Clinical trial NCT01976741
Conditions: Neoplasms
Keywords: Phase I Dose escalation refractory, locally advanced or metastatic solid tumor Bladder cancer squamous non-small cell lung cancer pan-FGFR inhibitor lung adenocarcinoma head and neck cancer
Sponsor: Bayer
Start date: 2013-12-30; Completion date: 2020-01-09
Enrollment: 168 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
* This was the first study where BAY1163877 was given to humans. Impact of the study was to evaluate if patients with advanced solid cancers show advanced clinical benefit under the treatment with the pan FGFR inhibitor. Patients (all comers) received the study drug treatment in a dose-escalation scheme (no placebo group) to determine the safety, tolerability and maximum tolerated dose (MTD) of BAY1163877. The relative bioavailability of liquid service formulation and tablets was determined.
* After the MTD was defined patients with solid tumors (all comers), lung cancer (lung adenocarcinoma \& squamous non-small cell lung cancer), head and neck cancer or bladder cancer was enrolled according to their FGFR expression profile (biomarker stratification).
* The study also assessed the pharmacokinetics, biomarker status, pharmacodynamic parameters and tumor response of BAY1163877.
* BAY1163877 was given twice daily as oral application. Treatment was stopped if the tumor continued to grow, if side effects, which the patient cannot tolerate, occurred or if the patient decided to exit treatment.

Detailed description:

Arms: arm 1: Participants with any type of solid tumor received escalating doses of Rogaratinib oral solution or tablet. The actual dose-escalation cohorts were 100 mg (50 mg BID), 200 mg (100 mg BID), 400 mg (200 mg BID), 800 mg (400 mg BID), 1200 mg (600 mg BID), and 1600 mg (800 mg BID). The participants in the 100 mg and 200 mg dose-escalation cohorts received oral solution and the participants in all the subsequent dose-escalation cohorts received tablet. And as an exception, on C1D-3 in the 200 mg dose-escalation cohort, the participants received tablet instead of oral solution. arm 2: Participants with cancer types other than bladder cancer (BC), squamous cell carcinoma of the head and neck (SCCHN), and squamous non-small cell lung cancer (sqNSCLC) received 800 mg Rogaratinib oral tablet b.i.d.

(1600 mg/day) in 21-days cycles. arm 3: Participants with bladder cancer (BC) received 800 mg Rogaratinib oral tablet b.i.d. (1600 mg/day) in 21-days cycles. arm 4: Participants with squamous cell carcinoma of the head and neck (SCCHN) received 800 mg Rogaratinib oral tablet b.i.d. (1600 mg/day) in 21-days cycles. arm 5: Participants with squamous non-small cell lung cancer (sqNSCLC) received 800 mg Rogaratinib oral tablet b.i.d. (1600 mg/day) in 21-days cycles.
Interventions: intervention 1: Rogaratinib (BAY1163877) oral solution intervention 2: Rogaratinib (BAY1163877) oral tablet intervention 3: Rogaratinib (BAY1163877) 800 mg BID
Intervention descriptions: intervention 1: Participants received Rogaratinib oral solution as a single dose on Cycle 1 Day 1 (C1D1) and twice daily (BID) from Cycle 1 Day 3 (C1D3) onward for the remaining 19 days of Cycle 1. For subsequent cycles, study drug was administered twice daily for 21 days each Cycle. intervention 2: Participants received Rogaratinib oral tablet as a single dose on C1D1 and BID from C1D3 onward for the remaining 19 days of Cycle 1. For subsequent cycles, study drug was administered twice daily for 21 days each Cycle. intervention 3: Participants received Rogaratinib 800 mg oral tablet as a single dose on C1D1 and BID (in total 1600 mg) from C1D3 onward for the remaining 19 days of Cycle 1. For subsequent cycles, study drug was administered twice daily for 21 days each Cycle.

Protocol documents:
Prot_000.pdf: 
 
Document Type: Study Protocol 
Official Title: 
An open label, non-randomized, Phase I dose escalation study to 
characterize safety, tolerability, pharmacokinetics and maximum 
tolerated dose of BAY 1163877 in subjects with refractory, 
locally advanced or metastatic solid tumors 
NCT Number: 
NCT01976741 
Document Date: 
17 Oct 2018 
 


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Cover page of the integrated protocol
An open label, non-randomized, Phase I dose escalation study to characterize safety, 
tolerability, pharmacokinetics and maximum tolerated dose of BAY 1163877 in 
subjects with refractory, locally advanced or metastatic solid tumors
This protocol version is an integration of the following documents / sections:

Original protocol, Version 1.0, dated 25 Jul 2013

Amendment no. 1 (described in Section 15.1)
forming integrated protocol Version 2.0, dated 31 Oct 2013

