate < 7 mg/dL). 
• Collect blood for hormone panel (thyroid function tests) (see Section 9.6.3.1). 
o Note: blood to be collected prior to atezolizumab administration. 
• Calculate eGFR according to MDRD abbreviated formula (see Appendix 16.4). 
• Urine pregnancy test in women of childbearing potential (see Sections 9.6.2 and 9.6.3.1).  
o Note: Pregnancy test to be repeated as frequently as required by local regulations. 
A serum pregnancy test must be performed if the urine pregnancy test is positive. 
• 12-lead ECG (see Section 9.6.3.4) 
o Note: before and 2, 3 hours after morning dose 
• Toxicity/AE assessment 
o Note: Chest X-ray should be done in case the patient shows symptoms of 
pulmonary toxicity. 
• Ask patient for changes in vision. If change in vision is reported, an ophthalmological 
examination must be performed (see Section 9.6.3.7) 
• Review concomitant medications (see Section 8.1) 
o Note: from signing of PI/ICF for study treatment eligibility up to 30 days after the 
last administration of study treatment, all concomitant medications (including 


 
 
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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. 
• Blood (plasma) samples for PK assessments (see Section 9.5 for further guidance and time 
windows) 
o Rogaratinib PK: 
▪ Cycle 1 Day 1 (Single dose PK): pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 hours 
post-dose (to be taken before the evening dose of rogaratinib). 
o Atezolizumab PK:  
▪ pre-dose, and 1 (EOI), 4 and 8 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 circulating in blood (see Section 9.7.1). During the treatment cycles, 
plasma samples are to be collected before administration of study drugs. 
• Dispense rogaratinib 
• Rogaratinib administration orally (see Section 7.4) 
o Note: Oral administration of the morning dose of rogaratinib will be done with a 
member of the site. 
• Atezolizumab administration i.v. (see Section 7.4) 
 
Day 2 of Cycle 1  
• ECOG PS (see Section 9.6.3.6) 
• Measure vital signs (see Section 9.6.3.5): 
o BP, HR and RR: before, and 1 and 2 hour(s) after morning dose 
o Body temperature 
• Perform physical examinations (see Section 9.6.3.2) including cardiovascular, respiratory, 
and abdominal system, a complete review of body systems, neurological examination and 
assessment of skin status. Orientating tests of neurological function will be included. 
• 12-lead ECG (see Section 9.6.3.4) 
o Note: 24 hours after first dose (i.e. before Cycle 1 Day 2 morning dose) 
• Toxicity/AE assessment 
o Note: Chest X-ray should be done in case the patient shows symptoms of 
pulmonary toxicity. 


 
 
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• Ask patient for changes in vision. If change in vision is reported, an ophthalmological 
examination must be performed (see Section 9.6.3.7) 
• Review concomitant medications (see Section 8.1) 
o Note: 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. 
• Rogaratinib administration orally (see Section 7.4) 
o Note: Oral administration of the morning dose of rogaratinib will be done with a 
member of the site. 
 
Day 8 of Cycle 1 
• ECOG PS (see Section 9.6.3.6) 
• Measure vital signs, including blood pressure, heart rate, respiratory rate and body 
temperature (see Section 9.6.3.5). 
• Perform physical examinations (see Section 9.6.3.2) including cardiovascular, respiratory, 
and abdominal system, a complete review of body systems, neurological examination and 
assessment of skin status. Orientating tests of neurological function will be included. 
• Collect blood for safety laboratory tests including clinical chemistry, hematology and 
coagulation panels (see Section 9.6.3.1). 
o In patients with an elevated serum phosphate level (≥ 7 mg/dL), phosphate levels 
should be evaluated weekly until resolution (serum phosphate < 7 mg/dL). 
• Calculate eGFR according to MDRD abbreviated formula (see Appendix 16.4). 
• Toxicity/AE assessment 
o Note: Chest X-ray should be done in case the patient shows symptoms of 
pulmonary toxicity. 
• Ask patient for changes in vision. If change in vision is reported, an ophthalmological 
examination must be performed (see Section 9.6.3.7) 
• Review concomitant medications (see Section 8.1) 
o Note: 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. 


 
 
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• Rogaratinib administration orally (see Section 7.4) 
o Note: Oral administration of the morning dose of rogaratinib will be done with a 
member of the site. 
 
Day 15 of Cycle 1  
• ECOG PS (see Section 9.6.3.6) 
• Measure vital signs (see Section 9.6.3.5). 
o BP, HR and RR: before, and 1 and 2 hour(s) after morning dose. 
o Body temperature 
• Measure body weight 
• Perform physical examinations (see Section 9.6.3.2) including cardiovascular, respiratory, 
and abdominal system, a complete review of body systems, neurological examination and 
assessment of skin status. Orientating tests of neurological function will be included. 
• Collect blood for safety laboratory tests including clinical chemistry, hematology and 
coagulation panels (see Section 9.6.3.1). 
o In patients with an elevated serum phosphate level (≥ 7 mg/dL), phosphate levels 
should be evaluated weekly until resolution (serum phosphate < 7 mg/dL). 
• Calculate eGFR according to MDRD abbreviated formula (see Appendix 16.4). 
• 12-lead ECG (see Section 9.6.3.4) 
o Note: before morning dose, and 2 and 3 hours thereafter 
• Toxicity/AE assessment 
o Note: Chest X-ray should be done in case the patient shows symptoms of 
pulmonary toxicity. 
• Ask patient for changes in vision. If change in vision is reported, an ophthalmological 
examination must be performed (see Section 9.6.3.7) 
• Review concomitant medications (see Section 8.1) 
o Note: 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. 
• Blood (plasma) samples for PK assessments (see Section 9.5 for further guidance) 
o Atezolizumab PK:  
▪ Approximately 336 hours post-dose 


 
 
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• Rogaratinib administration orally (see Section 7.4) 
o Note: Oral administration of the morning dose of rogaratinib will be done with a 
member of the site. 
 
9.2.2.2 
Cycles 2 – 4 
Day 1 of Cycle 2-4  
• PRO questionnaire (EORTC QLQ-C30) (see Section 9.7.2) 
o Questionnaire is to be completed before the patient meets with a clinician and 
before any examination or test is performed on that day. 
• ECOG PS (see Section 9.6.3.6) 
• Measure vital signs (see Section 9.6.3.5): 
o BP, HR and RR: within 60 minutes before infusion and at the end of infusion 
o Body temperature 
• Measure body weight 
• Perform physical examinations (see Section 9.6.3.2) including cardiovascular, respiratory, 
and abdominal system, a complete review of body systems, neurological examination and 
assessment of skin status. Orientating tests of neurological function will be included. 
• Collect blood/urine for safety laboratory tests including clinical chemistry, hematology 
and coagulation panels and urinalysis (see Section 9.6.3.1). 
o In patients with an elevated serum phosphate level (≥ 7 mg/dL), phosphate levels 
should be evaluated weekly until resolution (serum phosphate < 7 mg/dL). 
• On Cycle 4 only: collect blood for hormone panel (thyroid function tests) (see 
Section 9.6.3.1). 
o Note: blood to be collected prior to atezolizumab administration. 
• Calculate eGFR according to MDRD abbreviated formula (see Appendix 16.4). 
• Urine pregnancy test in women of childbearing potential (see Sections 9.6.2 and 9.6.3.1).  
o Note: Pregnancy test to be repeated as frequently as required by local regulations. 
A serum pregnancy test must be performed if the urine pregnancy test is positive. 
• 12-lead ECG (see Section 9.6.3.4) 
• Note: up to 1 hour after morning dose 
• Toxicity/AE assessment 
o Note: Chest X-ray should be done in case the patient shows symptoms of 
pulmonary toxicity. 


 
 
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• Ask patient for changes in vision (at every visit of every cycle) and send patient (on Day 1 
of every 2nd cycle, a time window of -7 days is allowed) for ophthalmological examination 
(see Section 9.6.3.7) 
o In case of any findings, see Section 9.6.3.7. 
• Review concomitant medications (see Section 8.1) 
o Note: 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. 
• Blood (plasma) samples for PK assessments (see Section 9.5 for further guidance) 
o Rogaratinib PK: 
▪ Cycles 2 to 5, Day 1 (for exposure-response modeling): pre-dose (before 
supervised dose administration), and 1 (± 0.5) hour 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 circulating in blood (see Section 9.7.1). During the treatment cycles, 
plasma samples are to be collected before administration of study drugs. 
• Dispense rogaratinib 
• Rogaratinib administration orally (see Section 7.4) 
o Note: Oral administration of the morning dose of rogaratinib will be done with a 
member of the site. 
• Atezolizumab administration i.v. (see Section 7.4) 
• Drug accountability 
 
Day 8 of Cycle 2-4  
• ECOG PS (see Section 9.6.3.6) 
• Measure vital signs (see Section 9.6.3.5). 
o BP, HR and RR: up to 1 hour after morning dose 
o Body temperature 
• Perform physical examinations (see Section 9.6.3.2) including cardiovascular, respiratory, 
and abdominal system, a complete review of body systems, neurological examination and 
assessment of skin status. Orientating tests of neurological function will be included. 
• Collect blood for safety laboratory tests including clinical chemistry, hematology and 
coagulation panels (see Section 9.6.3.1). 


 
 
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o In patients with an elevated serum phosphate level (≥ 7 mg/dL), phosphate levels 
should be evaluated weekly until resolution (serum phosphate < 7 mg/dL). 
• Calculate eGFR according to MDRD abbreviated formula (see Appendix 16.4). 
• Toxicity/AE assessment 
o Note: Chest X-ray should be done in case the patient shows symptoms of 
pulmonary toxicity. 
• Ask patient for changes in vision. If change in vision is reported, an ophthalmological 
examination must be performed (see Section 9.6.3.7) 
• Review concomitant medications (see Section 8.1) 
o Note: 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. 
• Rogaratinib administration orally (see Section 7.4) 
 
Day 15 of Cycle 2-4 
• ECOG PS (see Section 9.6.3.6) 
• Measure vital signs (see Section 9.6.3.5). 
o BP, HR and RR: Up to 1 hour after morning dose 
o Body temperature 
• Perform physical examinations (see Section 9.6.3.2) including cardiovascular, respiratory, 
and abdominal system, a complete review of body systems, neurological examination and 
assessment of skin status. Orientating tests of neurological function will be included. 
• Collect blood for safety laboratory tests including clinical chemistry, hematology and 
coagulation panels (see Section 9.6.3.1). 
o In patients with an elevated serum phosphate level (≥ 7 mg/dL), phosphate levels 
should be evaluated weekly until resolution (serum phosphate < 7 mg/dL). 
• Calculate eGFR according to MDRD abbreviated formula (see Appendix 16.4). 
• Toxicity/AE assessment 
o Note: Chest X-ray should be done in case the patient shows symptoms of 
pulmonary toxicity. 
• Ask patient for changes in vision. If change in vision is reported, an ophthalmological 
examination must be performed (see Section 9.6.3.7) 
• Review concomitant medications (see Section 8.1) 


 
 
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o Note: 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. 
• Rogaratinib administration orally (see Section 7.4) 
 
9.2.2.3 
Cycles ≥ 5 
Day 1 of Cycle ≥ 5  
• ECOG PS (see Section 9.6.3.6) 
• Measure vital signs (see Section 9.6.3.5): 
o BP, HR and RR: within 60 minutes before infusion and at the end of the infusion 
o Body temperature 
• Measure body weight 
• Perform physical examinations (see Section 9.6.3.2) including cardiovascular, respiratory, 
and abdominal system, a complete review of body systems, neurological examination and 
assessment of skin status. Orientating tests of neurological function will be included. 
• Collect blood for safety laboratory tests including clinical chemistry, hematology and 
coagulation panels (see Section 9.6.3.1). 
o In patients with an elevated serum phosphate level (≥ 7 mg/dL), phosphate levels 
should be evaluated weekly until resolution (serum phosphate < 7 mg/dL). 
• Every third cycle (Cycles 7, 10, 13 etc.): collect blood for hormone panel (thyroid 
function tests) (see Section 9.6.3.1). After primary completion, hormone panel (thyroid 
function tests) should be done periodically, according to local standard of care. 
o Note: blood to be collected prior to atezolizumab administration. 
• Blood (plasma) samples for PK assessments (see Section 9.5 for further guidance) 
o Rogaratinib PK: 
▪ Cycle 5, Day 1 (for exposure-response modeling): pre-dose (before 
supervised dose administration), and 1 (± 0.5) hour post-dose. 
• Calculate eGFR according to MDRD abbreviated formula (see Appendix 16.4). 
• Urine pregnancy test in women of childbearing potential (see Sections 9.6.2 and 9.6.3.1).  
o Note: Pregnancy test to be repeated as frequently as required by local regulations. 
A serum pregnancy test must be performed if the urine pregnancy test is positive. 
• Optional 12-lead ECG (see Section 9.6.3.4) (at the investigator’s discretion) 


 
 
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• Toxicity/AE assessment 
o Note: Chest X-ray should be done in case the patient shows symptoms of 
pulmonary toxicity. 
• Ask patient for changes in vision (at every visit of every cycle) and send patient (on Day 1 
of every 4th cycle, a time window of -7 days is allowed) for ophthalmological examination 
(see Section 9.6.3.7) 
o In case of any findings, see Section 9.6.3.7. 
• Review concomitant medications (see Section 8.1) 
o Note: 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. 
• Dispense rogaratinib 
• Rogaratinib administration orally (see Section 7.4) 
o Note: Oral administration of the morning dose of rogaratinib will be done with a 
member of the site. 
• Atezolizumab administration i.v. (see Section 7.4) 
• Drug accountability 
 
9.2.2.4 
Tumor assessments during treatment period 
Scans (CT or MRI with contrast unless contraindicated) for tumor assessments according to 
RECIST v1.1 and iRECIST are to be done every 14 weeks (± 14 days) until radiological disease 
progression or end of the study. A minimum of at least 9 weeks from start of treatment is 
mandatory for the 1st “on treatment” tumor assessment. 
See Section 9.4 for further information on tumor assessments, and Appendix 16.2 for RECIST 
and iRECIST guidance. 
 
9.2.2.5 
End-of-treatment (EOT) visit 
An end-of-treatment (EOT) visit will be performed within 14 days after permanent 
discontinuation of study treatment.  
Note: If the study treatment was permanently discontinued after dose interruption/delay of 
more than 30 days, the active follow-up visit should also 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. 
 


 
 
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The following examinations will be done: 
• ECOG PS (see Section 9.6.3.6) 
• Measure vital signs, including blood pressure, heart rate, respiratory rate and body 
temperature (see Section 9.6.3.5). 
• Measure body weight. Additionally, BMI will be derived by the sponsor. See Section 
9.6.3.3. 
• Perform physical examinations (see Section 9.6.3.2) including cardiovascular, respiratory, 
and abdominal system, a complete review of body systems, neurological examination and 
assessment of skin status. Orientating tests of neurological function will be included. 
• Collect blood for safety laboratory tests including clinical chemistry, hematology and 
coagulation panels (see Section 9.6.3.1). 
o In patients with an elevated serum phosphate level (≥ 7 mg/dL), phosphate levels 
should be evaluated weekly until resolution (serum phosphate < 7 mg/dL). 
• Collect blood for hormone panel (thyroid function tests) (see Section 9.6.3.1). After 
primary completion, hormone panel (thyroid function test) should be done periodically, 
according to local standard of care. 
• Blood sampling (pre-dose) for plasma-based biomarker analyses.  
o Note: the blood samples are intended for isolation of plasma to study tumor 
markers circulating in blood (see Section 9.7.1). 
• Calculate eGFR according to MDRD abbreviated formula (see Appendix 16.4). 
• Urine pregnancy test in women of childbearing potential (see Sections 9.6.2 and 9.6.3.1).  
o Note: Pregnancy test to be repeated as frequently as required by local regulations. 
A serum pregnancy test must be performed if the urine pregnancy test is positive. 
• Optional 12-lead ECG (see Section 9.6.3.4) (at the investigator’s discretion) 
• Toxicity/AE assessment 
o Note: Chest X-ray should be done in case the patient shows symptoms of 
pulmonary toxicity. 
• Ask patient for changes in vision and send patient for ophthalmological examination in 
case the patient reports any changes in vision (see Section 9.6.3.7) 
o In case of any findings, see Section 9.6.3.7. 
o Note: 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. 
• Tumor assessment (CT or MRI) according to RECIST v1.1 and iRECIST (see Section 
9.4) (within 14 days after permanent discontinuation of study treatment). This is not 


 
 
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necessary if the previous tumor evaluation was performed within 4 weeks (up to week 18) 
or within 7 weeks (beyond week 18). 
• Review concomitant medications (see Section 8.1) 
o Note: 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. 
• Return of rogaratinib and diary. 
9.2.3 
Follow-up periods 
After primary completion, follow-up information will not be collected after the safety 
assessment visit. 
9.2.3.1 
Active follow-up 
After permanent treatment discontinuation, a safety assessment visit must be scheduled for all 
patients at least 30 (up to +7) days after the last dose of study treatment. 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. In addition, any AEs 
after the active follow-up visit qualifying as SAEs or AESIs with an onset up to 90 days after 
last atezolizumab dosing that are reported to the sites need to be documented unless a new 
anti-cancer therapy has been initiated. 
 
The following examinations will be done for all patients: 
• 
Measure vital signs, including blood pressure, heart rate, respiratory rate and body 
temperature (see Section 9.6.3.5). 
• 
Perform physical examinations (see Section 9.6.3.2) including cardiovascular, 
respiratory, and abdominal system, a complete review of body systems, neurological 
examination and assessment of skin status. Orientating tests of neurological function will 
be included. 
• 
Collect blood for safety laboratory tests including clinical chemistry, hematology and 
coagulation panels (see Section 9.6.3.1). 
o In patients with an elevated serum phosphate level (≥ 7 mg/dL), phosphate levels 
should be evaluated weekly until resolution (serum phosphate < 7 mg/dL). 
• 
Toxicity/AE assessment. 
o 
Note: Chest X-ray should be done in case the patient shows symptoms of 
pulmonary toxicity. 


 
 
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• 
Ask patient for changes in vision. If change in vision is reported, an ophthalmological 
examination must be performed (see Section 9.6.3.7). 
• 
Review of concomitant medications (see Section 8.1) 
o 
Note: 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. 
• 
Document subsequent systemic anti-cancer therapy (if applicable) 
• An optional tumor biopsy is highly encouraged to be taken during Cycle 2 or later and/or 
at the time of disease progression or recurrence as per investigator’s decision, if 
technically feasible (see Section 9.7.1). 
 
Additionally, up to primary completion, the following assessment is to be done for patients 
who discontinue study treatment for reasons other than radiological disease 
progression: 
• 
Tumor assessment (CT or MRI) according to RECIST v1.1and iRECIST (see 
Section 9.4) 
o 
Note: During the active follow-up period, CT/MRI evaluations will be performed 
every 14 weeks ± 14 days (from the previous scan date) until disease progression 
and/or start of subsequent systemic anti-cancer treatment, whichever comes first, 
or any other criterion for withdrawal is met. No tumor assessments will be 
performed after primary completion. 
9.2.3.2 
Long-term follow-up 
Long-term follow-up will not be performed after primary completion. All patients in the long-
term follow-up period will be contacted (telephone contact by site is sufficient) every 3 
months (±14 days) from completion of the active follow-up until the end of the study (i.e. 
until last patient’s last visit [LPLV] (see Section 6.4.1.3)). 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. In addition, any AEs after the active follow-up visit 
qualifying as SAEs or AESIs with an onset up to 90 days after last atezolizumab dosing that 
are reported to the sites need to be documented unless a new anti-cancer therapy has been 
initiated. 
The information to be recorded at these contacts: 
• Survival status 
• Document subsequent systemic anti-cancer therapy (if applicable) 
 


 
 
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9.3 
Population characteristics 
9.3.1 
Demographic 
The following demographic characteristics will be collected: 
• Year of birth 
• Age at Informed Consent 
• Gender 
• Race (as allowed by local regulation) and 
• Ethnicity (as allowed by local regulation). 
 
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 (i.e. all patients 
signing the PI/ICF for FGFR testing) during the FGFR testing period: 
• Urothelial carcinoma diagnosis/classification including  
o date of initial diagnosis 
o type of assessment  
o date of the most recent progression / relapse  
o histology  
o location of primary cancer  
o TNM classification of urothelial carcinoma at study entry according to the 
AJCC 8th edition  
o grading at initial diagnosis  
Prior systemic anti-cancer medications 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: 
• Prior systemic anti-cancer medication. 
• Liver metastases (absence vs. presence) and  
• Visceral metastases (liver, bone, lung) (absence vs. presence) 
• 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 4 weeks before 
start of study treatment 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.  
• Review TNM classification (AJCC 8th edition) 


 
 
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• Karnofsky performance status (see Section 9.6.3.6) 
• Alcohol and smoking habits/history 
 
MSKCC categories and Bellmunt risk score 
Prognostic factors have been identified for both first- and second-line treatment of patients 
with urothelial carcinoma. MSKCC established a prognostic model predicting overall survival 
in first-line urothelial carcinoma, which includes Karnofsky performance status (see 
Section 9.6.3.6) and visceral metastases as independent prognostic factors (35). For second-
line the Bellmunt score defines ECOG performance status, hemoglobin level and liver 
metastases as main adverse prognostic factors for overall survival (36).  
Bellmunt risk score will be derived by the sponsor based on the following parameters 
collected during screening assessments: 
• Hemoglobin level < 10 g/dL vs. ≥ 10 g/dL 
• ECOG PS 0 vs. ≥ 1  
• Liver metastases absent vs. present 
MSKCC categories will be derived by the sponsor based on the following parameters 
collected during screening assessments: 
• Visceral metastases (liver, bone, lung) absent vs. present 
• Karnofsky performance status ≥ 80% vs < 80 % 
 
9.4 
Efficacy 
Patient survival will be followed up and tumor assessment will be performed using computed 
tomography (CT) or magnetic resonance imaging (MRI) (with contrast unless 
contraindicated) to determine the efficacy variables of this study: objective response rate 
(ORR), disease control rate (DCR), duration of response (DOR), best overall response (CR, 
PR, SD, Non CR/Non PD, PD), progression-free survival (PFS) and overall survival (OS).  
For definitions and analyses of the efficacy variables, please refer to Section 10.3.3.  
 
Radiological tumor assessment 
Radiological tumor assessments will be performed locally by investigators. All scan should be 
interpreted by the same radiologist/investigator during the study, where at all possible. 
Tumor response will be measured using CT or MRI scans (with contrast unless 
contraindicated) and evaluated using RECIST v1.1 (37) (see Appendix 16.2) to determine the 
secondary efficacy variables (objective response rate [ORR], disease control rate [DCR] and 
duration of response [DOR], best overall response (CR, PR, SD, Non CR/Non PD, PD), and 


 
 
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progression-free survival [PFS]). According to RECIST v1.1, confirmation of PR and CR is 
not required considering the nature of the study and the protocol requirements. 
In addition, modified RECIST v1.1 for immune-based therapeutics (iRECIST) will be 
documented as exploratory variables and used as supportive evidence for the detection of 
pseudoprogression and the determination of progressive disease for treatment decision (see 
(38) and Appendix 16.2). 
To facilitate an independent evaluation of outcome in this study, tumor assessment imaging 
data will be collected, image quality controlled and stored for a potential central review of 
tumor evaluation by independent readers prior to the final efficacy analysis. The decision to 
perform the central review will be based on the outcome of the local efficacy assessments. 
Treatment decisions with immune-based therapeutics require assessment of the clinical 
presentation of patients that can only be performed by the investigator; therefore, central 
review will not be used for treatment decisions. Details will be outlined in the Image Review 
Charter. Images for tumor assessment, de-identified with respect to patient identification 
related privacy data (except study related subject identification number) will be collected for 
all patients enrolled at baseline and at all post-baseline evaluations and will be submitted for 
collection and image quality control to facilitate a potential central review. Specific 
information on image handling, imaging guidelines, instructions for image acquisition and 
image evaluation procedures will be outlined in the Imaging Manual for the study sites. 
The first radiological tumor evaluation will be conducted during clinical screening within 28 
days before start of study treatment (see Section 9.1). Tumor assessments are to be done every 
9 weeks (± 7 days) starting from Cycle 1 Day 1 until radiological disease progression or end 
of the study. A minimum of at least 9 weeks from start of treatment is mandatory for the 1st 
“on treatment” tumor assessment.  
For patients who discontinue study treatment without radiological 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 every 9 weeks (from the previous scan date). After 1 year of 
follow-up, CT scans may be scheduled approximately every 12 weeks. After primary 
completion, no tumor assessments will be done. 
The radiological evaluation must include computed tomography (CT) or magnetic resonance 
imaging (MRI) of the chest, abdomen and pelvis with contrast media unless contraindicated. 
In case of contraindication to both, iodinated contrast agent for CT and gadolinium based 
contrast agent for MRI, evaluation should be performed with MRI (except chest region). 
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. 
At investigator’s discretion, CT or MRI scan should be repeated at any time if progressive 
disease is suspected. 
A CT (with contrast if not contraindicated) or MRI scan of the brain must be done at 
screening to exclude CNS metastasis. An MRI scan of the brain is required to confirm or 


 
 
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refute the diagnosis of CNS metastasis at baseline in the event of an equivocal scan. Patients 
with definitely treated stable CNS metastases may be eligible for the Study (see also Sections 
6.1 and 6.2; inclusion/exclusion criteria). 
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 clinically indicated. 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. 
If radiographic changes are believed by the investigator to be secondary to drug induced 
inflammation and not to tumor progression (e.g. in case of suspected pseudoprogression), the 
investigator may postpone a diagnosis of progressive disease (PD) until the next radiographic 
evaluation in the study if all the following criteria are met: 
• Evidence of clinical benefit (defined as the stabilization or improvement of disease-
related symptoms) as assessed by the investigator. 
• Absence of symptoms and signs indicating unequivocal progression of disease 
(including worsening of laboratory values [e.g. new or worsening hypercalcemia]). 
• No decline in ECOG performance status that can be attributed to disease progression. 
• Absence of tumor progression at critical anatomical sites (e.g. leptomeningeal disease) 
that cannot be managed by protocol-allowed medical interventions. 
Treatment beyond initial RECIST v1.1-defined progression is permitted only for patients who 
are clinically stable to continue on treatment until next imaging assessment (≥ 4 weeks later); 
this next imaging assessment should be no longer than 8 weeks later, to ensure that patients 
remain fit for salvage therapies. A longer time frame before the next assessment might be 
reasonable if no effective salvage therapies are available. 
In addition, treatment beyond progression should not delay an imminent intervention to 
prevent serious complications of disease progression (e.g. central nervous system [CNS] 
metastases).  
Patients for whom radiographic disease progression is confirmed at a subsequent tumor 
assessment may be considered for continuing study treatment at the discretion of the 
investigator if they still meet the criteria above and in absence of unacceptable toxicity.  


 
 
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9.5 
Pharmacokinetics / pharmacodynamics 
9.5.1 
Drug measurements 
Blood (plasma) samples for pharmacokinetic assessment of rogaratinib will be collected at the 
following time points:  
• Cycle 1 Day 1 (Single dose PK): pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post-dose (to 
be taken before the evening dose of rogaratinib). 
• Cycles 2 to 5, Day 1 (for exposure-response modeling): pre-dose (before supervised 
dose administration), and 1 (± 0.5) hour post-dose. 
For monitoring purposes of atezolizumab, blood (plasma) samples will be collected at the 
following time points: 
• Cycle 1 Day 1: pre-dose, 1 (EOI), 4 and 8 hours post-dose. 
• Cycle 1 Day 15: approximately 336 hours post-dose.  
Whenever possible, all efforts should be made to adhere to the blood sampling schedule as 
given above. However, based on practical considerations, the following time range is 
provided: for planned time points ≤ 6 hours, PK samples should be collected within 
± 15 minutes of the planned time, and for planned time points > 6 hours, PK samples should 
be collected within ±30 minutes. It is of importance that the actual date and time of blood 
sampling and related dosing date and time is documented in the eCRF and patient`s source 
document because PK calculations will be based on the actual sampling times relative to 
dosing times. 
Sampling times outside these suggested intervals will be considered as “other deviations”.  
Cumulated substantial deviations of sampling times and/or consecutive, missing PK samples 
may lead to an insufficient (inadequate) description of the plasma concentration vs. time 
profiles of rogaratinib and thus affect the quality of the PK evaluation of the respective 
patient(s). In this case, these deviations should be classified as “important” and may lead as 
declared “validity findings” to the exclusion of the respective patient(s) from the PK analysis 
set. 
When blood pressure measurement and PK sample collection are scheduled at the same time 
point, patient’s blood pressure will be measured before collection of the PK sample. 
Plasma concentrations of rogaratinib and atezolizumab will be measured using a validated 
method. Instructions for sample collection, processing, storage and shipment will be described 
in a separate document (e.g. lab manual). 
Exploratory monitoring of metabolites may also be performed in pooled plasma samples. 


 
 
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9.5.2 
Non-compartmental pharmacokinetic evaluation 
PK parameters will be calculated by non-compartmental analysis (NCA) according to current 
Bayer guidelines using Phoenix (WinNonlin) software. Details regarding the software version 
will be given in the clinical study report. Based on plasma concentration versus time results, 
the following parameters are planned to be calculated for rogaratinib: 
Main PK parameters: 
• Cycle 1, Day 1 – single dose PK: Cmax, AUC(0-8)  
Additional PK parameters: 
• AUC(0-tlast), tmax and tlast on Cycle 1 Day 1  
Other PK parameters (plasma): 
• Rstart, Rend, points terminal and %AUC(tlast-∞)  
Additional parameters, e.g. apparent oral clearance (CL/F) and apparent volume of 
distribution after extravascular administration (VZ/F), may be estimated, if appropriate. 
Please refer to Section 10.3.5 for the analysis of the PK variables. 
Pharmacokinetic evaluation – Population analysis 
Pharmacokinetic data might be analyzed using nonlinear mixed effects models. Details of the 
model development and evaluation will be described in a separate Evaluation Plan and the 
results reported in a separate Evaluation Report. 
Details on the collection, processing, storage, and shipment of PK samples will be provided in 
separate documents (e.g. sample handling sheets or lab manual). 
 
9.6 
Safety 
Overview 
Safety will be evaluated in this study through the monitoring of all serious and non-serious 
adverse events, defined and graded according to NCI CTCAE v.4.03. Patients will be 
assessed for safety (including laboratory values) according to the tabular schedule of 
evaluations (Section 9.1). Laboratory values must be reviewed prior of each infusion. 
The safety outcome measures for this study are as follow: 
• Incidence, nature and severity of AEs, graded according to NCI CTCAE v.4.03 
• Change in vital signs, physical finding and clinical laboratory results 


 
 
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Safety assessments include: 
• Physical examinations (see Section 9.6.3.2 for details) 
• Vital signs (see Section 9.6.3.5 for details)  
• Standard ECG variables (see Section 9.6.3.4 for details) 
• Standard laboratory variables (see Section 9.6.3.1 for details) 
• Ophthalmological examinations (see Section 9.6.3.7 for details) 
Findings will be recorded as adverse events (AEs) or serious adverse events (SAEs) as 
applicable following main categorizations (see Section 9.6.1 for details): 
• Treatment-emergent adverse events (TEAEs), drug-related TEAEs, and treatment-
emergent serious adverse events 
All serious adverse events and protocol-defined events of special interest (see Section 9.6.1.6) 
will be reported in an expedited fashion (see Section 9.6.1.4). 
Each toxicity will be assessed as to whether it is dose limiting (see Section 7.4.1). The MTD 
and/or RP2D will be identified based on the incidence of DLTs during Cycle 1 in dose 
selection groups (for details see Section 10.3.4).  
The investigator(s) and the sponsor or its representative will review regularly the safety data 
throughout the course of the study.  
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 combination drug (atezolizumab), please refer to the 
investigator’s brochure. 
Therapeutic monitoring should be performed following dose selection or 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 other chemotherapy/treatment. 


 
 
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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, 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 are recorded as medical history (e.g. seasonal allergy without acute 
complaints). 
• Conditions that started before signing of informed consent 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 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 rogaratinib intake or 90 days after the 
last atezolizumab administration. 
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. 


 
 
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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 
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 PI/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 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). 
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. 


 
 
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• 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 treatments 
(e.g. owing to a suspected underlying interaction), the same assessment will be documented 
for each study treatment. 
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. 


 
 
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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 
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. 


 
 
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The study treatment action should be recorded separately for each study treatment as detailed 
in the eCRF. 
- Drug withdrawn 
- Drug interrupted 
- Dose reduced 
- Dose not changed 
- Dose increased 
- 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) 
must be fully documented in the source data. AEs are obtained by observation and as 
volunteered by the patients. In addition, any AEs after the active follow-up visit qualifying as 
SAEs or AESIs with an onset up to 90 days after last atezolizumab dosing that are reported to 
the sites need to be documented unless a new anti-cancer therapy has been initiated. 
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. 


 
 
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• 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, only AEs related to the study drugs have to be recorded until the 
end of active follow-up. In addition, any AEs after the active follow-up visit 
qualifying as SAEs or AESIs with an onset up to 90 days after last atezolizumab 
dosing that are reported to the sites need to be documented unless a new anti-cancer 
therapy has been initiated. 
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 up to primary completion). 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. In addition, any AEs after the 
active follow-up visit qualifying as SAEs or AESIs of atezolizumab with an onset up to 90 
days after last atezolizumab dosing that are reported to the sites need to be documented unless 
a new anti-cancer therapy has been initiated. 
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 discontinuation of rogaratinib treatment or within 90 days 
of discontinuation of atezolizumab treatment, 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 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, should be reported as 
an AE.  


 
 
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“Death” should not be recorded as an AE on the AE page. Instead, “death” is the outcome of 
underlying AE(s). 
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) 
• 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. 


 
 
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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. 
9.6.1.5 Expected adverse events 
For this study, the applicable reference document is the most current version of the 
investigator’s brochure (IB) for rogaratinib and atezolizumab. 
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 
Adverse events of special interest (AESIs) should be reported to the sponsor immediately 
within 24 hours using a safety report form as outlined in Section 9.6.1.4 (Reporting of serious 
adverse events). 
Rogaratinib-specific AESIs 
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):  
• Soft tissue mineralization 
o 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 LLTs tissue calcification, 
metastatic calcification, calcification of muscles, intestinal calcification, 
cutaneous calcification).  
o 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) 
o Any symptomatic retinal disorders including retinal detachment / retinal 
pigment epithelial detachment / central 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 including any other 
abnormal ophthalmological findings should be reported in a dedicated eCRF 
page.  


 
 
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o Specific dose modification schemes for retinal disorders are defined in Section 
7.4.3.2.3.  
Atezolizumab-specific AESIs 
The following adverse events are considered AESIs in this study and should be reported 
immediately, within 24 hours to the sponsor: 
• Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
Law  
• Suspected transmission of an infectious agent by the study treatment, as defined below 
o Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product. This term applies only 
when a contamination of study treatment is suspected. 
• Pneumonitis 
• Colitis 
• Endocrinopathies: diabetes mellitus, pancreatitis, adrenal insufficiency, 
hyperthyroidism, and hypophysitis 
• Hepatitis, including AST or ALT  10  ULN 
• Systemic lupus erythematosus 
• Neurological disorders: Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis 
• Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release 
syndrome, influenza-like illness, systemic inflammatory response syndrome, and 
systemic immune activation 
• Nephritis 
• Ocular toxicities (e.g. uveitis, retinitis, optic neuritis) 
• Myositis 
• Myopathies, including rhabdomyolysis 
• Grade  2 cardiac disorders (e.g. atrial fibrillation, myocarditis, pericarditis) 
• Vasculitis 
• Autoimmune hemolytic anemia 
• Severe cutaneous reactions (e.g. SJS, dermatitis bullous, TEN) 


 
 
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• Myelitis 
• Facial paresis 
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. 
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 will be performed locally according to the tabular schedule of 
evaluations shown 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).  
Collection of blood for safety laboratory tests, including clinical chemistry, hematology and 
coagulation panels, can be performed within 2 days before administration of the study 
treatment. 
Clinical chemistry 
The clinical chemistry panel includes: sodium, potassium, chloride, magnesium, total 
calcium, phosphate, glucose (fasting or non-fasting), AST, ALT, bilirubin (total and direct), 
ALP, total protein, albumin, lactic dehydrogenase (LDH), blood urea nitrogen (BUN) or urea, 
creatinine, lipase and amylase. 
Phosphate levels should be evaluated weekly in patients with an elevated serum phosphate 
level (≥ 7 mg/dL) until resolution (serum phosphate < 7 mg/dL). 