Amendment no. 2 (described in Section 15.2 )
forming integrated protocol Version 3.0, dated 19 Mar 2014

Amendment no. 3 (described in Section 15.3)
forming integrated protocol Version 4.0, dated 19 Jun 2014

Amendment no. 4 (described in Section 15.4)
forming integrated protocol Version 5.0, dated 31 Oct 2014

Amendment no. 5 (described in Section 15.5)
forming integrated protocol Version 6.0, dated 19 Sep 2016

Amendment no. 7 (described in Section 15.6) 
forming integrated protocol Version 7.0, dated 16 Mar 2017

Amendment no. 9 (described in Section 15.7)
forming integrated protocol Version 8.0, dated 17 Oct 2018.
This document integrates the original protocol and all global amendments.
Amendments not included in the consecutive numbering of amendments above are local 
amendments not forming part of this integrated global protocol. This currently includes:

Amendment no. 6 (local amendment for US only), dated 06 Dec 2016

Amendment no. 8 (local amendment for South Korea only) dated 30 Oct 2017


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1
Title page - amended
An open label, non-randomized, Phase I dose escalation study to characterize safety, 
tolerability, pharmacokinetics and maximum tolerated dose of BAY 1163877 in 
subjects with refractory, locally advanced or metastatic solid tumors 
Phase I dose escalation pan-FGFR inhibitor
Test drug:
BAY 1163877 / pan-FGFR inhibitor
Study purpose:
To determine the maximum tolerated dose (MTD) 
Clinical study phase:
I (first-in human)
Date:
17 Oct 2018
EudraCT no.:
2013-002155-15
Version no.:
8.0
Study no.:
BAY 1163877 / 16443
Sponsor:
Sponsor (Non-US): Bayer AG,  D-51368 Leverkusen,  
Germany
Sponsor (US territory): Bayer HealthCare Pharmaceuticals 
Inc., 100 Bayer Boulevard, P.O. Box 915, Whippany 
NJ 07981-0915, USA
Sponsor’s medical 
expert: 1
Bayer AG
Muellerstrasse 178, 13353 Berlin, Germany
Phone No: 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements.
Confidential
The information provided in this document is strictly confidential and is intended solely for 
the guidance of the clinical investigation. Reproduction or disclosure of this
document - whether in part or in full - to parties not associated with the clinical 
investigation, or its use for any other purpose, without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (, TM) are not displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
                                                
1 The medical expert changed, see Amendment 7, see section 15.6.2.1
PPD
PPD


17 Oct 2018 
Integrated Clinical Study Protocol 
No. BAY 1163877I16443 
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Signature of the sponsor's medically responsible person 
The signatory agrees to the content of the clinical study protocol as presented. 
Name 
Role 
Date 
2 The medical expert changed with Amendment 7 
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PPD
PPD


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Signature of coordinating / principal investigator
The signatory agrees to the content of the clinical study protocol as presented.
Name
Role 
Date
Signature


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Synopsis - amended
Title
An open label, non-randomized, Phase I dose escalation 
study to characterize safety, tolerability, 
pharmacokinetics and maximum tolerated dose of 
BAY 1163877 in subjects with refractory, locally 
advanced or metastatic solid tumors
Short title
Phase I dose escalation pan-FGFR inhibitor
Clinical study phase
I (first-in human)
Project number
445410
Study objective(s)
Primary objectives
To determine the safety and maximum tolerated dose 
(MTD) of BAY 1163877 in subjects with advanced
solid organ malignancies 
To characterize the pharmacokinetics (PK) of
BAY 1163877
Secondary objectives
To evaluate biomarker status, pharmacodynamic (PD) 
parameters and tumor response
Exploratory objective3
To evaluate selected immune parameters
Test drug(s) 
BAY 1163877 
Name of active ingredient 
BAY 1163877
Formulation IMP 1
Ready-to use solution for oral application 
(10 mg BAY 1163877 per 1 mL solution)
Formulation IMP 2
Tablet (50 mg tablet and 200 mg tablet)
                                                
3 Exploratory objective added by Amendment 7, see section 15.6.2.2


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Dose(s)
Study Part 1 / dose escalation (all comer) 

Starting dose: 
50 mg once on Cycle 1, Day 1 (single dose)
50 mg twice daily (b.i.d. = bis in die) from Cycle 1, 
Day 3 (100 mg / day) ongoing
Study Part 1 / MTD expansion (all comer)

Subjects receive the MTD of BAY 1163877 
determined at the end of dose escalation.
Study Part 2 / MTD expansion (sqNSCLC + LAC + BC 
+ SCCHN):

Subjects receive the MTD of BAY 1163877 
determined in study Part 1.
Study Part 3 / MTD expansion “Safety cohort”
(sqNSCLC + LAC + BC):