 
 
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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 absolute 
counts of neutrophils, lymphocytes, monocytes, basophils, and eosinophils. 
Coagulation panel 
Coagulation panel includes: PTT or activated PTT and PT-INR. 
Urinalysis 
The dipstick test includes: specific gravity, WBC, nitrite, pH, glucose, protein, ketones, 
bilirubin, urobilinogen, blood. 
Additional microscopic examinations will be performed if clinically indicated. 
After primary completion, urinalysis is no longer required 
Estimated glomerular filtration rate (eGFR) 
eGFR is to be determined according to the schedule summarized in the study flow chart in 
Section 9.1. 
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). 
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. After 
screening, a urine pregnancy test is used. The test (urine test) is to be repeated as frequently as 
required by local regulations. A serum pregnancy test must be performed if the urine 
pregnancy test is positive. 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). After primary 
completion, pregnancy tests are no longer required when there are no female patients of child-
bearing potential. 
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 


 
 
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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 
The physical examination (by means of inspection, palpation and auscultation) will be 
performed according to the schedule of evaluations in Section 9.1 by a physician covering at 
least the organs of the cardiovascular, respiratory, and abdominal system, a complete review 
of body systems, neurological examination and assessment of skin status. Orientating tests of 
neurological function will be included.  
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 PI/ICF for study treatment eligibility, respectively). 
9.6.3.3 
Body height, weight and BMI 
Height is recorded only at screening. 
Weight is recorded at screening, on Day 1 and Day 15 of Cycle 1 and thereafter on Day 1 of 
every cycle, and at the EOT visit. 
Body mass index (BMI) will be derived by the sponsor (at the screening examination and at 
the end-of-treatment [EOT] visit).  
9.6.3.4 
12-lead ECG 
Standard single 12-lead ECGs will be recorded in all patients according to the tabular 
schedule of evaluations shown in Section 9.1. 
Standard single 12-lead ECG readings will be performed in the supine position as possible at 
the following time points (± 15 minutes): 
• Screening  
o 
Note: at screening, ECG readings should be performed in triplicate in close 
sequence and not more than 2 minutes apart. 
• Cycle 1, Day 1 and Day 2  
• Before and 2, 3 (Day 1) and 24 hours after first dose (i.e. before Cycle 1 Day 2 
morning dose) 
• Cycle 1, Day 15  
• Before morning dose, and 2 and 3 hours thereafter 


 
 
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• Cycle ≥ 2, Day 1; after primary completion, ECGs are optional and at the 
investigator’s discretion 
• Up to 1 hour after morning dose 
• EOT visit; after primary completion, ECGs are optional and at the investigator;s 
discretion 
Beyond that schedule, weekly ECGs will be performed in patients with an elevated serum 
phosphate level (≥ 7 mg/dL) 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 the day of detection of hypocalcemia and should be repeated as clinically 
indicated. 
9.6.3.5 
Vital signs 
Vital signs will include body temperature (axillary), respiratory rate (RR), heart rate and 
blood pressure (systolic and diastolic). Systolic and diastolic blood pressure and the heart rate 
will be obtained as duplicate measurements after 5 minutes supine or sitting position quiet 
rest. The vital sign assessments should be performed within the window of ±5 minutes from 
the planned time. Where the assessments coincide, the same resting period may be used for 
ECG and vital signs (ECG must be obtained before vital signs).  
Blood pressure (BP) / heart rate (HR) profile will be measured as follows:  
• Patient seated for at least 5 minutes before measurement with their arms bared and 
supported at heart level.  
• At screening, duplicate measurements of BP must be done in both arms to see whether 
there is a difference in blood pressure readings between the patient’s right and left arm. If 
one arm has higher blood pressure than the other, that arm should be used for further BP 
measurements (all further BP measurements must be done on the same arm whenever 
possible).  
• Measurements (on the same arm) will be in duplicate and the mean value will be used for 
assessment. If the first two readings differ by more than 5 mmHg, additional two readings 
should be obtained and averaged.  
• If a reduction of systolic BP below 90 mmHg or an increase in HR above 120 bpm is 
detected, the assessment has to be repeated after 2 hours. 
• When blood pressure measurement and PK sample collection are scheduled at the same 
time point, patient’s blood pressure will be measured before collection of PK sample.  
RR, BP, HR and body temperature will be measured at the following time points (see also 
Section 9.1): 
• Screening (one measurement within 28 days before start of treatment) 
• Cycle 1 Day 1  


 
 
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o 
BP, HR and RR: 60 minutes before, every 15 (±5) minutes during, and 30 (±10) 
minutes after atezolizumab infusion  
o 
Body temperature 
• Cycle 1 Day 2 
o 
BP, HR and RR: Before, and 1 and 2 hour(s) after morning dose 
o 
Body temperature 
• Cycle 1 Day 8  
• Cycle 1 Day 15 
o 
BP, HR and RR: Before, and 1 and 2 hour(s) after morning dose 
o 
Body temperature 
• Cycle ≥ 2 Day 1 
o 
BP, HR and RR: Within 60 minutes before infusion and at the end of the infusion 
o 
Body temperature 
• Cycle 2-4, Day 8, Day 15  
o BP, HR and RR: Up to 1 hour after morning dose 
o Body temperature 
• Cycle ≥ 5 Day 15 
o 
BP, HR and RR: Up to 1 hour after morning dose  
o 
Body temperature 
• At EOT visit 
• At the safety assessment visit of the active follow-up. 
 
9.6.3.6 
ECOG and Karnofsky 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 
Section 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 for safety reasons.  
Karnofsky performance status is used for determination of the MSKCC categories (see 
Section 9.3.3). 
Grading definitions for both performance statuses are given in Table 9–3 below. 
 


 
 
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Table 9–3: 
Definitions for ECOG PS and Karnofsky PS grading 
Karnofsky Status  
Karnofsky 
Grade 
ECOG 
Grade 
ECOG Status  
Normal, no complaints  
100  
0  
Fully active, able to carry on all 
pre-disease performance without 
restriction  
Able to carry on normal activities. Minor 
signs or symptoms of disease  
90  
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  
Normal activity with effort  
80  
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  
Care for self. Unable to carry on normal 
activity or to do active work  
70  
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  
Requires occasional assistance, but able 
to care for most of his needs  
60  
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  
Requires considerable assistance and 
frequent medical care  
50  
3  
Capable of only limited self-care, 
confined to bed or chair more than 
50% of waking hours  
Disabled. Requires special care and 
assistance  
40  
3  
Capable of only limited self-care, 
confined to bed or chair more than 
50% of waking hours  
Severely disabled. Hospitalization 
indicated though death non-imminent  
30  
4  
Completely disabled. Cannot carry 
on any self-care. Totally confined to 
bed or chair  
Very sick. Hospitalization necessary. 
Active supportive treatment necessary  
20  
4  
Completely disabled. Cannot carry 
on any self-care. Totally confined to 
bed or chair  
Moribund  
10  
4  
Completely disabled. Cannot carry 
on any self-care. Totally confined to 
bed or chair  
Dead  
0  
5  
Dead  
ECOG PS = Eastern cooperative oncology group performance status; PS = performance status. 
Source: (39) 
 
9.6.3.7 
Ophthalmological examination 
Ophthalmological examination will be performed by an ophthalmologist or an equivalent 
specialist according to the tabular schedule of evaluations shown in Section 9.1.  
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, slit lamp exam, tonometry, dilated indirect 
ophthalmoscopy with macular involvement assessment and optical coherence tomography 
(OCT) including measurement of central retinal thickness. The examination findings will be 


 
 
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described in the source data. Any findings qualifying as an adverse event will be recorded 
accordingly. 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. 
Patients who experience any decrease in visual acuity, ocular pain or discomfort, or any 
retinal disorders including retinal disorders including retinal detachment / RPED / central 
serous retinopathy / retinal vein occlusion have to undergo ophthalmologic examinations on 
Day 1 of every cycle. 
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. 
For dose modification of rogaratinib due to ophthalmological findings, see Section 7.4.3.2.3. 
For AESI reporting (retinal disorders Grade ≥ 2), see Section 9.6.1.6. 
For additional details on management of atezolizumab-related ocular events see investigator’s 
brochure for atezolizumab. 
9.6.3.8 
Chest X-ray 
A chest X-ray should be performed (unless prohibited by local regulations) at screening to 
allow monitoring in case of suspected immune-related pneumonitis. The screening chest X-
ray may be substituted with a chest X-ray that had been performed as part of the patient’s 
previous routine care in the 3 months before start of study treatment. Any finding on a repeat 
chest X-ray that is judged by the investigator as a clinically significant change (worsening) 
compared to a baseline value will be considered an adverse event, recorded and monitored. 
Lesions identified on the baseline chest X-ray should also be evaluated by computed 
topography (CT) or magnetic resonance imaging (MRI) scan. 
 
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. 
If archival tissue is not available in sufficient quantity or quality for the FGFR1/3 RNAscope 
assays 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. Acceptable samples include excisional, incisional, punch, or forceps 
biopsies. 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, 


 
 
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pancreas, or endoscopic procedures extending beyond the esophagus, stomach or bowel are 
excluded. 
The UC tumor tissue 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). 
Method applied for patient selection in trial 19131 
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 FGFR1/3 RNA-ISH 
test (RNAscope technology by Advanced Cell Diagnostics) will be used to aid in the selection 
of cancer patients who may benefit from the pan-FGFR inhibitor (rogaratinib) therapy. The 
RNAscope technology allows for the respective FGFR probe to bind to the target FGFR 
mRNA, and in combination with RNAscope 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 according to the scoring scheme given in Table 9–4. The analysis 
will be performed centrally. 
Table 9–4: 
FGFR1/3 RNA-ISH test (RNAscope® Assay): Preliminary stain intensity criteria 
Stain Intensity Score 
Stain Intensity Criteria 
0 
No staining or <1 dot per 10 cells 
1 
1-3 dots per cell 
2 
4-9 dots per cell. No or very few signal clusters. 
3 
10-15 dots per cell and less than 10% of signals in clusters 
4 
>15 dots per cell and more than 10% of signals in clusters 
FGFR = Fibroblast growth factor receptor; ISH = In situ hybridization; RNA = Ribonucleic acid. 
 
In pre-clinical studies, only xenograft models with either FGFR1, or FGFR2 or FGFR3 scores 
of 3+ or 4+ by RNAscope 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 an RNAscope score of 3+ or 4+. Therefore, having at least one FGFR 
isoform with a score of at least 3+ was selected as inclusion criterion for FGFR-positivity for 
this Study 19131. 
Details about the collection, processing, storage and shipment of samples will be provided 
separately (laboratory manual). 
Tumor-based biomarker analysis 
For all enrolled patients, exploratory biomarker analyses will be performed from UC tumor 
specimens provided beyond the number of slides needed for FGFR1/3 testing. This procedure 
is covered by the PI/ICF for FGFR testing. 


 
 
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These tumor tissue specimens may be used for the following purposes: (1) to evaluate 
mutations, copy numbers or gene rearrangements in known oncogenes such as p53, PTEN, 
RAS, PIK3CA 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 makers, such as PD-L1 and CD8A in tumor specimen, 
e.g. by IHC. 
As per investigator’s decision, and if technically feasible, biopsy during Cycle 2 or later 
and/or at the time of disease progression or recurrence is highly encouraged to be taken. This 
sample would allow generation of information about the identification of tumor biomarkers 
playing a role in therapy resistance. Note, however, that this is not considered to be 
mandatory by this study protocol. 
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. 
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. The types of 
analyses may comprise the identification of mutations or splice variants. Furthermore, these 
plasma samples will serve as source for non-coding microRNA, as possible markers 
describing treatment response. 
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 will be prepared from blood samples 
obtained according to the tabular schedule of evaluations shown in Section 9.1. 
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. 
In addition to the biomarkers listed above, other biomarkers deemed relevant to gain further 
knowledge about the pathomechanism of the disease or about the drug (i.e. mode of action 
related effect or safety of the drug) may be measured, based on newly emerging data from 
other ongoing studies and / or literature data. 


 
 
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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) 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. 
Data collection 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. After primary completion, 
questionnaire will not be done. 
9.8 
Appropriateness of procedures / measurements 
All efficacy and safety variables, 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. 
 
10. 
Statistical methods and determination of sample size 
10.1 
General considerations 
Statistical analysis will be performed using the software package SAS (SAS Institute Inc., 
Cary, NC, USA); the version used will be specified in the statistical analysis plan. 
All data will be listed, and study summary tables will be provided where appropriate. 
Quantitative data will be described by the following summary statistics: arithmetic mean, 
standard deviation, median, minimum and maximum. Where appropriate, summary statistics 
will be provided for the original data as well as for the changes versus baseline. Graphical 
illustrations will be provided where appropriate. Frequency tables will be provided for 
qualitative data.  
Due to the exploratory character of this Part A of the study, no confirmatory analysis will be 
performed. All calculated p-values and confidence intervals are to be interpreted in the 
exploratory sense. 
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. 


 
 
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10.2 
Analysis sets 
Safety analysis set (SAF)  
All patients who received at least 1 dose of study drug and have post-treatment safety data 
available will be included in the safety evaluation. 
MTD analysis set 
All patients who completed Cycle 1 and who took at least 80% of the required total dose 
(protocol-defined dose reductions will not be considered incompliant) of either study drug 
(rogaratinib or atezolizumab) during Cycle 1 or discontinued during Cycle 1 due to a DLT 
will be included in the MTD evaluation. 
Efficacy analysis set 
All patients who have received at least 1 dose of study drug and who have post-baseline 
efficacy data available will be included in the efficacy evaluation. 
Pharmacokinetics (PK) analysis set (PKS)  
All patients who have received at least 1 dose of study drug and with at least 1 valid 
concentration after first dosing and no important protocol deviations affecting the validity will 
be included in the PK evaluation. 
10.3 
Variables and planned statistical analyses 
10.3.1 
Disposition of patients 
The number of patients enrolled and included in each analysis set will be tabulated by region, 
country and center. A summary table will also be presented for the number of patients 
enrolled and the number and percentage of patients in each of the defined analysis sets. The 
reasons for patients excluded from each of the analysis sets will also be tabulated. In addition, 
the number of patients who were enrolled, treated and discontinued will be summarized. 
Reasons for discontinuation of study treatment will be tabulated. 
10.3.2 
Demographic and other baseline characteristics 
Summary statistics (arithmetic mean, standard deviation, median, minimum and maximum for 
quantitative variables) will be presented. Frequency tables for qualitative data will be 
provided. Medical history findings will be summarized using MedDRA (Medical Dictionary 
for Regulatory Activities) terms (v.20.0 or later). 
10.3.3 
Efficacy variables 
All efficacy variables evaluated using the RECIST v1.1 (see Appendix 16.2) are linked to the 
secondary objective of the study Part A (see Section 4). All variables evaluated using the 
iRECIST v1.1 (see Appendix 16.2) are exploratory only.  
Efficacy data will be summarized using descriptive statistics and will be graphically displayed 
if appropriate. The correlation between pharmacodynamic parameters and selected safety, 
efficacy, or PK parameters may be graphically displayed. Further statistical analyses may be 
conducted. 


 
 
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10.3.3.1 
Secondary efficacy variable 
The secondary efficacy variable is objective response rate. 
Objective response rate (ORR) is defined as the percentage of patients whose best response 
is either a complete response (CR) or partial response (PR). Patients for whom best tumor 
response is not CR or PR, as well as patients without any efficacy assessment will be 
considered non-responders. According to RECIST v1.1, confirmation of PR and CR is not 
required considering the nature of the study and the protocol requirements. 
10.3.3.2 
Exploratory efficacy variables 
Exploratory efficacy variables will include disease control rate (DCR) and duration of 
response (DOR), progression-free survival (PFS) and overall survival (OS). 
These variables are defined according to RECIST v1.1 as below: 
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 with SD as response, that is performed prematurely after assignment to treatment 
of the patient (i.e. substantially earlier than the first planned radiological tumor assessment at 
9 weeks), will not be taken into account. 
Duration of response (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. 
Progression-free survival (PFS) is defined as the time (days) from start of study treatment to 
date of first observed disease progression (investigator’s 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 the 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. 
Overall survival (OS) is defined as the time from start of study treatment 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 assignment to 
treatment, this patient will be censored at 1 day. 
10.3.4 
Safety variables 
10.3.4.1 
Determination of MTD 
The objective of the dose selection phase is to determine the maximum tolerated dose (MTD) 
or confirm that the start dose level of rogaratinib (800 mg b.i.d.) is safe. The MTD is defined 
as the highest dose that can be given so that toxicity probability is below the target toxicity 


 
 
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PT=30%. Estimation of the MTD will be based on the estimation of the observed dose 
dependent incidence rate of DLT in the first 21 days of dosing. 
The modified toxicity probability interval (mTPI) design (40) will be applied to guide the 
dose selection decisions in the study. The equivalence interval of the toxicity probability for 
the MTD is set to [25%, 35%], in which any dose with a toxicity probability falling into this 
interval is considered as an estimate close to the true MTD. The dose selection part will be 
finished after 20 patients are evaluable for the MTD assessment. A beta-binomial Bayesian 
model with Beta(1,1) prior will be used to compute the posterior probabilities that the true 
rate of DLT is contained in each of the 3 toxicity intervals: 
• [0, 25%] 
under-dosing (below the MTD) 
• [25%, 35%] 
target dosing (close to the MTD) 
• [35%, 100%] over-dosing (above the MTD) 
The mTPI method calculates the unit probability mass (UPM) for above intervals with safety 
rules to stop due to excessive toxicity. In addition doses that are estimated to have excessive 
toxicity will be excluded from the trial.  
The UPM for a given interval is defined as the probability of the interval divided by the 
length of the interval. Then an appropriate dose-finding action will be chosen based on the 
interval with the largest UPM. Specifically, if the UPM for the under-dosing interval is the 
largest, the dose is considered lower than the MTD and the recommendation is to escalate to 
the next higher dose or to stay on the dose level if current dose is the highest possible dose 
(800 mg b.i.d. being the highest possible dose) (letter E in Table 10–1); if the target dosing 
interval has the largest UPM, the mTPI design will recommend remaining at the current dose 
(letter S in Table 10–1); if the over-dosing interval has the largest UPM, the design will 
recommend de-escalating to the previous lower dose (letter D in Table 10–1). If the safety 
stopping rule is met, the toxicity of the current dose will be considered as unacceptable high 
and never be used again in the remainder of the trial (letters DU in Table 10–1). The safety 
rule is triggered if the posterior probability that the current dose is above the MTD is greater 
than 95%. All of these rules are summarized and precalculated in Table 10–1 below. No 
decision is made before data of at least 4 patients are available on the first dose level and are 
evaluable for DLTs. The sponsor in consultation with the investigators will decide how many 
additional patients need to be evaluable for DLTs on the same dose level before the next 
decision. See Table 7–2 for rogaratinib dose levels. 
The decision on the number of additional patients and on the next dose level will be based on 
the recommendations from the mTPI, clinical assessment, all available PK and safety data.  
The dose selection part will be finished after 20 patients are evaluable for DLT assessment 
and are available for the MTD determination. The RP2D will be defined once sufficient data 
is available. The final decision about the RP2D will be made by the sponsor in consultation 
with the investigators. 
 


 
 
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Table 10–1: 
Possible dose finding actions 
Number of patients treated at current dose 
Number of 
patients 
with 
observed 
DLTs 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
0 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
1 
S 
S 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
2 
S 
S 
S 
S 
S 
S 
S 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
3 
DU 
D 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
E 
E 
E 
E 
E 
4 
DU DU DU 
D 
D 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
5 
DU DU DU DU DU 
D 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
6 
DU DU DU DU DU DU 
D 
S 
S 
S 
S 
S 
S 
S 
S 
7 
DU DU DU DU DU DU DU 
D 
S 
S 
S 
S 
S 
S 
8 
DU DU DU DU DU DU DU DU DU 
D 
S 
S 
S 
9 
DU DU DU DU DU DU DU DU DU DU DU 
S 
10 
DU DU DU DU DU DU DU DU DU DU DU 
11 
DU DU DU DU DU DU DU DU DU DU 
12 
 
 
 
 
 
 
 
 
DU DU DU DU DU DU DU DU DU 
13 
DU DU DU DU DU DU DU DU 
14 
DU DU DU DU DU DU DU 
15 
DU DU DU DU DU DU 
16 
DU DU DU DU DU 
17 
DU DU DU DU 
18 
DU DU DU 
19 
DU DU 
20 
DU 
The column represents the number of patients treated at a given dose level in the trial. Each row represents the number of 
patients treated at the dose level and who have experienced dose-limiting toxicity (DLT) events. The letters in each cell 
provides the dose-assignment decision based on the data readout from the row and column numbers. 
E: Escalate to the next higher dose (or stay if current dose is the highest possible dose) 
S: Stay at the same dose 
D: De-escalate to the previous lower dose (or stop if current dose is lowest possible dose) 
DU: De-escalate to the previous lower dose and the current dose will never be used again. 
 


 
 
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10.3.4.2 
Adverse events (AEs) 
Individual listings of adverse events will be provided. Adverse events will be reported using 
MedDRA terms (v.20.0 or later) and graded according to NCI CTCAE v.4.03. The incidence 
of treatment-emergent adverse events (TEAEs) and treatment-emergent drug-related adverse 
events (TEADRs), respectively, will be summarized in frequency tables using worst CTCAE 
v.4.03 grade. Frequency tables will also be provided for the changes of worst CTCAE v.4.03 
grade after start of treatment versus baseline.  
AEs will be considered to be treatment-emergent if they have started or worsened after first 
administration of study drug up to 30 days after the last dose of rogaratinib or 90 days after 
the last atezolizumab administration, whichever comes later. 
10.3.4.3 
Clinical laboratory evaluations 
Laboratory data outside the reference range will be listed with abnormal values flagged. The 
incidence of laboratory data outside the reference range (low, high) will be summarized in 
frequency tables. The incidence of laboratory toxicities will be summarized by worst CTCAE 
v.4.03 grade. Frequency tables will be provided for the changes of worst CTCAE v.4.03 grade 
after start of treatment versus baseline. 
10.3.4.4 
Other safety measures 
Quantitative data (vital signs, ECG) will be described by the following summary statistics: 
arithmetic mean, standard deviation, median, minimum and maximum. These summary 
statistics will be presented for the original data as well as for the difference to baseline. 
Frequency tables will be provided for qualitative data. 
10.3.5 
Pharmacokinetic variables 
The concentration-times courses of rogaratinib in Cycle 1 will be tabulated by dose level. The 
following statistics will be calculated for each of the sampling points: arithmetic mean, 
standard deviation and coefficient of variation (CV), geometric mean, geometric standard 
deviation (re-transformed standard deviation of the logarithms) and CV, minimum, median, 
maximum value and the number of measurements. Means at any time will only be calculated 
if at least 2/3 of the individual data were measured and were above the lower limit of 
quantification (LLOQ). For the calculation of the mean value a data point below LLOQ will 
be substituted by one half of this limit. In tables showing mean values, where values below 
LLOQ are included in the calculation of mean values, these means will be marked. 
Individual and geometric mean concentration vs. time curves of all analytes (using the actual 
sampling times for individual plots and the planned sampling times for mean plots) will be 
plotted using both linear and semilogarithmic scale. 
Pharmacokinetic characteristics (tmax, tlast, Rstart, Rend, points terminal and %AUC [tlast-∞] 
excluded) will be summarized by the statistics mentioned above. Tmax and tlast will be 
described utilizing minimum, maximum and median as well as frequency counts.  
Concentration data from Cycle 2 to 5 as well as atezolizumab data will only be listed. 
 


 
 
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10.3.6 
Biomarker variables 
Biomarker data will be summarized using descriptive statistics and will be graphically 
displayed if appropriate. The correlation between biomarkers and selected safety, efficacy, or 
PK parameters may be graphically displayed. Further statistical analyses may be conducted. 
10.3.7 
Patient-reported outcomes (PRO) 
PRO data as measured by the EORTC QLQ-C30 will be analyzed to assess differences in 
health-related Quality of Life (HRQoL) and health utility values using all available data. The 
scoring of the PRO endpoints and handling of missing data will be detailed in the statistical 
analysis plan. 
PRO data will be summarized using descriptive statistics and will be graphically displayed if 
appropriate. Further statistical analyses may be conducted. 
10.4 
Determination of sample size 
This Part A of the study is primarily a descriptive safety and tolerability Phase 1b trial.  
No formal sample size calculation has been done for the dose selection part due to the 
exploratory nature of this Part A of the study. It is expected that up to 20 evaluable patients 
will be enrolled for safety and for the dose selection part. After 20 patients included in the 
dose selection, enrollment will continue up to a total of 26-30 patients at the most promising 
dose with regard to safety and efficacy to obtain additional data on safety, PK, and clinical 
activity.  
A sample size of at least 26 evaluable patients at the MTD/RP2D will lead to a Bayesian 
posterior probability P(0.4 | data) of at least 91% with a power of at least 96% and a 
Bayesian posterior probability P(0.4 | data) of at least 92% and with 80% power assuming a 
true population proportion for the response rate of u=0.6 under the alternative hypothesis for 
the upper criteria and a population proportion of l=0.15 under the alternative hypothesis for 
the lower criteria. 
In case that the highest dose of rogaratinib (800 mg b.i.d.) is well tolerated in combination 
with atezolizumab, it is expected that the minimum of 26-30 evaluable patients is included. 
Assuming a dropout rate of 15%, a total minimum sample size of approximately 30 patients at 
the MTD/RP2D is expected. 
Based on tolerability, different rogaratinib starting doses may be explored in this study. And 
in addition to FGFR testing, tumor tissue will be tested for further potential predictors of 
response (e.g. PIK3CA mutations). If, for example, the most promising rogaratinib dose or 
patient subgroups are not clearly defined, approximately 20 additional patients may be 
enrolled up to a total of 50 patients to confirm signals in a larger sample size, when 
rogaratinib in combination with atezolizumab seems to be tolerated and early signs of clinical 
activity have been observed. This decision will be made by the Sponsor after consultation 
with the investigators. 
All calculations were performed with SAS 9.4 using non-informative Jeffrey’s priors. 


 
 
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10.5 
Planned interim analyses 
Safety data will be reviewed on an ongoing basis during dose selection. Additional analysis, 
as Bayesian dose-response and / or PK modeling of DLTs rates and CTCAE v.4.03 gradings 
may be performed after selected groups of patients in order to generate additional relevant 
information for the adaptive dose selection decisions. The sponsor together with all 
investigators will review all available data and make the final decision as to dose selection, 
de-escalation or group expansion during the adaptive dose selection part. This group of 
sponsor and investigators will also determine when to implement predefined stopping rules. 
No formal interim analysis of the data collected during Part A is planned. 
 
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 
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. 
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. 


 
 
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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 treatment 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 has source 
documentation available at the site.  
Data recorded during FGFR testing period 
(Note: FGFR testing period will be considered as a pre-screening period and for the purpose 
of data collection it will be represented as Pre-Screening (FGFR testing) in the eCRF.) 
At minimum, the following data should be recorded in the eCRF: 
• Date of informed consent(s) that were signed (PI/ICF for FGFR testing) 
• Subject (patient) identification  
• Subject (patient) visit and visit date 
• Inclusion/exclusion 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 
• Urothelial carcinoma classification/diagnosis (see Section 9.3.3) including  
o date of initial diagnosis  
o type of assessment 
o date of the most recent progression / relapse,  
o histology  
o location of primary cancer  
o TNM classification of urothelial carcinoma at study entry according to the 
AJCC 8th edition  
o grading at initial diagnosis  
• ECOG performance status (see Section 9.6.3.6) 
• 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 


 
 
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• End of FGFR testing period, primary reason for discontinuation 
• Date of last visit  
Data recorded during screening  
In addition to the data listed above, the following data should be recorded in the eCRF: 
• Date of informed consent that was signed (PI/ICF for study treatment eligibility) 
• Inclusion/exclusion criteria for screening met (yes / no) 
• Prior anti-cancer therapy for urothelial carcinoma and outcome (any prior medications, 
significant non-drug therapies and diagnostic procedures for the study indication) (see 
Section 9.3.3). 
• Review TNM classification (AJCC 8th edition) 
• ECOG PS (see Section 9.6.3.6) 
• Karnofsky performance status (see Section 9.6.3.6) 
• Liver metastases (absence vs. presence) 
• Visceral metastases (liver, bone, lung) (absence vs. presence) 
• Medical history (see Section 9.3.2) 
• Alcohol and smoking habits/history 
• Reason for discontinuation and date of last visit 
These data will be transferred to the respective database. 
For patients who signed PI/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 
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 


 
 
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source documentation, as well as on the appropriate pages of the eCRF. During active and 
long-term follow-up period, any new anti-cancer therapy (including systemic therapy, 
radiotherapy, surgery) has to be reported up to primary completion. 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/CRO’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.  
Supporting data may be requested (example: blood glucose readings to support a 
diagnosis of diabetes).  
• 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. 
In the event of significant trial-continuity issue (e.g. caused by a pandemic), alternate 
strategies for monitoring may be implemented by the sponsor or the investigator, as per local 
health authority / ethics requirements. This includes the need for Remote Data Verification 
(RDV) which must only be used as a temporary measure where on-site monitoring visits are 
not possible and should focus on highest priority data (e.g. critical data). RDV and the 
mechanism used for this by the investigator site/country must be documented appropriately. 
 


 
 
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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. ECG, 
adjudication committees). 
For data coding (e.g. AEs, medication), internationally recognized and accepted dictionaries 
will be used. 
After its initial release for biometrical analysis, the clinical database is planned to be re-
opened for the inclusion of the following 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.). 
All missing or partial data will be presented in the subject data listing as they are recorded on 
the eCRF.  
Missing data will not be replaced. Possible impact of missing values on the analysis will be 
discussed in the clinical study report. 
Further details will be described in the SAP, if appropriate. 
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 
the archiving procedures do not meet the minimum timelines required by the sponsor, 


 
 
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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 HealthCare Pharmaceuticals Inc.,  
100 Bayer Boulevard, P.O. Box 915, 
Whippany, NJ 07981-0915, US 
Telephone no.:  
 
Email: 
 
 
Co-ordinating investigator(s) 
Name: 
Jonathan Rosenberg, MD 
Title: 
Doctor 
Address: 
Memorial Sloan Kettering Memorial Hospital 
1275 York Avenue 
New York, NY 10065, 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 
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. 
PPD
PPD
PPD
PPD
PPD
PPD


 
 
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External data evaluation bodies 
Central laboratory 
PK and biomarker (FGFR expression and plasma/tumor based biomarker analysis) 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 subinvestigators) who is directly involved in 
the treatment or evaluation of research patients has to provide a financial disclosure 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. 


 
 
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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 test and exploratory biomarker analyses 
FGFR-positive tested patients along with information on any trial risks from the fresh biopsy 
sampling (this applies only in case archival tumor sample is not available).  
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 FGFR positive urothelial carcinoma and still has interest to participate in this study, no 
longer than 28 days prior to start of 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. 


 
 
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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. 
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. For 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 


 
 
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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 female patients who 
become pregnant or for those fertile male patients whose female partner becomes pregnant. 
The PI/ICF will be signed by the female patient or the male patient and their pregnant female 
partner.  
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. 
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, while 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. 


 
 
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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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14. 
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von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, et al. 
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Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom 
AT, et al. Seven year update of an EORTC phase III trial of high-dose intensity M-
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tumours. Eur J Cancer. 2006;42(1):50-4. 
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Sternberg CN, de Mulder PH, Schornagel JH, Theodore C, Fossa SD, van Oosterom 
AT, et al. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, 
doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human 
granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial 
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Szabados B, Heijden MSVD, Lista AGDL, Tang YZ, Powles T. Responses to 
chemotherapy in patients with metastatic urothelial cancer (MUC) after frontline 
immunotherapy. J Clin Oncol. 2017;35(15_suppl):e16004-e. 
18. 
Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, et al. 
Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally 
advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. 
Lancet. 2017;389(10064):67-76. 
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Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi 
A, et al. Atezolizumab in patients with locally advanced and metastatic urothelial 
carcinoma who have progressed following treatment with platinum-based 
chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 
2016;387(10031):1909-20. 
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Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, et al. Pembrolizumab as 
Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med. 
2017;376(11):1015-26. 
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BAVENCIO® Prescribing information. FDA Prescribing information for 
BAVENCIO® (avelumab) injection, for intravenous use. 2017. 
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IMFINZI™ Prescribing information. FDA Prescribing information for IMFINZI™ 
(durvalumab) injection, for intravenous use. 2017. 
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Sweis RF, Spranger S, Bao R, Paner GP, Stadler WM, Steinberg G, et al. Molecular 
Drivers of the Non-T-cell-Inflamed Tumor Microenvironment in Urothelial Bladder 
Cancer. Cancer Immunol Res. 2016;4(7):563-8. 
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Guancial EA, Werner L, Bellmunt J, Bamias A, Choueiri TK, Ross R, et al. FGFR3 
expression in primary and metastatic urothelial carcinoma of the bladder. Cancer Med. 
2014;3(4):835-44. 
25. 
Turo R, Harnden P, Thygesen H, Fleischmann A, Thalmann GN, Seiler R, et al. 
FGFR3 expression in primary invasive bladder cancers and matched lymph node 
metastases. J Urol. 2015;193(1):325-30. 
26. 
Liu X, Zhang W, Geng D, He J, Zhao Y, Yu L. Clinical significance of fibroblast 
growth factor receptor-3 mutations in bladder cancer: a systematic review and meta-
analysis. Genet Mol Res. 2014;13(1):1109-20. 
27. 
Pal SK, Rosenberg JE, Keam B, Wolf J, Berger R, Dittrich C, et al. Efficacy of 
BGJ398, a fibroblast growth factor receptor (FGFR) 1-3 inhibitor, in patients (pts) 
with previously treated advanced/metastatic urothelial carcinoma (mUC) with FGFR3 


 
 
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Tabernero J, Bahleda R, Dienstmann R, Infante JR, Mita A, Italiano A, et al. Phase I 
Dose-Escalation Study of JNJ-42756493, an Oral Pan-Fibroblast Growth Factor 
Receptor Inhibitor, in Patients With Advanced Solid Tumors. J Clin Oncol. 
2015;33(30):3401-8. 
29. 
Lee J, Bendell JC, Rha SY, Bang Y-J, Clark L, Xiang H, et al. Antitumor activity and 
safety of FPA144, an ADCC-enhanced, FGFR2b isoform-selective monoclonal 
antibody, in patients with FGFR2b+ gastric cancer and advanced solid tumors. 
Presented at 2016 ASCO Annual Meeting. J Clin Oncol. 2016;34:(suppl; abstr 2502). 
30. 
Kilgour E, Ferry D, Saggese M, Arkenau H-T, Rooney C, Smith NR, et al. 
Exploratory biomarker analysis of a phase I study of AZD4547, an inhibitor of 
fibroblast growth factor receptor (FGFR), in patients with with advanced solid tumors. 
J Clin Oncol. 2014;32(5s):(suppl; abstr 11010). 
31. 
Dreicer R, Hoffman-Censits JH, Flaig TW, Grande E, Balmanoukian AS, Amsberg 
Gv, et al. Updated efficacy and > 1-y follow up from IMvigor210: Atezolizumab 
(atezo) in platinum (plat) treated locally advanced/metastatic urothelial carcinoma 
(mUC). J Clin Oncol. 2016;34(15_suppl):4515. 
32. 
Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. 
Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415-21. 
33. 
Knowles MA. Novel therapeutic targets in bladder cancer: mutation and expression of 
FGF receptors. Future Oncol. 2008;4(1):71-83. 
34. 
FDA. Biotin (Vitamin B7): Safety Communication - May Interfere with Lab Tests. 
2017; available online: https://wayback.archive-
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n/SafetyAlertsforHumanMedicalProducts/ucm586641.htm. 
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Bajorin DF, Dodd PM, Mazumdar M, Fazzari M, McCaffrey JA, Scher HI, et al. 
Long-term survival in metastatic transitional-cell carcinoma and prognostic factors 
predicting outcome of therapy. J Clin Oncol. 1999;17(10):3173-81. 
36. 
Bellmunt J, Choueiri TK, Fougeray R, Schutz FA, Salhi Y, Winquist E, et al. 
Prognostic factors in patients with advanced transitional cell carcinoma of the 
urothelial tract experiencing treatment failure with platinum-containing regimens. J 
Clin Oncol. 2010;28(11):1850-5. 
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Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45(2):228-47. 
38. 
Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al. 
iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. 
Lancet Oncol. 2017;18(3):e143-e52. 
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Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin 
Oncol. 1982;5(6):649-55. 
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Ji Y, Liu P, Li Y, Bekele BN. A modified toxicity probability interval method for 
dose-finding trials. Clin Trials. 2010;7(6):653-63. 


 
 
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Inducers. Available online: 
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Schwartz LH, Bogaerts J, Ford R, Shankar L, Therasse P, Gwyther S, et al. Evaluation 
of lymph nodes with RECIST 1.1. Eur J Cancer. 2009;45(2):261-7. 
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Matsuo S, Yasuda Y, Imai E, Horio M. Current status of estimated glomerular 
filtration rate (eGFR) equations for Asians and an approach to create a common eGFR 
equation. Nephrology (Carlton). 2010;15 Suppl 2:45-8. 
 