Subjects receive the MTD of BAY 1163877 
determined in study Part 1.4
Route of administration
Oral (p.o.)
Duration of treatment
Duration and dosing schedule for subjects participating 
in PK assessments (all subjects of study Part 1 and at 
least 12 subjects of study Part 2):
Subjects will receive BAY 1163877 (tablet or 
solution) on a continuous schedule starting with 
single-dose administration on Cycle 1, Day 1, 
followed by a “drug-free day” (to enable single dose 
PK assessments). Treatment with BAY 1163877 will 
resume on Day 3 of Cycle 1 if no protocol-defined 
dose-limiting toxicities (DLTs) are reported. Starting 
on Cycle 1, Day 3, the study drug will be self-
administered twice daily for the remaining 19 days 
of Cycle 1. For subsequent cycles, study drug will be 
administered twice daily for 21 days each Cycle.
Duration and dosing schedule of subjects enrolled for 
tablet relative bioavailability assessment (“tablet 
bridging cohort”) of study Part 1: 
                                                
4 Part 3 - Safety cohort - was added by Amendment 7, see section 15.6.2.2


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Duration of treatment
(continued)
Subjects will receive a single dose of tablet 
formulation on Cycle 1, Day -3, and then continue 
with the solution formulation starting on Cycle 1, 
Day 1, according to the schedule described above. 
Duration and dosing schedule of subjects enrolled for 
food effect assessment in the MTD expansion cohorts 
of study Part 1 and Part 2:
Approximately 8 subjects will receive single doses 
of BAY 1163877 on Cycle 1, Day -3 (after 
consumption of a high-fat, high-calorie breakfast) 
and on Cycle 1, Day 1 (after an overnight fast of at 
least 8 hours) followed by treatment according to the 
schedule described above starting on Cycle 1, Day 3.
Duration and dosing schedule for subjects of study 
Part 2 without PK assessment: 
Subjects will receive BAY 1163877 (tablet or 
solution) twice daily from Cycle 1, Day 1 ongoing.
Evidence of tumor progression, unacceptable 
toxicity, consent withdrawal or subject’s withdrawal 
from the study at the discretion of the Investigator 
may lead to termination of treatment.
Duration and dosing schedule for subjects of study 
Part 3: 
Subjects will receive BAY 1163877 twice daily from 
Cycle 1, Day 1 ongoing. Evidence of tumor 
progression, unacceptable toxicity, consent 
withdrawal or subject’s withdrawal from the study at 
the discretion of the Investigator may lead to 
termination of treatment.5
Reference drug (s)
Not applicable 
Indication
Refractory, locally advanced or metastatic solid tumors
                                                
5 Part 3 was added by Amendment 7, see section 15.6.2.2


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Diagnosis and main criteria for 
inclusion
Inclusion criteria:
Eligibility criteria for FGFR expression / FGFR
mutation testing (only for MTD expansion cohorts of 
study Part 1, Part 2, and Part 3)
6

Ability to understand and willingness to sign the 
written subjects information sheet / informed 
consent form (SIS / ICF) for FGFR expression / 
FGFR mutation testing. Signed informed consent 
(IC) has to be obtained before any study specific 
procedure. 

Subjects with histologically or cytologically
confirmed, refractory, locally advanced or 
metastatic solid tumors (all comer for study Part1; 
sqNSCLC, LAC, BC or SCCHN for Part 2; 
sqNSCLC, LAC, or BC for Part 3) who are not 
candidates for standard therapy.  7

Male or female subjects ≥ 18 years of age

Eastern Cooperative Oncology Group (ECOG) 
Performance Status of 0, 1 or 2

Life expectancy of at least 3 months

Existence of archival or fresh tumor biopsy 
specimen for FGFR expression / FGFR mutation 
testing
Besides these basic criteria, any criterion as outlined 
below already known to prohibit the patient’s 
participation in the study should be considered.
Eligibility criteria for study treatment

Ability to understand and willingness to sign the 
written SIS / ICF for study treatment eligibility. 

Signed informed consent (IC) obtained before any 
(further) study specific procedure.

Subjects with histologically or cytologically 
confirmed, refractory, locally advanced or 
metastatic solid tumors who are not candidates for 
standard therapy.
Subjects with any type of solid tumors (all comer) 
                                                
6 Part 3 was added by Amendment 7, see section 15.6.2.2
7 Part 3 was added by Amendment 7, see section 15.6.2.2


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Diagnosis and main criteria for 
inclusion
(continued)
will be eligible for dose escalation and dose 
expansion at MTD in Part 1.