15. 
Protocol amendments 
15.1 
Amendment no.1 
Amendment no.1 is a global amendment forming integrated protocol version 2.0, dated 
04 DEC 2018. 
Overall rationale for the amendment 
The protocol was amended to address emerging safety data. In this regard, immune-related 
nephritis was added as new identified risk for atezolizumab and the management guideline of 
rogaratinib-induced hyperphosphatemia was updated. 
The readability of the protocol was improved by reducing the introductory sections and 
inconsistencies were resolved in some parts of the protocol. 
In addition, the option of transferring patients to a roll-over study was included. 
The number of patients potentially included in the trial was changed.  
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 
7.4.3.3 Dose modifications of 
atezolizumab 
Grade 2 immune-related 
nephritis is added as a criterion 
for withhold from atezolizumab 
treatment, and Grade 3 or 4 
immune-related nephritis is 
added as a criterion for 
permanent discontinuation from 
atezolizumab treatment. 
According to Atezolizumab IB, 
immune-related nephritis is 
identified as a new risk of for 
atezolizumab. 


 
 
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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, 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. 
6.1 Inclusion criteria, 9.2.1.1 
FGFR testing, 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 be consistent 
with other rogaratinib 
protocols. 
2. Synopsis, 6.1 Inclusion 
criteria 
Inclusion criterion 10 is modified 
for consistency. 
For consistency with inclusion 
criterion 9 for cisplatin-
ineligibility. 
3.3 Rogaratinib, 6.4.1.3 
Withdrawal criteria, 7.4.3.1 
Dose limiting toxicities (DLTs), 
7.4.3.2 Dose modifications of 
rogaratinib (Table 7–3), 
7.4.3.2.1 Hyperphosphatemia, 
9.1 Tabular schedule of 
evaluations (Table 9–2 
footnote g), 9.2.2.1 Cycle 1, 
9.2.2.2 Cycles 2 – 4, 9.2.2.3 
Cycles ≥ 5, 9.2.2.5 End-of-
treatment (EOT) visit, 9.2.3.1 
Active follow-up, 9.6.3.1 
Laboratory evaluations, 9.6.3.4 
12-lead ECG 
Content relevant to dose 
modifications of rogaratinib and 
management for 
hyperphosphatemia is updated. 
A formula to calculate calcium-
phosphorus product (Ca x PO4) 
is added in the protocol. 
The clinical chemistry panel is 
modified for calcium to only 
measure total calcium (instead 
of total or ionized) as total 
calcium is needed for the 
formula. 
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. 
Serum phosphate will guide 
dose modifications of 
rogaratinib but Ca x PO4 
product will still be calculated 
for future data comparisons. 
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. 
8.1 Prior and concomitant 
therapy 
It is clarified that all medication 
and therapies which are 
considered necessary for the 
patient’s welfare, and which are 
not expected to interfere with the 
evaluation of the study drug, 
including antibiotics, may be 
given at the discretion of the 
investigator. 
For clarity and to emphasize 
antibiotics are not prohibited 
(except during the 14 days 
prior to start of study 
treatment). 


 
 
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Section # and Name 
Description of Change 
Brief Rationale 
5.2.3 Follow-up periods, 9.1 
Tabular schedule of 
evaluations (Table 9-2 footnote 
r), 9.2.3.1 Active follow-up, 9.4 
Efficacy 
It is clarified that during the 
active follow-up, tumor 
evaluations will be performed 
every 9 weeks from the previous 
scan date. The evaluation 
interval is increased to 12 weeks 
after one year. 
For clarity and to provide a 
more relaxed schedule of 
assessment to the patient in 
order to reduce both hospital 
admissions and patient burden 
as well as renal toxicity due to 
contrast medium (i.e. patients 
starting active follow up have 
often chronic renal failure or 
contrast medium allergy or 
reported toxicity leading to 
treatment withdrawal). 
9.1 Tabular schedule of 
evaluations (Table 9-2), 9.2.2 
Treatment period, 9.2.3.1 
Active follow-up, 9.7.1 
Biomarker investigations 
The timing of the optional tumor 
biopsy is modified to allow 
biopsy during Cycle 2 and/or at 
the time of disease progression. 
To provide more flexibility in 
collecting tumor samples and 
to allow investigations in 
responding patients. 
9.1 Tabular schedule of 
evaluations, 9.2.1.2 Screening, 
9.2.2.1 Cycle 1, 9.2.2.2 Cycles 
2 – 4, 9.2.2.3 Cycles ≥ 5, 
9.2.2.5 End-of-treatment 
(EOT) visit, 9.6.3.1 Laboratory 
evaluations 
Hormones are moved from the 
clinical chemistry panel to a 
separate hormone panel. 
To be in alignment with the 
eCRF and the protocol 
standards, and to clarify the 
blood sampling schedule. 
6.4.1.3 Withdrawal criteria 
It is clarified that the patient 
being off study drug 
(atezolizumab) longer than 42 
days beyond the next scheduled 
dosing is considered a 
substantial non-compliance with 
study procedures and the patient 
must be withdrawn from study 
treatment. 
For consistency with Section 
7.4.3.3 Dose modifications of 
atezolizumab. 
9.6.3.4 12-lead ECG 
A time window of ± 15 minutes is 
added for 12-lead ECG 
readings. 
To allow flexibility for practical 
considerations. 
6. Study population, 6.4.1.1 
Screening failure, 9.2.1.1 
FGFR testing 
It is clarified that “FGFR testing 
failure” does not mean a failure 
of the FGFR test (i.e. the 
RNAscope assay), but a 
negative FGFR test result and/or 
not meeting the 
inclusion/exclusion criteria. 
For further clarity.  


 
 
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Section # and Name 
Description of Change 
Brief Rationale 
7.2.2 Atezolizumab – 
combination drug, 7.4.1.2 
Atezolizumab – combination 
drug, 7.4.3.3 Dose 
modifications of atezolizumab, 
9.6.1. Adverse events, 9.6.1.5 
Expected adverse events 
Prescribing information is 
deleted as a reference and 
Summary of Product 
Characteristics (SmPC) is used 
as reference only for the 
preparation instructions for 
atezolizumab. 
SmPC should only be referred 
to for the preparation 
instructions for atezolizumab. 
The IB is the reference for all 
other information about 
atezolizumab. 
7.4.1.1 Rogaratinib – test drug, 
9.1 Tabular schedule of 
evaluations (Table 9-2, 
footnote o) 
It is clarified that on C1D1 
patients will receive 800 mg of 
rogaratinib in the morning (not 
only one tablet i.e. 400 mg), and 
the second dose of 800 mg in 
the evening. 
For clarity (to avoid false 
interpretation of “single dose”). 
 
7.4.1.1 Rogaratinib – test drug, 
9.1 Tabular schedule of 
evaluations (Table 9-2, 
footnote k), 9.2.2.1 Cycle 1, 
9.5.1 Drug measurements 
A time window of ± 3 hours is 
added for the 2nd dose of 
rogaratinib on C1D1. 
Clarifications are included for PK 
sampling timepoints on C1D1 
accordingly. 
For flexibility for the 2nd dose 
for practical considerations. 
7.4.3.2.2 Liver toxicity 
Information on the incidence of 
liver toxicities in the rogaratinib 
FiH study was added. 
To provide further data for 
investigators in this section. 
9.5.1 Drug measurements 
New best practice wording is 
included for handling of PK 
sampling times outside 
suggested time intervals and/or 
missing samples. 
To clarify the sampling time 
points. 
 
9.5.1 Drug measurements 
It is clarified that the method 
used for measuring plasma 
concentrations of atezolizumab 
is also validated (not only the 
method for rogaratinib 
concentrations).  
Missing information is added. 
9.5.2 Non-compartmental 
pharmacokinetic evaluation 
Additional PK parameter Vss/F 
(apparent volume of distribution 
at steady state after 
extravascular administration) is 
changed to VZ/F. 
Parameter Vss is a reliable PK 
parameter only for intravenous 
administration. 
10.3.5 Pharmacokinetic 
variables 
Statistical analyses of 
pharmacokinetic characteristics 
are further clarified. 
To add clarity, in case there 
are more than one dose 
levels. Also, “other” PK 
parameters for technical 
documentation don’t need to 
be included in statistics 
anymore, as per internal 
guidance.  


 
 
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Section # and Name 
Description of Change 
Brief Rationale 
16.2 Evaluation Criteria in 
Solid Tumors (RECIST and 
iRECIST) 
Central confirmation of PD per 
iRECIST is deleted. 
In Part A of the 19131 study 
there is no central review for 
treatment decisions. 
3.3 Rogaratinib, 3.4 
Atezolizumab 
Detailed information about 
clinical studies of rogaratinib and 
atezolizumab are deleted. 
Details about rogaratinib and 
atezolizumab studies and 
clinical experience are omitted 
to avoid the need to amend 
the protocol when IB is 
updated. All details can be 
found from the most recent 
version of the IB. 
1.Title page, 13.1 
Investigator(s) and other study 
personnel 
Sponsor’s medical expert’s 
name and contact details are 
changed. 
Reorganization of the medical 
team. 
2. Synopsis, 5.1 Design 
overview, 10.4 Determination 
of sample size,  
Sample size wording is clarified 
and modified to allow 
recruitment of up to 50 patients. 
To allow the option to adjust 
the sample size based on 
emerging data. 
6.4.2 Replacement 
Wording regarding replacement 
for efficacy assessment was 
clarified 
For further clarity. 
6.4.1.3 Withdrawal criteria, 
7.4.3.1. Dose limiting toxicities 
(DLTs), 7.4.3.2.3 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. 
9.2.3.2 Long-term follow-up 
It is clarified that all patients in 
the long-term follow-up period 
will be contacted every 3 months 
(±14 days) from completion of 
the active follow-up. 
To clarify the beginning of the 
long-term follow-up as 
requested by the coordinating 
investigator. 
9.6.3.1 Laboratory evaluations 
RBC and hemoglobin are 
removed from urinalysis 
coverage. 
Specification is not necessary 
as blood covers both RBC and 
hemoglobin 
6.1 Inclusion criteria 
It is added to #8 that regionally 
available standard of care 
options must be considered for 
all patients. 
To exclude patients where 
standard of care options are 
more appropriate. 
6.1 Inclusion criteria 
The hearing loss criteria are 
revised to comply with CTCAE v 
4.03. 
For compliance with CTCAE v 
4.03. 


 
 
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Section # and Name 
Description of Change 
Brief Rationale 
6.1 Inclusion criteria 
The time after last study drug 
administration, when male 
patients with a female partner of 
childbearing potential must use a 
condom and ensure that an 
additional form of contraception 
is also used, is changed from 12 
weeks to 5 months. 
For consistency within the 
inclusion criterion #14 and with 
Atezolizumab IB 
6.2 Exclusion criteria 
It is added that baseline chest X-
ray and CT can be used for 
tuberculosis screening. 
To clarify the determination of 
active tuberculosis. 
6.4.1.3 Withdrawal criteria, 
7.4.3.2.2 Liver toxicity 
Criteria for liver toxicity are 
modified.  
The liver toxicity criteria are 
changed to make the 
elevations consistent with the 
CTCAE grading. 
9.2.2.1 Cycle 1, 9.6.3.5 Vital 
signs 
The number of time points for 
monitoring the vital signs, 
including blood pressure, heart 
rate, respiratory rate and body 
temperature, on C1D15 are 
reduced. 
Based on the schedule of 
study treatment (patients 
receive atezolizumab on Day 1 
of every cycle, i.e. once every 
3 weeks) no safety concerns 
are expected on C1D15 
requiring intensive monitoring 
of vital signs (i.e. vital signs, 
including blood pressure, heart 
rate, respiratory rate and body 
temperature before and 0.5, 1, 
2, 3, 4, 6 and 8 hours after 
morning dose). 
7.4.1.2 Atezolizumab – 
combination drug, 9.2.2.1 
Cycle 1, 9.2.2.2 Cycles 2 – 4, 
9.2.2.3 Cycles ≥ 5 and 9.6.3.5 
Vital signs 
Body temperature measurement 
is separated from other vital 
signs blood pressure, heart rate 
and respiratory rate and 
scheduling is clarified and 
aligned with other parts of the 
protocol. 
To ensure consistency in the 
frequency and timing of vital 
signs including HR, BP, RR 
and body temperature 
between the protocol sections 
and to allow flexibility for 
practical considerations. 
2. Synopsis 
Wording regarding rogaratinib 
dose was clarified. 
To clarify that also lower 
doses of rogaratinib may be 
used. 
 
In addition, editorial and administrative changes have been made throughout the document. 


 
 
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15.2 
Amendment no.2 
Amendment no.2 is a global amendment forming integrated protocol version 3.0, dated 
10 FEB 2021. This amendment is considered substantial based on the relevant criteria of the 
(EU) clinical trial legislation. 
Overall rationale for the amendment 
The protocol was amended to address emerging safety data. In this regard, immune-related 
myositis and severe cutaneous adverse reactions were added as new identified risks for 
atezolizumab and the respective management guidelines were added. 
In addition, the option of continuing post-study therapy in any other form of continued study 
drug supply with no cost to the patient was included. 
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 
7.4.3.3 Dose modifications of 
atezolizumab 
Suspected SJS and TEN are 
added as criteria to withhold 
atezolizumab treatment, and 
confirmed SJS and TEN are 
added as criteria for permanent 
discontinuation of atezolizumab 
treatment. 
Severe cutaneous adverse 
reactions are identified as a 
new risk associated with the 
use of atezolizumab. 
7.4.3.3 Dose modifications of 
atezolizumab 
Grade 2 or 3 immune-related 
myositis is added as a criterion 
to withhold atezolizumab 
treatment, and Grade 4 immune-
related myositis is added as a 
criterion for permanent 
discontinuation of atezolizumab 
treatment. 
Immune-related myositis is 
identified as a new risk 
associated with the use of 
atezolizumab. 
9. Procedures and variables 
Alternate strategies for 
participant visits, assessments, 
medication distribution and 
monitoring are allowed in the 
event of a significant trial-
continuity issue (e.g. caused by 
a pandemic). 
To ensure trial-continuity in 
exceptional circumstances. 


 
 
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Section # and Name 
Description of Change 
Brief Rationale 
6.2 Exclusion criteria, 8.1 Prior 
and concomitant therapy 
COVID-19 vaccines are added 
as permitted prior and 
concomitant therapy. Vaccines 
based on mRNA technology are 
preferred, but also live, 
attenuated vaccines can be 
allowed if deemed appropriate 
for cancer patients. Live, 
attenuated, replication 
competent virus vaccines are 
not permitted. 
To allow the use of COVID-19 
vaccines during study 
treatment. Vaccines based on 
mRNA technology are 
considered safest for cancer 
patients. 
6.1 Inclusion criteria 
Duration of required 
contraception use after stopping 
rogaratinib is decreased based 
on the updated IB. 
To take into account the 
possibility that a patient stops 
atezolizumab earlier than 
rogaratinib. 
2. Synopsis, 6.2 Exclusion 
criteria, 6.4.1.3 Withdrawal 
criteria, 7.4.3.1 Dose limiting 
toxicities (DLTs), 7.4.3.2.3 
Retinal disorders, 9.1 Tabular 
schedule of evaluations, 
9.6.1.6 Adverse events of 
special safety interest, 9.6.3.7 
Ophthalmological examination 
Term “serous retinopathy” is 
updated to “central serous 
retinopathy”. 
For consistency with IB. 
8.1 Prior and concomitant 
therapy 
Text is modified to clarify that 
antibiotics are permitted during 
the study. 
For further clarity. 
9.6.1.3 Assessments and 
documentation of adverse 
events 
Clarification is added that only 
SAEs or AESIs of atezolizumab 
need to be reported until 90 
days after the last atezolizumab 
administration (for rogaratinib 30 
days). 
For clarity and prevention of 
unnecessary reporting. 
9.6.1.4 Reporting of serious 
adverse events 
Regarding SAE reporting of AML 
and MDS, “occurring after 
chemotherapy for cancer’’ is 
removed. 
Correction (not applicable). 
7.4.3.2 Dose modifications of 
rogaratinib 
Guidance for dose modification 
of Grade 3 toxicity (Table 7–3) is 
corrected to be consistent with 
the rest of the protocol. “Delay 
until recovery to  Grade 1.” 
Corrected to avoid 
inconsistency in the protocol. 
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. 


 
 
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Section # and Name 
Description of Change 
Brief Rationale 
9.6.3.1 Laboratory evaluations 
Ca x PO4 product formula is 
removed. 
Ca x PO4 product is no longer 
required to be calculated by 
sites. 
9.1 Tabular schedule of 
evaluations 
Urinalysis and hormone panel 
can be performed up to 2 days 
prior to drug administration. 
To allow urinalysis and 
hormone panel the same time 
window as for safety 
laboratory tests. 
5.5 End of study, 7.2 Identity of 
study treatment, 
8.2 Post-study therapy 
The option of continuing post-
study therapy in any other form 
of continued study drug supply 
with no cost to the patient is 
included. 
To offer more flexible 
possibilities to continue study 
treatment when this trial is 
stopped but benefits are 
observed for individual 
patients. 
7.4.3.2.2 Liver toxicity, 
7.4.3.3 Dose modifications of 
atezolizumab 
Detailed numbers of AEs in 
clinical studies of rogaratinib and 
atezolizumab are deleted and 
references to IB are added. 
To avoid the need to amend 
the protocol when IB is 
updated. Details can be found 
from the most recent version 
of the IB. 
1. Title page, 13.1 
Investigator(s) and other study 
personnel 
The name and contact 
information of sponsor’s medical 
expert are changed. 
Personnel change. 
Signature of the sponsor’s 
medically responsible person 
The signature of the Sponsor’s 
medically responsible person is 
removed from the clinical study 
protocol. 
Administrative change of 
Bayer process. 
In addition, editorial changes have been made throughout the document. 
15.3 
Amendment no.3 
Amendment no.3 is a global amendment forming integrated protocol version 4.0, dated 
4 OCT 2021. This amendment is considered substantial based on the relevant criteria of the 
(EU) clinical trial legislation. 
Overall rationale for the amendment 
After primary completion, study procedures were reduced to decrease burden to patients and 
sites. The updated schedule of events is intended to mimic standard of care. 


 
 
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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. 


 
 
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Section # and Name 
Description of Change 
Brief Rationale 
9. Procedures and variables 
Table 9.2 Schedule of 
evaluations: Treatment and 
follow-up periods 
9.2.2 Treatment period 
9.2.2.3 Cycles ≥ 5 
9.2.3.1 Active follow-up 
After primary completion, 
Cycle ≥5 Day 15 evaluations 
and assessments were 
removed: 
Toxicities / AE assessment, 
physical examinations, vital 
signs, ECOG performance 
status, changes in vision, blood 
samples for safety laboratory 
tests, calculation of eGFR, 
concomitant medication 
To relieve the burden on the 
patients remaining on 
treatment after study primary 
completion. 
 
9. Procedures and variables 
Table 9.2 Schedule of 
evaluations: Treatment and 
follow-up periods 
9.2.2.3 Cycles ≥ 5 
9.2.2.5 End-of-treatment 
(EOT) visit 
9.6.3 Further safety 
After primary completion, C ≥5  
and EOT dipstick urinalysis was 
removed.  
To relieve the burden on the 
patients remaining on 
treatment after study primary 
completion. 
9. Procedures and variables 
Table 9.2 Schedule of 
evaluations: Treatment and 
follow-up periods 
9.2.2.3 Cycles ≥ 5 
9.2.2.5 End-of-treatment 
(EOT) visit 
9.6.3 Further safety 
After primary completion, C ≥5  
and EOT 12-lead ECG are 
considered optional and at the 
investigator’s discretion 
The primary completion safety 
data (as per cut date of July 
2021) did not identify 
myocarditis or any other 
cardiac event as a safety 
signal.   
Optional ECG will give the 
flexibility for the investigators 
to use this resource as needed 
in addition to the management 
guidance provided on table 
7-10. 
9. Procedures and variables 
Table 9.2 Schedule of 
evaluations: Treatment and 
follow-up periods 
Footnote f 
9.2.2.3 Cycles ≥ 5 
9.2.2.5 End-of-treatment 
(EOT) visit 
After primary completion, the 
frequency of ophthalmologic 
examinations was reduced: The 
examination is performed on D1 
of every 4th instead of every 2nd 
cycle, starting at C2. At the EOT 
visit, ophthalmologic 
examination is done only in case 
the patient reports changes in 
vision. 
After primary completion, the 
patients that are currently in 
the study have been on 
treatment for at least 2 years, 
therefore, the chance of 
developing new 
ophthalmologic issues is 
small. In case of reported 
changes in vision, 
ophthalmological examinations 
will be performed. 


 
 
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Section # and Name 
Description of Change 
Brief Rationale 
9. Procedures and variables 
Table 9.2 Schedule of 
evaluations: Treatment and 
follow-up periods 
Footnote h 
 
9.2.2.3 Cycles ≥ 5 
 
After primary completion, 
hormone panel (thyroid function 
test) done periodically to reduce 
frequency of testing, according 
to local standard of care. 
After primary completion, the 
testing frequency can be 
reduced and will be done 
according to local standard of 
care. The detection of 
asymptomatic thyroid function 
abnormality will rely on AE 
assessment at each visit. The 
investigators can order ad hoc 
TSH, T3 and T4 when 
hypothyroidism or 
hyperthyroidism is suspected 
based on symptomatic AE 
collection and decide the 
action to be taken for 
atezolizumab. 
9. Procedures and variables 
Table 9.2 Schedule of 
evaluations: Treatment and 
follow-up periods 
Footnote j 
 
9.2.2 Treatment period 
9.2.2.3 Cycles ≥ 5 
9.2.2.5 End-of-treatment 
(EOT) visit  
9.2.3 Follow-up periods  
9.2.3.1 Active follow-up 
9.6.3 Further safety 
After primary completion, 
pregnancy tests no longer 
required if there are no active 
patients that are women of child-
bearing potential. 
After primary completion, 
pregnancy tests are no longer 
required because there are no 
female patients of child-
bearing potential left in the 
study. 
2. Synopsis 
5.2.3 Follow-up periods 
9. Procedures and variables 
Table 9.2 Schedule of 
evaluations: Treatment and 
follow-up periods 
9.2.3.1 Active follow-up 
9.2.2.4 Tumor assessments 
during treatment period 
9.2.3 Follow-up periods 
The interval for tumor 
assessments was prolonged 
from every 9 weeks to every 14 
weeks during the treatment and 
active follow-up periods. 
To relieve the burden on the 
patients remaining on 
treatment after study primary 
completion. 
 


 
 
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Section # and Name 
Description of Change 
Brief Rationale 
2. Synopsis 
9. Procedures and variables 
Table 9.2 Schedule of 
evaluations: Treatment and 
follow-up periods 
9.2.2.3 Cycles ≥ 5 
9.2.2.5 End-of-treatment 
(EOT) visit 
9.2.3 Follow-up periods 
After primary completion, the 
PRO questionnaire was 
removed from C4 onwards. 
To relieve the burden on the 
patients remaining on 
treatment after study primary 
completion. 
 
9. Procedures and variables 
Table 9.2 Schedule of 
evaluations: Treatment and 
follow-up periods 
Footnote t 
 
9.2.2.3 Cycles ≥ 5 
9.7.1 Biomarker investigations 
Plasma-based biomarker 
analysis 
9.2.3 Follow-up periods 
9.7.1 Biomarker investigations 
After primary completion, blood 
sampling for plasma-based 
biomarker analyses are not done 
beyond C4 except at the EOT 
visit. 
To relieve the burden on the 
patients remaining on 
treatment after study primary 
completion. 
 
7.4.3.3 Dose modifications of 
atezolizumab 
Management of Grade 1 and 2 
atezolizumab infusion-related 
reactions was updated. 
Alignment with updated 
atezolizumab IB. 
10.3.5 Pharmacokinetic 
variables 
The concentration-times courses 
of only rogaratinib in C1 is 
tabulated by dose level. 
Concentration data from C2-5 
and all atezolizumab data is only 
listed. 
Clarification 
11.2 Monitoring 
 
Remote data verification was 
allowed. 
Introducing flexibility in case of 
trial conduct continuity issues. 
Modification request by BfArM. 
1.Title page  
13.1 Investigator(s) and other 
study personnel 
Sponsor’s medical expert’s 
name was changed. 
Reorganization of the medical 
team. 
9.5.2 Non-compartmental 
pharmacokinetic evaluation 
Update of software name. 
Clarification 
In addition, editorial changes have been made throughout the document. 


 
 
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15.4 
Amendment no.4 
Amendment no.4 is a global amendment forming integrated protocol version 5.0, dated 
09 NOV 2022. This amendment is considered substantial based on the relevant criteria of the 
(EU) clinical trial legislation. 
Overall rationale for the amendment 
The protocol was amended to address emerging safety data: Immune-mediated pericardial 
disorders were added as new identified risk for atezolizumab and the respective management 
guidelines were added. Management guidelines for atezolizumab-specific adverse events were 
revised. 
In addition, no further analysis is planned for this study after primary completion and the 
active and long-term follow-ups were concluded.  
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 
7.4.3.3 Dose modifications of 
atezolizumab 
Management guidelines for 
immune-mediated pericardial 
disorders are added and 
grouped under immune-
mediated cardiac events along 
with immune-mediated 
myocarditis. 
Immune-mediated pericardial 
disorders are identified as a 
new risk associated with the 
use of atezolizumab. 
7.4.3.3 Dose modifications of 
atezolizumab 
Management guidelines for 
atezolizumab-specific adverse 
events are aligned with the IB. 
To harmonize with the IB. 
2. Synopsis, 5.1 Design 
overview, 5.2.3 Follow-up 
periods, 6.4.1.3 Withdrawal 
criteria, 9.2.3 Follow-up 
periods, 9.2.3.1 Active follow-
up, 9.4 Efficacy, 9.6.1.3 
Assessments and 
documentation of adverse 
events, 11.1 Data recording 
After primary completion, follow-
up data is no longer collected 
after the safety assessment visit 
in the active and long-term 
follow-ups. 
Follow-up data is no longer 
needed. 
5.5 End of study 
LPLV definition is changed. 
Option for study termination by 
sponsor guided by strategic 
expectations for the study 
compounds after primary 
completion is added. 
To give flexibility for strategic 
decisions of the sponsor. 
In addition, editorial changes have been made throughout the document. 
 


 
 
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15.5 
Amendment no.5 
Amendment no.5 is a global amendment forming integrated protocol version 6.0, dated 
23 MAY 2023. This amendment is considered substantial based on the relevant criteria of the 
(EU) clinical trial legislation. 
Overall rationale for the amendment 
The protocol was amended to address emerging safety data: immune-mediated myelitis and 
immune-mediated facial paresis were added as new identified risks for atezolizumab and the 
respective management guidelines were added. Management guidelines for atezolizumab-
specific adverse events were revised. 
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 
7.4.3.3 Dose modifications of 
atezolizumab 
9.6.1.6 Adverse events of 
special safety interest 
Management guidelines for 
neurologic disorders, including 
immune-mediated myelitis and 
immune-mediated facial paresis, 
are added. 
Myelitis and facial paresis are 
added as atezolizumab-specific 
adverse events of special 
interests. 
Immune-mediated myelitis and 
immune-mediated facial 
paresis are identified as a new 
risk associated with the use of 
atezolizumab. 
7.4.3.3 Dose modifications of 
atezolizumab 
Management guidelines for 
Grade 3 immune-mediated 
gastrointestinal events (diarrhea 
or colitis) and Grade 1 
hyperthyroidism are updated. 
Harmonization with the IB. 
7.4.3.3 Dose modifications of 
atezolizumab 
Grade 1 immune-mediated 
pericarditis is added in the list of 
reasons to withhold 
atezolizumab. 
For consistency. 
1.Title page  
13.1 Investigator(s) and other 
study personnel 
Sponsor’s medical expert’s 
name and contact information 
are changed. 
Personnel change. 
In addition, editorial changes have been made throughout the document. 
 


 
 
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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 (41)  
 
16.2 
Response Evaluation Criteria in Solid Tumors (RECIST and iRECIST) 
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 (37) as 
well as the modified iRECIST guidelines for immune-based therapeutics as supportive data 
for efficacy and treatment decision. iRECIST is based on RECIST 1.1. Responses assigned 
using iRECIST have a prefix of “i” (i.e. immune). Investigators should note the different 


 
 
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requirements for confirmatory scans as well as follow up for the two criteria. Further details 
can be found in the Imaging Manual. 
RECIST 
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: 
• 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 (42)). 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. 
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 


 
 
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Lesions with prior local treatment: 
• Tumor lesions situated in a previously irradiated area, or in an area of 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 
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.  


 
 
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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 
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 
≥ 9 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. 


 
 
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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). 
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. 
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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Description of the iRECIST Process for Assessment of Disease Progression 
Assessment at Screening and Prior to RECIST 1.1 Progression 
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST 
assessment. 
Assessment and Decision at RECIST 1.1 Progression 
For patients who show evidence of radiological PD by RECIST 1.1 the investigator will 
decide whether to continue a patient on study treatment until repeat imaging is obtained 
(using iRECIST for patient management). This decision by the investigator should be based 
on the patient’s overall clinical condition and agreement. 
Clinical stability is defined as the following:  
• Absence of symptoms and signs indicating clinically significant progression of 
disease 
• No decline in ECOG performance status  
• No requirements for intensified management, including increased analgesia, radiation, 
or other palliative care 
For any patient deemed clinically unstable the investigator should discontinue the study 
treatment. 
 
If the investigator decides to continue treatment, the patient may continue to receive study 
treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm or reject 
PD by iRECIST and to ensure that patients remain fit for salvage therapies.  
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including: 
• Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and 
≥5 mm from nadir 
o Note: the iRECIST publication uses the terminology “sum of measurements”, but 
“sum of diameters” (SOD) will be used in this protocol, consistent with the 
original RECIST 1.1 terminology. 
• Unequivocal progression of non-target lesion(s) identified at baseline 
• Development of new lesion(s) 
iRECIST defines new response categories, including iUPD (unconfirmed progressive disease) 
and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, the first 
visit showing progression according to RECIST 1.1 will be assigned a visit (overall) response 
of iUPD, regardless of which factors caused the progression. 
At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be 
assessed as usual. 


 
 
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New lesions will be classified as measurable or non-measurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target 
(NLT). The sum of diameters of these lesions will be calculated, and kept distinct from the 
sum of diameters for target lesions at baseline. All other new lesions will be followed 
qualitatively as New Lesions – Non-target (NLNT). 
Assessment at the Confirmatory Imaging 
On the confirmatory imaging, the patient will be classified as progression confirmed (with an 
overall response of iCPD), or as showing persistent unconfirmed progression (with an overall 
response of iUPD), or as showing disease stability or response (iSD/iPR/iCR). 
Confirmation of Progression 
Progression is considered confirmed, and the overall response will be iCPD at the immediate 
next visit, if ANY of the following occurs: 
• Any of the factors that were assessed as being the basis for the initial iUPD show 
worsening 
o For target lesions that had shown SOD increase from nadir of at least 20% and ≥5 
mm in total this is a further increase in the sum of diameters of ≥5 mm 
o For non-target lesions that had shown unequivocal growth worsening means any 
continued obvious growth in lesions overall tumor burden; this does not have to 
meet the “unequivocal” standard of RECIST 1.1 but as a guidance it should be 
approximately comparable with the definition for worsening of TL or NLT (i.e. 
SOD ≥5 mm) 
o For new lesions worsening is any of these: 
▪ An increase in the new lesions-target (NLT) sum of diameters by ≥5 mm  
▪ Obvious growth of new lesions-non-target (NLNT)  
▪ The appearance of additional new lesions 
• Any new factor appears that would have triggered PD by RECIST 1.1 
Persistent iUPD 
Progression is considered not confirmed, and the overall response remains iUPD, if: 
• None of the progression-confirming factors identified above occurs AND 
• The target lesion sum of diameters (initial target lesions) does not show any decrease 
beyond the initial PD threshold (by RECIST 1.1) 
If progression is not confirmed, imaging should continue as originally planned (e.g., if scans 
were to be done at 9, 18, and 27 weeks, and a confirmatory scan was done at 13 weeks, then 
the next scans should be done at 18 weeks and 27 weeks) with possible outcomes of iCPD, 
iUPD, and iSD/iPR/iCR or NE. 


 
 
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Resolution of iUPD 
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if: 
• None of the progression-confirming factors identified above occurs, AND 
• The target lesion sum of diameters (initial target lesions) does show a decrease beyond 
the initial PD threshold  
The response is classified as iSD (decrease of SOD < 30 % from baseline and increase < 20% 
from nadir) or iPR (decrease of SOD ≥ 30% from baseline) compared to baseline, or iCR if all 
lesions resolve. 
In this case, the initial iUPD is considered to be pseudoprogression, and the level of suspicion 
for progression is “reset”. This means that the next visit that shows radiographic progression, 
whenever it occurs, is again classified as iUPD by iRECIST, and the confirmation process is 
repeated before a response of iCPD can be assigned. 
Management Following the Confirmatory Imaging 
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
patient continues to be clinically stable, study treatment may continue and follow the regular 
imaging schedule. If PD per iRECIST is assessed by the investigator, patients will be 
discontinued from study treatment. 
Note: If a patient has confirmed radiographic progression (iCPD) as defined above, but the 
patient is achieving a clinically meaningful benefit, an exception to continue study treatment 
may be considered following consultation with the Sponsor. In this case, if study treatment is 
continued, tumor imaging should continue to be performed following the intervals as 
originally planned and submitted to the central imaging vendor. 
Detection of Progression at Visits after Pseudoprogression Resolves 
After resolution of pseudoprogression and tumor shrinkage (i.e., achievement of 
iSD/iPR/iCR), the bar is reset again and iUPD is indicated by any of the following events: 
• Target lesions 
o Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from 
nadir) either for the first time, or after resolution of previous 
pseudoprogression. The nadir is always the smallest sum of diameters seen 
during the entire trial, either before or after an instance of pseudoprogression. 
• Non-target lesions 
o If non-target lesions have never shown unequivocal progression, their doing so 
for the first time results in iUPD. 
o If non-target lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any obvious further growth of 
non-target lesions, taken as a whole. 


 
 
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• New lesions 
o New lesions appear for the first time 
o Additional new lesions appear 
o Previously identified new lesions-target (NLT) show an increase of ≥5 mm in 
the new lesion sum of diameters, from the nadir value of that sum 
o Previously identified new lesions-non-target (NLNT) show further obvious 
growth 
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging subsection above) is 
repeated.  
The decision process is identical to the iUPD confirmation process for the initial PD, with one 
exception: if new lesions occurred at a prior instance of iUPD, and at the confirmatory 
imaging the burden of new lesions has increased from its smallest value (for new target 
lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve to 
iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows 
resolution to iSD or iPR, or until a confirmatory factor causes iCPD. 
Additional details about iRECIST are provided in the Imaging Manual and the iRECIST 
publication (38). 
 
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. 
 


 
 
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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 (43): 
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 (44). 

SAP_001.pdf: 
Document Type: 
Statistical Analysis Plan 
 
Official Title: 
An international, multicenter, Phase 1b/2 study of rogaratinib 
(BAY1163877) in combination with atezolizumab as first-line 
treatment in cisplatin-ineligible patients with FGFR-positive 
locally advanced or metastatic urothelial carcinoma 
 
NCT Number: 
NCT03473756 
Document Date: 
05 APR 2022 
 


Statistical Analysis Plan Supplement
BAY 1163877/19131 Part A
Page: 1 of 18
Title page
An international, multicenter, Phase 1b/2 study of rogaratinib (BAY 
1163877) in combination with atezolizumab as first-line treatment in 
cisplatin-ineligible patients with FGFR-positive locally advanced or 
metastatic urothelial carcinoma
Phase 1b/2 study of rogaratinib (BAY 1163877) in combination with atezolizumab in 
urothelial carcinoma 
Bayer study drug
BAY 1163877 / rogaratinib / pan FGFR inhibitor
Study purpose:
Dose finding
Clinical study 
phase:
Ib
Date:
05 APR 2022
Study No.:
19131 – Part A
Version:
4.0
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 Supplement
BAY 1163877/19131 Part A
Page: 2 of 18
Table of Contents
Title page................................................................................................................................... 1
Abbreviations............................................................................................................................ 3
1.
Introduction....................................................................................................................... 4
2.
Study Objectives................................................................................................................ 5
3.
Study Design ...................................................................................................................... 5
4.
General Statistical Considerations .................................................................................. 7
4.1
General Principles............................................................................................................ 7
4.2
Handling of Dropouts ...................................................................................................... 7
4.3
Handling of Missing Data................................................................................................ 8
4.4
Interim Analyses and Data Monitoring ........................................................................... 8
4.5
Data Rules........................................................................................................................ 8
4.5.1
Baseline ........................................................................................................................ 8
4.5.2
Repeated Measurements............................................................................................... 8
4.5.3
Laboratory Values Outside the Calibration Range....................................................... 8
4.6
Blind Review ................................................................................................................... 9
5.
Analysis Sets ...................................................................................................................... 9
5.1
Assignment of analysis sets ............................................................................................. 9
6.
Statistical Methodology .................................................................................................. 10
6.1
Population characteristics .............................................................................................. 10
6.1.1
Subjects Validity and Disposition .............................................................................. 10
6.1.2
Demographics and Other Baseline Characteristics .................................................... 10
6.1.3
Prior and Concurrent Medication/Therapy................................................................. 10
6.1.4
Medical and Surgical History..................................................................................... 11
6.2
Efficacy.......................................................................................................................... 11
6.2.1
Primary Efficacy Variable.......................................................................................... 11
6.2.2
Secondary Efficacy Variable...................................................................................... 11
6.2.3
Exploratory Efficacy Variables .................................................................................. 12
6.2.4
Health-Related Quality of Life................................................................................... 13
6.3
Pharmacokinetics/ Pharmacodynamics.......................................................................... 13
6.3.1
Biomarker/ Pharmacodynamics.................................................................................. 13
6.3.2
Pharmacokinetics........................................................................................................ 14
6.4
Safety ............................................................................................................................. 14
6.4.1
Determination of MTD............................................................................................... 14
6.4.2
Adverse Events (AEs) ................................................................................................ 16
6.4.3
Clinical Laboratory Data ............................................................................................ 17
6.4.4
COVID-19 additional analysis ................................................................................... 17
6.4.5
Other Safety Data ....................................................................................................... 17
7.
Document history and changes in the planned statistical analysis............................. 17
8.
References ........................................................................................................................ 18


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Table of Tables
Table 6-1: Possible dose finding actions.................................................................................. 16
Table of Figures
Figure 3-1: Study 19131 Part A – Design overview.................................................................. 6
Abbreviations
A
Asian
AE
Adverse event
AJCC
American Joint Committee on Cancer
B
Black
b.i.d./BID
bis in die (twice daily)
BL
Baseline
Cmax
Maximum observed drug concentration in measured matrix after single dose
CI
Confidence interval
CR
Complete response
CV
Coefficient of variation
DCR
Disease control rate
DLT
Dose-limiting toxicity
DOR
Duration of repsonse
e.g.
exempli gratia (for example)
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EFS
Efficacy analysis set
EORTC QLQ-C30
European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30
F
Female
FGFR
Fibroblast growth factor receptor
i.e.
id est (that is)
ICF
Informed consent form
iCPD
Confirmed progressive disease according to iRECIST
iRECIST
Response Evaluation Criteria in Solid Tumors Modified for Immune-based Therapeutics
iUPD
Unconfirmed progressive disease according to iRECIST
KM
Kaplan Meier
LLOQ
Lower limit of quantification
M
Male
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
mRNA
Messenger ribonucleic acid
MTD
Maximum tolerated dose
mTPI
Modified toxicity probability interval
NA
Not applicable
NCI CTCAE
National Cancer Institute’s Common Terminology Criteria for Adverse Events
NE
Not evaluable
NR
Not reported
ORR
Objective response rate
OS
Overall survival
PFS
Progression-free survival
PD
Progressive disease
PD-1
Programmed death protein 1
PD-L1
Programmed death-ligand 1
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic analysis set
PR
Partial response


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PRO
Subject-reported outcomes
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
Recommended phase 2 dose
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical analysis plan
SAS
Statistical Analysis System
SD
Stable disease
TA
Tumor assessment
TCGA
The Cancer Genome Atlas
TEAE
Treatment-emergent adverse event
TEADR
Treatment-emergent drug-related adverse events
TNM
Classification of Malignant Tumors (T = tumor, N = lymph node, M = metastasis)
tlast
Time of last plasma concentration above LLOQ
tmax
Time to reach Cmax (in case of two identical Cmax values, the first tmax will be used)
UPM
Unit probability mass
W
White
WHO-DD
World Health Organization – Drug Dictionary
1.
Introduction
This Statistical Analysis Plan (SAP) is based on the Clinical Study Protocol No. BAY 
1163877 / 19131, Version 4.0, dated 04 OCT 2021 [1].
The study 19131 is planned to evaluate the safety, tolerability, pharmacokinetics (PK) and 
efficacy of oral twice daily rogaratinib in combination with atezolizumab in subjects with 
fibroblast growth factor receptor (FGFR)-positive locally advanced or metastatic urothelial 
carcinoma who are cisplatin-ineligible and have had no prior systemic treatment for locally 
advanced or metastatic disease.
Urothelial cancer is a highly immunogenic tumor, in large part as a result of the relatively 
high level of mutations, which represents at least one of the mechanisms for the generation of 
tumor neo-antigens for the host immune system to recognize. Programmed death-ligand 1 
(PD-L1) overexpression in the tumor microenvironment and its binding to programmed death 
protein 1 (PD-1) on tumor antigen-specific T cells is a mechanism for immune escape in 
urothelial cancer.
Dysregulation of FGFRs has been identified in bladder cancer as compared with normal
bladder. Increased expression was associated with mutation, 85% of mutant tumors showed 
high level expression, overall 42% of tumors with no detectable mutation showed over-
expression including many muscle invasive. This may represent a non-mutant subset of 
tumors in which FGFR3 signaling contributes to the transformed phenotype and which may 
benefit from FGFR-targeted therapy. 
It was shown that FGFR3 expression is associated with a non-T-cell-inflamed phenotype in 
tumor tissue of subjects with urothelial bladder cancer. Expression analysis of PD-L1 in 
archival biopsy samples collected in study 16443, showed that PD-L1 level is lower in 
subjects with FGFR mRNA overexpression. A similar correlation was detected in subjects 
with non-small-cell lung carcinoma using publically available TCGA data sets. It is assumed 
that a causal relationship between FGFR expression and T-cell exclusion leads to the 
observed findings and to a poorer response to inhibition of the PD-L1 axis by recently 
approved checkpoint inhibitors. Potentially, inhibition of FGFR can overcome this interaction 
and render tumors targetable by the immune system.


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Atezolizumab is a PD-L1 antibody that demonstrated durable responses in urothelial bladder 
cancer as first-line and second-line treatment for subjects with locally advanced or metastatic 
urothelial carcinoma. It is assumed that subjects with FGFR overexpression exhibit a poorer 
response to atezolizumab treatment based on the non-T-cell-inflamed phenotype. Therefore it 
is suggested, that a combination of rogaratinib and atezolizumab can overcome this immune 
evasion improving immune-checkpoint inhibitor efficacy and disease response.
2.
Study Objectives
Study 19131 originally comprised two separate parts: Phase 1b (Part A) and Phase 2 (Part B). 
The study parts differ in design, objectives, and treatment. Part B of the study will no longer 
be conducted. 
The primary objectives of this Part A of the study are:

To determine the safety and tolerability of rogaratinib in combination with 
atezolizumab in subjects with FGFR-positive locally advanced or metastatic urothelial 
carcinoma.

To determine the recommended Phase 2 dose (RP2D) of rogaratinib in combination 
with atezolizumab in this subject population.
The secondary objectives of this Part A of the study are:

To assess the efficacy of the combination of rogaratinib and atezolizumab in this 
subject population.

To characterize the PK of rogaratinib in combination with atezolizumab in this subject
population.
The exploratory objectives of this Part A of the study are:

To assess new potential predictive or prognostic biomarkers and their association with 
tumor-related biomarkers, disease response, drug-resistance and subject outcome. 

To evaluate further biomarkers to investigate the drug (i.e. mode-of-action-related 
effect and / or safety) and / or the pathomechanism of the disease.

To evaluate the combination of rogaratinib and atezolizumab with regard to subject-
reported outcomes (PRO).
3.
Study Design
This study 19131 Part A is an open-label, single-arm, international, multicenter, Phase 1b 
study of rogaratinib in combination with atezolizumab in subjects with FGFR-positive locally 
advanced or metastatic urothelial carcinoma. 
The primary objectives of this Phase 1b study (Part A) are to determine the safety, 
tolerability, RP2D and PK of rogaratinib in combination with atezolizumab in these subjects. 
For all study objectives, see Section 2.
Before entering the screening, subjects are to be tested for FGFR1 and 3 mRNA expression 
levels. Only subjects with FGFR-positive tumors (RNA scope score of +3 or +4) can enter the 
study. 
The study will comprise the following periods:

Pre-treatment period, including FGFR testing and screening,


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
Treatment period, and 

Follow-up period, including active follow-up and long-term follow-up. 
An overview of the study design is presented in Figure 3-1.
The study is conducted in subjects who are cisplatin-ineligible and have had no prior systemic 
treatment for locally advanced or metastatic disease.
Treatment is divided into cycles. A cycle consists of 21 days of BAY 1163877 twice daily.
Subjects will receive rogaratinib plus atezolizumab combination treatment.
Figure 3-1: Study 19131 Part A – Design overview
FGFR = Fibroblast growth factor receptor
a: Only FGFR positive subjects can enter screening.
b: Safety information is collected for all discontinued subjects for at least 30 (up to +7) days after the last administration of study 
treatment, and both safety and efficacy information is collected for subjects who discontinue study treatment without radiological 
disease progression.
Dose selection
The dose selection part of the study 19131 will assess the safety and tolerability of the 
combination. The maximum tolerated dose (MTD) will be determined by using stepwise dose 
selection design based on a modified toxicity probability interval (mTPI) method. Dose 
selection will stop after 20 valid subjects are available, and are evaluable for the MTD 
assessment. At the end of the DLT observation period of 20 subjects, the recommendations 
from the mTPI method will be regarded as guidance and will be integrated with the clinical 
assessments of the available PK and safety data to determine the MTD. A total of 
approximately 26-30 evaluable subjects will be enrolled to obtain additional safety data for
confirming the MTD and to determine the RP2D that will be used in the Part B of the study. 
The mTPI provides a practical dose-finding scheme guided by the posterior inference for a 
simple Bayesian model. The MTD is defined as the highest dose level that could be given so 
that the toxicity probability is closest to 30%. The starting dose of rogaratinib will be 800 mg 
b.i.d. Initially, at least 4 (4-6) subjects will be enrolled. The next group of subjects will be 
enrolled once the decision regarding the next dose level is made based on all available PK and 
safety data and the occurrence of DLTs. The decision about time of enrollment and the 
number of subjects evaluable for DLTs on a dose level will be made by the sponsor in 
consultation with investigators during regularly held safety calls. For details on what 
constitute DLTs, please refer to Section 7.4.3.1 of the protocol.
Safety will be regularly assessed during each cycle for potential adverse events, DLTs and 
disease-related signs and symptoms. Rogaratinib dosing will be interrupted/delayed or 
reduced in case of clinically significant toxicities. Atezolizumab dosing will not be adjusted, 


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however dosing will be interrupted or delayed in case of clinically significant toxicities. For 
more detailed information on dose modifications see Section 7.4.3 of the protocol.
The mTPI method will recommend de-escalation, re-escalation or expansion of the current 
dose level on basis of the observed DLTs. The first dose finding action on a dose level will be 
performed after at least 4 subjects are available on that dose level and are evaluable for DLTs. 
The possible dose finding actions are ‘E’=escalate to next higher dose level (800 mg b.i.d. 
being the highest possible dose), ‘S’=stay at the current dose level, ‘D’=de-escalate to next 
lower dose level and ‘DU’= de-escalate to next lower dose level and exclude the current and 
higher dose levels from the further dose escalation due to unacceptably high toxicity. If the 
probability that a dose is above the MTD is greater than 95%, the dose will be declared as 
toxic and only lower doses will be given in subsequent cohorts. If the highest dose is reached, 
escalation (‘E’) leads to staying at that dose. At the lowest dose level de-escalation (‘D’) or 
de-escalation with unacceptable high toxicity (‘DU’) lead to stop of the study. Details are 
provided in Section 6.4.1.
Intra-subject dose escalation is not permitted. Part B will start once safety and efficacy data 
are found to support study continuation.
4.
General Statistical Considerations
4.1
General Principles
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 mean, standard deviation, minimum, median, and maximum will be calculated for metric 
data. Frequency tables will be generated for categorical data.
Due to the exploratory character of this Part A of the study, no confirmatory analysis will be 
performed. All calculated p-values and confidence intervals are to be interpreted in the 
exploratory sense.
Data displays will follow the standard table catalogs for oncology standards, global standards, 
and clinical pharmacology standards, respectively.
All summaries will be performed by dose group. The dose groups “Rogaratinib XX mg BID+ 
Atezolizumab” will be analyzed, in which “XXmg” stands for the assigned dose. Pooled 
summary statistics (or frequency counts) will be provided where appropriate. Listings will 
also be provided by dose group.
4.2
Handling of Dropouts
Pre-screening failure = Subject signed ICF for FGFR testing but, for any reason, did not sign 
the ICF for study treatment eligibility.
Screening failure = Subject signed ICF for study treatment eligibility but, for any reason (e.g. 
failure to satisfy the selection criteria), terminated the study before start of study treatment.
Dropout = Subject discontinued study participation prematurely for any reason after start of 
study treatment. The start of the treatment period is defined by the first administration of 
study treatment.


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Replacement of subjects may occur in Part A in order to ensure the necessary number of 
evaluable subjects for dose selection (at least 4 subjects per tested dose level, a total of 20 
evaluable subjects) and to ensure at least 26 valid subjects for assessment of the RP2D.
Subjects maybe replaced in the following circumstances:
Dose selection:
Subjects who discontinue or took less than 80% of the per protocol required total dose of 
either study drug (rogaratinib or atezolizumab) during the first cycle due to any reason 
other than a DLT (note: protocol-defined dose reductions will not be considered 
incompliant). 
Efficacy:
Subjects who took less than 80% of the per protocol required total dose of either study 
drug (rogaratinib or atezolizumab) during the first two cycles or subjects without an 
efficacy assessment.
4.3
Handling of Missing Data
Missing data will not be replaced. Analyses will be performed considering all data observed 
for the respective analysis sets.
All missing or partial data will be presented in the subject data listing as they are recorded on 
the Case Report Form. 
4.4
Interim Analyses and Data Monitoring
Safety data will be reviewed on an ongoing basis during this study. Additional analysis, as 
Bayesian dose-response and / or PK / PD modeling of DLTs rates and CTCAE version 4.03 
gradings may be performed on selected groups of subjects in order to generate additional 
relevant information for the adaptive dose selection decisions. The sponsor together with all 
investigators will review all available data and make the final decision as to dose escalation, 
de-escalation or group expansion during the adaptive dose selection part. This group of 
sponsor and investigators will also determine when to implement predefined stopping rules.
No formal interim analysis of the data collected during Part A is planned.
4.5
Data Rules
4.5.1
Baseline
The baseline values will be the latest valid pre-administration available value.
4.5.2
Repeated Measurements
If control measurements for a planned timepoint before study drug administration are 
available, the last value (i.e. of the measurement closest to the study drug administration) will 
be used for the calculation of descriptive statistics. If control measurements for a planned time 
point after study drug administration are available, the first value (i.e. of the planned 
measurement) will be used for the calculation of descriptive statistics. 
4.5.3
Laboratory Values Outside the Calibration Range
Means at any time will only be calculated if at least 2/3 of the individual data were measured
and were above the lower limit of quantification (LLOQ). For the calculation of the mean 
value a data point below LLOQ will be substituted by one half of this limit. In tables showing 


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mean values, where values below LLOQ are included in the calculation of mean values, these 
means will be marked. Differences (e.g. changes from baseline) will only be calculated if at 
least one measurement is not substituted.
4.6
Blind Review
This phase 1 study is performed in a non-blinded design because this is considered adequate 
to meet the study objectives.
The results of the validity review meeting will be documented in the Validity Review Report 
and may comprise decisions and details relevant for statistical evaluation. Any changes to the 
statistical analysis prompted by the results of the validity review meeting will be documented 
in an amendment and, if applicable, in a supplement to this SAP or will be documented in the 
clinical study report.
5.
Analysis Sets
5.1
Assignment of analysis sets
Final decisions regarding the assignment of subjects 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).
All subjects who signed the informed consent form (ICF) for FGFR testing will be included in 
the ‘All enrolled subjects’ evaluations. All subjects assigned to treatment will be included in 
the ‘All subjects assigned to treatment’ evaluations.
Safety analysis set (SAF) 
All subjects who received at least one dose of study drug (i.e. rogaratinib or atezolizumab)
and have post-treatment safety data available will be included in the safety evaluation.
MTD analysis set (MTD)
All subjects who completed Cycle 1 and who took at least 80% of the required total dose 
(protocol-defined dose reductions will not be considered incompliant) of either study drug 
(rogaratinib or atezolizumab) during Cycle 1 or discontinued during Cycle 1 due to a DLT 
will be included in the MTD evaluation.
Only subjects from the dose selection part are to be considered for the MTD analysis set. 
Efficacy analysis set (EFS)
All subjects who have received at least one dose of study drug and who have post-baseline 
efficacy data available will be included in the efficacy evaluation.
Pharmacokinetics analysis set (PKS) 
All subjects who have received at least one dose of study drug and with at least one valid 
concentration after first dosing and no important protocol deviations affecting the validity will 
be included in the PK evaluation.


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6.
Statistical Methodology
6.1
Population characteristics
Analysis for population characteristics will be performed on the SAF, unless otherwise 
specified.
6.1.1
Subjects Validity and Disposition
The number of subjects enrolled and included in each analysis set will be tabulated by region, 
country and center. The number of countries and study centers will be presented. A summary 
table will also be presented for the number of subjects enrolled and the number and 
percentage of subjects in each of the defined analysis sets. The reasons for subjects excluded 
from each of the analysis sets will also be tabulated. In addition, the number of subjects who 
were enrolled, treated and discontinued will be summarized. Reasons for discontinuation of 
study treatment will be tabulated. Important deviations will be summarized using frequency 
tables. These analyses will be performed on appropriate analysis sets like ‘All subjects 
assigned to treatment’ or ‘All enrolled subjects’.
6.1.2
Demographics and Other Baseline Characteristics
Summary statistics (arithmetic mean, standard deviation, median, minimum and maximum for 
quantitative variables) and frequency counts (for qualitative data) will be provided for 
demographics. 
Demographics variables include sex, race, ethnicity, region, age in years (as reported in the 
CRF), weight, height and body mass index (BMI). If the PKS, MTD analysis set or EFS differ 
from the SAF, summary statistics and frequency tables for PKS and/or MTD analysis set 
and/or EFS will be provided as well.
Medical history findings will be summarized using MedDRA (Medical Dictionary for 
Regulatory Activities) terms (version 20.0 or later).
Cancer baseline characteristics will also be summarized. Variables include for example 
baseline Eastern Cooperative Oncology Group (ECOG) Performance Status, number of target 
lesions, number of non-target lesions, cancer type, histology, grade at initial diagnosis, stage 
at study entry, time since initial diagnosis. Please note that the list of the above mentioned 
parameters may not be exhaustive.
In addition, demographics (sex, race, ethnicity and age) and cancer baseline characteristics 
will be summarized for all subjects who signed the ICF for FGFR testing (“all enrolled 
subjects”).
6.1.3
Prior and Concurrent Medication/Therapy
Prior anti-cancer therapy and surgical therapeutic procedures will be summarized. The counts 
and percentages of subjects who were previously treated using radiotherapy, local anti-cancer 
therapy, systemic anti-cancer therapy, and who had any diagnostic and therapeutic  
procedure(s) will be presented. The number of subjects with radiotherapy and systemic or 
local anti-cancer therapy will be presented by intent of procedure and number of 
regimens/procedures. In addition, concurrent radiotherapy, diagnostic and therapeutic 
procedures will be summarized. Systemic anticancer therapy and type of systemic anticancer 
therapy during follow-up will be summarized. Immunotherapy during follow-up will be 
listed. Prior and concomitant medications will be coded to generic terms using the World 
Health Organization Drug Dictionary (WHO-DD) version 2005/Q3 or later and will be 


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provided in two tables, one for 'Prior medication' (i.e. medications that are ongoing at, or 
began before the start of study drug) and one for 'Concomitant medication' (i.e. medications 
that are ongoing at, or began after the start of study drug). The version used in analyses will 
be presented in the clinical study report.
6.1.4
Medical and Surgical History
Medical history findings will be summarized by primary system organ class, high level term 
and preferred term of MedDRA version 20.0 or later. The version used in analyses will be 
presented in the clinical study report.
6.2
Efficacy
Efficacy analyses will be performed on the EFS, unless otherwise specified.
All efficacy variables evaluated using the Response Evaluation Criteria in Solid Tumors
(RECIST) version 1.1 are linked to the secondary and exploratory objectives of the study Part 
A. All variables evaluated using the Response Evaluation Criteria in Solid Tumors Modified 
for Immune-based Therapeutics (iRECIST) version 1.1 are exploratory only.
Efficacy data will be summarized using descriptive statistics and will be graphically displayed 
if appropriate. The correlation between pharmacodynamic parameters and selected safety, 
efficacy, or PK parameters may be graphically displayed. Further statistical analyses may be 
conducted.
Response as defined by RECIST version 1.1: complete response (CR), partial response (PR), 
stable disease (SD), progressive disease (PD). Response and progression will be evaluated in 
this trial using the new international criteria proposed by the RECIST committee for solid 
tumor.
iRECIST defines new response categories, including iUPD (unconfirmed progressive disease) 
and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, the first 
visit showing progression according to RECIST 1.1 will be assigned a visit (overall) response 
of iUPD, regardless of which factors caused the progression.
Best overall tumor response according to RECIST criteria will be summarized using 
frequency counts. Best % change in Target Lesion sum of diameter from baseline will be 
displayed graphically for all subjects from worst to best in a waterfall plot.
6.2.1
Primary Efficacy Variable
Not applicable.
6.2.2
Secondary Efficacy Variable
The efficacy variable linked to the secondary objective of this study is the objective response 
rate.


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Objective response rate (ORR) is defined as the percentage of subjects whose best response 
is either a CR or PR. Subjects for whom best tumor response is not CR or PR, as well as 
subjects without any efficacy assessment will be considered non-responders. According to 
RECIST version 1.1, confirmation of PR and CR is not required considering the nature of the 
study and the protocol requirements.
6.2.3
Exploratory Efficacy Variables
Exploratory efficacy variables defined according to RECIST version 1.1 will include disease 
control rate (DCR), duration of response (DOR), progression-free survival (PFS) (according 
to both RECIST and iRECIST), time to progression (TTP), time to response (TTR), overall 
survival (OS) and follow-up time.
These variables are defined as below:
Follow-up time is defined as the time from the date of first study treatment until death or the 
date of last contact, if the subject is still alive at the time of analysis.
Disease control rate (DCR) is defined as the percentage of subjects 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 assignment to treatment
of the subject (i.e. substantially earlier than the first planned radiological tumor assessment at 
9 weeks), will not be taken into account.
Duration of response (DOR) (for PR and CR) is defined as the time (days) 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. subjects with a CR or PR. The actual dates the tumor scans were 
performed will be used for this calculation. DOR for subjects who have not progressed or died 
at the time of analysis will be censored at the date of their last tumor assessment.
Kaplan-Meier (KM) product-limit estimates for median, 25th and 75th percentile with its 95% 
CI together with total number of subjects, total censored and total events will be provided for 
DOR per dose group. In addition KM survival curves will be presented for each dose group.
Progression-free survival (PFS) is defined as the time (days) from start of study treatment to 
date of first observed disease progression (investigator’s 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 the same evaluation), the earliest date will be used for the calculation of PFS. For subjects 
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.
Kaplan-Meier (KM) product-limit estimates for median, 25th and 75th percentile with its 95% 
CI together with total number of subjects, total censored and total events will be provided for 
PFS per dose group. In addition KM survival curves will be presented for each dose group.
Overall survival (OS) is defined as the time (days) from start of study treatment to death due 
to any cause. Subjects alive at the date of data cut-off for analysis will be censored at the last 
date known to be alive. If a subject is lost to follow-up before any assessment after 
assignment to treatment, this subject will be censored at day 1.


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KM product-limit estimates for median, 25th and 75th percentile with its 95% CI together 
with total number of subjects, total censored and total events will be provided for OS per dose 
group. In addition KM survival curves will be presented for each dose group.
Time to progression (TTP) is defined as the time (days) from start of study treatment to date 
of first observed disease progression (radiological or clinical). TTP for subjects without 
disease progression at the time of analysis will be censored at the last date of tumor 
evaluation. TTP for subjects who have no tumor assessments after baseline will be censored 
at day 1.
KM product-limit estimates for median, 25th and 75th percentile with its 95% CI together 
with total number of subjects, total censored and total events will be provided for TTP. In 
addition KM survival curves will be presented for each dose group.
Time to Response (TTR) is defined as the time (days) from start of study treatment to the 
date of first observed partial or complete response. Only subjects with a partial or complete 
response are considered for TTR.
KM product-limit estimates for median, 25th and 75th percentile with its 95% CI together 
with total number of subjects, total censored and total events will be provided for TTR. In 
addition KM survival curves will be presented for each dose group.
6.2.4
Health-Related Quality of Life
Subjects’ health-related quality of life and health utility values will be measured using the 
EORTC QLQ-C30. A PRO information sheet will be provided and completed by the study 
nurse/investigator at each visit in which the protocol requires the questionnaires to be 
administered, whether or not the questionnaire was completed by the subject, in order to 
document information on questionnaire assessment such as questionnaire completion, date of 
completion, if assistance was needed, and reasons for non-completed questionnaires.
The EORTC QLQ-C30 includes 5 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. 
For the majority of the EORTC QLQ-C30 items a 4-point Likert-type response scale is used. 
The only exception is the global health status/quality of life scale in which a 7-point Likert-
type scale is used. For ease of interpretation, all scales and individual item responses are 
linearly converted to a 0 to 100 scale. For the functional and global quality of life scales a 
higher score represents better level of functioning. However in regard to symptom scales and 
single items a higher score reflects a greater degree of symptomatology. Summary statistics 
and changes from baseline by visit will be provided for EORTC QLQ-C30 for day 1 of each 
cycle, end of treatment visit and active follow-up based on the efficacy analysis set.
6.3
Pharmacokinetics/ Pharmacodynamics
6.3.1
Biomarker/ Pharmacodynamics
Retrospective exploratory biomarker/ pharmacodynamic data may be summarized using 
descriptive statistics and may be graphically displayed if appropriate. All pharmacodynamics 
analysis may be performed on the SAF population. The correlation between biomarker or 
pharmacodynamic parameters and selected safety, efficacy, or PK parameters may be 


Statistical Analysis Plan Supplement
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evaluated and graphically displayed. Further exploratory statistical analyses may be 
conducted. Biomarker data and analyses may be reported separately.
6.3.2
Pharmacokinetics
Analyses will be performed on the PKS.
The concentration-time courses of rogaratinib in Cycle 1 will be tabulated. The following 
statistics will be calculated for each of the sampling points: arithmetic mean, standard 
deviation and coefficient of variation (CV), geometric mean, geometric standard deviation 
(re-transformed standard deviation of the logarithms) and CV, minimum, median, maximum 
value and the number of measurements. Means at any time will only be calculated if at least 
2/3 of the individual data were measured and were above the lower limit of quantification 
(LLOQ). For the calculation of the mean value a data point below LLOQ will be substituted 
by one half of this limit. In tables showing mean values, where values below LLOQ are 
included in the calculation of mean values, these means will be marked.
Individual and geometric mean concentration vs. time curves of all analytes (using the actual 
sampling times for individual plots and the planned sampling times for mean plots) will be 
plotted using both linear and semilogarithmic scale.
PK characteristics (tmax , tlast , Rstart, Rend, points terminal and %AUC [tlast-∞] excluded) will be 
summarized by the statistics mentioned above. tmax and tlast will be described utilizing 
minimum, maximum and median as well as frequency counts. 
Concentration data from cycle 2 to 5 of rogaratinib and all concentration data of 
Atezolizumab will only be listed.
6.4
Safety
Analyses will be performed on the SAF, unless otherwise specified.
Duration of treatment will be summarized using summary statistics. Actual dose, total amount 
of dose, and percent of planned dose during study period will be also summarized. Dose 
modification will be summarized.
6.4.1
Determination of MTD
The objective of the dose selection phase is to determine the MTD or confirm that the start 
dose level of rogaratinib (800 mg b.i.d.) is safe. The MTD is defined as the highest dose that 
can be given so that toxicity probability is closest to the target toxicity PT=30%. Estimation of 
the MTD will be based on the estimation of the observed dose dependent incidence rate of 
DLT in the first 21 days of dosing.
The modified toxicity probability interval (mTPI) design will be applied to guide the dose 
selection decisions in the study. The equivalence interval of the toxicity probability for the 
MTD is set to [25%, 35%], in which any dose with a toxicity probability falling into this 
interval is considered as an estimate close to the true MTD. The dose selection part will be 
finished after 20 subjects are evaluable for the MTD assessment. A beta-binomial Bayesian 
model with Beta(1,1) prior will be used to compute the posterior probabilities that the true 
rate of DLT is contained in each of the 3 toxicity intervals:

[0, 25%]
under-dosing (below the MTD)

[25%, 35%]
target dosing (close to the MTD)

[35%, 100%] over-dosing (above the MTD)


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The mTPI method calculates the unit probability mass (UPM) for above intervals with safety 
rules to stop due to excessive toxicity. In addition doses that are estimated to have excessive 
toxicity will be excluded from the trial. 
The UPM for a given interval is defined as the probability of the interval divided by the 
length of the interval. Then an appropriate dose-finding action will be chosen based on the 
interval with the largest UPM. Specifically, if the UPM for the under-dosing interval is the 
largest, the dose is considered lower than the MTD and the recommendation is to escalate to 
the next higher dose (800 mg b.i.d. being the highest possible dose) or to stay on the dose 
level if current dose is the highest possible dose (letter E in Table 6-1); if the target dosing 
interval has the largest UPM, the mTPI design will recommend remaining at the current dose 
(letter S in Table 6-1); if the over-dosing interval has the largest UPM, the design will 
recommend de-escalating to the previous lower dose (letter D in Table 6-1). If the safety 
stopping rule is met, the toxicity of the current dose will be considered as unacceptable high 
and never be used again in the remainder of the trial (letters DU in Table 6-1). The safety rule 
is triggered if the posterior probability that the current dose is above the MTD is greater than 
95%. All of these rules are summarized and precalculated in Table 6-1 below. No decision is 
made before data of at least 4 subjects are available on the first dose level and are evaluable 
for DLTs. The sponsor in consultation with the investigators will decide how many additional 
subjects need to be evaluable for DLTs on the same dose level before the next decision. 
The decision on the number of additional subjects and on the next dose level will be based on 
the recommendations from the mTPI, clinical assessment, all available PK and safety data. 
The dose selection part will be finished after 20 subjects are evaluable for DLT assessment 
and are available for the MTD determination. The RP2D will be defined once sufficient data 
is available. The final decision about the RP2D will be made by the sponsor in consultation 
with the investigators.


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Table 6-1: Possible dose finding actions
Number of subjects treated at current dose
Number of
subjects 
with 
observed
DLTs
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
0
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
1
S
S
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
2
S
S
S
S
S
S
S
E
E
E
E
E
E
E
E
E
E
3
DU
D
S
S
S
S
S
S
S
S
S
S
E
E
E
E
E
4
DU
DU
DU
D
D
S
S
S
S
S
S
S
S
S
S
S
S
5
DU
DU
DU
DU
DU
D
S
S
S
S
S
S
S
S
S
S
6
DU
DU
DU
DU
DU
DU
D
S
S
S
S
S
S
S
S
7
DU
DU
DU
DU
DU
DU
DU
D
S
S
S
S
S
S
8
DU
DU
DU
DU
DU
DU
DU
DU
DU
D
S
S
S
9
DU
DU
DU
DU
DU
DU
DU
DU
DU
DU
DU
S
10
DU
DU
DU
DU
DU
DU
DU
DU
DU
DU
DU
11
DU
DU
DU
DU
DU
DU
DU
DU
DU
DU
12
DU
DU
DU
DU
DU
DU
DU
DU
DU
13
DU
DU
DU
DU
DU
DU
DU
DU
14
DU
DU
DU
DU
DU
DU
DU
15
DU
DU
DU
DU
DU
DU
16
DU
DU
DU
DU
DU
17
DU
DU
DU
DU
18
DU
DU
DU
19
DU
DU
20
DU
The column represents the number of subjects treated at a given dose level in the trial. Each row represents the number of 
subjects treated at the dose level and who have experienced dose-limiting toxicity (DLT) events. The letters in each cell 
provides the dose-assignment decision based on the data readout from the row and column numbers.
E: Escalate to the next higher dose (or stay if current dose is the highest possible dose)
S: Stay at the same dose
D: De-escalate to the previous lower dose (or stop if current dose is lowest possible dose)
DU: De-escalate to the previous lower dose and the current dose will never be used again.
6.4.2
Adverse Events (AEs)
Individual listings of AEs will be provided. AEs will be reported using MedDRA terms 
(version 20.0 or later) and graded according to NCI CTCAE version 4.03. 


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AEs will be considered to be treatment-emergent if they have started or worsened after first 
administration of study drug up to 30 days after the last dose of rogaratinib or 90 days after 
the last atezolizumab administration, whichever comes later.
The incidence of treatment-emergent adverse events (TEAEs), drug-related adverse events 
(TEADRs), treatment-emergent and drug-related serious adverse events (SAEs), respectively, 
will be summarized by MedDRA system organ class and worst NCI-CTCAE grade. TEAEs, 
SAEs, TEADRs, and drug-related SAEs for events of Grade 3/4/5 will be summarized 
similarly.
Subject listings of all AEs, SAEs, AESI, TEAEs leading to dose reduction, TEAEs leading to 
dose interruption, TEAEs leading to discontinuation, AEs leading to DLTs and deaths will be 
presented. For death, two listings (“during treatment and within 30 days post permanent 
treatment discontinuation” and “after 30 days post permanent treatment discontinuation”) will 
be provided.
6.4.3
Clinical Laboratory Data
The incidence of laboratory data outside the reference range (low, high) will be summarized 
in frequency tables. The incidence of hematological and biochemical laboratory values will be 
summarized by worst NCI CTCAE version 4.03 grade. Frequency tables will be provided for 
the changes of worst NCI CTCAE version 4.03 grade after start of treatment versus baseline
and under treatment Descriptive statistics (number of observations, mean, standard deviation, 
minimum, median and maximum values) will be presented for clinical laboratory tests 
(hematology, general chemistry and coagulation), their changes from baseline (including 
baseline value). Mean and standard deviation will be graphically displayed as well.. The 
number of subjects with urinalysis results will be tabulated by visit. Subjects will also be 
presented subdivided into classes according to their calcium phosphate product lower than 70 
mg2/dL2 and equal to or higher than 70 mg2/dL2.
6.4.4
COVID-19 additional analysis 
Due to the global pandemic, listings of all COVID-19 related important PDs, COVID-19 
related study disruptions and subjects with COVID-19 related AEs will be provided.
6.4.5
Other Safety Data
Quantitative data (such as vital signs, electrocardiogram) will be described by the following 
summary statistics: arithmetic mean, standard deviation, median, minimum and maximum. 
These summary statistics will be presented for the original data as well as for the difference to 
baseline. Frequency tables will be provided for qualitative data, such as ECG findings and 
interpretation.
The average of triplicate quantitative ECG parameters at all ECG time points will be used for 
all analyses.
ECOG performance status will be summarized by visit for observed values and changes from 
baseline using summary statistics.  Ophthalmologic interpretation will be tabulated in 
frequency tables. 
Number of women taking a pregnancy test and the result will be tabulated by visit.
7.
Document history and changes in the planned statistical analysis

SAP, Version 1.0, 19 JUN 2018


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Page: 18 of 18

SAP Amendment, 02 APR 2020

Wording was harmonized throughout the document;

Added wording changes from protocol amendment 2;

Added definitions for pre-screening failures and screening failures;

Added information on the validity review meeting; 

Clarified that only subjects from the dose selection part are to be 
considered for the MTD analysis set;

Planned analysis for prior immunotherapy, duration of treatment, TTP, 
dose modifications;

Added plan for the biomarker/pharmacodynamics analysis.

SAP Amendment, 05 OCT 2021

PK concentration data of only rogaratinib (previously also atezolizumab) 
will be tabulated in Cycle 1

Addition of TTR definition

Addition of Covid-19 analyses

Wording change: patient replaced by subject

Specification of CSP reference: Section 7.4.3

SAP Supplement, 05 APR 2022

Section 2: Addition of wording about part B not being conducted

Section 6.1.1: Addition of presentation of countries and study centers

Section 6.1.2: Deletion of NYHA in demographic variables

Section 6.1.2: Deletion of status of primary tumor and clinical status at 
study entry in cancer baseline characteristics

Section 6.1.3: Addition of wording about therapies during follow-up

Section 6.2.3: Addition of Follow-up time definition and more detailed 
wording

Section 6.2.4: Addition of visits of the summary statistics of EORTC QLQ-
C30 and the analysis set

Section 6.4.2: Deletion of frequency tables for change of CTCAE grade 
from pre-treatment

Section 6.4.3: Deletion of listing of laboratory data outside the reference 
range with abnormal values flagged

Section 6.4.3: Addition of more details about clinical laboratory data
analysis

Section 6.4.5: Addition of more details about other safety data
8.
References
[1] Clinical Study Protocol No. BAY 1163877 / 19131, version 4.0, 04 Oct 2021