Subjects enrolled in the MTD expansion cohorts of 
Study Part 1, Part 2, and Part 3 must present high 
FGFR expression levels based on archival or fresh 
tumor biopsy specimen analysis.
Bladder cancer subjects with low overall FGFR 
expression levels can be included if activating 
FGFR3 mutations are confirmed. 
(only for MTD expansion cohorts of study Part 1 
(all comer), Part 2 (sqNSCLC + LAC +BC + 
SCCHN)) and Part 3 (sqNSCLC + LAC + BC)8

Subjects must have at least one measurable or 
evaluable lesion according to Response Evaluation 
Criteria in Solid Tumors (RECIST), version 1.1. 
A lesion in a previously irradiated area is eligible 
and to be considered as measurable disease as long 
as there is objective evidence of progression of the 
lesion prior to study enrollment.

Subjects with resected primary tumors who have 
documented metastases are eligible.

Subjects consent to undergo a paired biopsy at 
screening and on Cycle 2, Day 1
(only for MTD expansion cohorts of study Part 1 
(all comer))
Note: Anticancer chemotherapy must have been 
stopped for at least 5 half-lives of the last applied 
therapy before the pre-treatment biopsy for 
biomarker (p-ERK1/2) studies is taken.9 Mitomycin 
C, nitrosoureas or monoclonal antibodies with 
anticancer activity (e.g. bevacizumab or cetuximab 
etc.) should not be given within 6 weeks of pre-
treatment biopsy for biomarker (p-ERK1/2) studies.

Only for study Part 3: Subjects consent to undergo a 
paired biopsy at screening and between Cycle 2, 
Day 1 and Cycle 2, Day 2110
                                                
8 Part 3 was added by Amendment 7, see section 15.6.2.2
9 Amended by Amendment 7, see section 15.6.2.2
10 Part 3 was added by Amendment 7, see section 15.6.2.2


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Diagnosis and main criteria for 
inclusion
(continued)

Male or female subjects ≥ 18 years of age

Life expectancy of at least 3 months 

Recovery to National Cancer Institute’s Common 
Terminology Criteria for Adverse Events, version 
4.03 (CTCAE v4.03) Grade 0 or 1 level or recovery 
to baseline preceding the prior treatment from any 
previous drug / procedure-related toxicity (subjects 
with persistent alopecia, anemia, and / or 
hypothyroidism can be included).

Eastern Cooperative Oncology Group (ECOG) 
Performance Status of 0, 1 or 2

Adequate bone marrow, liver and renal function as 
assessed by the following laboratory requirements 
conducted within 7 days of starting the study 
treatment:

Absolute neutrophil count (ANC) ≥ 1,500/mm3

Platelet count ≥ 75,000/mm3

Total bilirubin ≤ 1.5 times the upper limit of normal 
(ULN). Documented Gilbert syndrome is allowed if 
total bilirubin is mildly elevated (< 6 mg/dL). 

Alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) ≤2.5 x ULN (≤5 x ULN 
for subjects with liver involvement of their cancer)

Alkaline phosphatase limit ≤ 2.5 x ULN (≤5 x ULN 
for subjects with liver involvement of their cancer)

Lipase ≤ 5 x ULN 

Not more than Child-Pugh score B7 hepatic 
impairment

Glomerular filtration rate (GFR) 
≥30 mL/min/1.73 m2 according to the modified 
diet in renal disease (MDRD) abbreviated 
formula

International normalized ratio (INR) ≤ 1.5 x ULN 
and partial thromboplastin time (PTT) or activated 
partial thromboplastin time (aPTT) ≤ 1.5 x ULN. 
Subjects being treated with anticoagulant, e.g. 
warfarin or heparin, will be allowed to participate 
provided no prior evidence of an underlying 
abnormality in these parameters exists. Close 
monitoring of at least weekly evaluations will be 
performed until INR is stable based on a pre-dose 
measurement as defined by the local standard of 
care.


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Diagnosis and main criteria for 
inclusion
(continued)

Subjects with a history of hypertension should be on 
stable anti-hypertensive medicine for more than 
7 days before start of study treatment.

Women of childbearing potential and men must 
agree to use adequate contraception before entering 
the program until at least 8 weeks after the last 
study drug administration. The investigator or a 
designated associate is requested to advise the 
subject on how to achieve an adequate birth control. 
Adequate contraception is defined in the study as 
any medically recommended method (or 
combination of methods) as per standard of care.

Women of childbearing potential must have a 
pregnancy test performed a maximum of 7 days 
before start of study treatment, and a negative result 
must be documented before start of study treatment.
Study design
Phase I, first-in-human, open-label, non-randomized, 
multi-center, 2-part, dose-escalation / dose-expansion
study of BAY 1163877 in sequential cohorts of subjects 
with refractory, locally advanced or metastatic solid 
tumors. 
Study Part 1 will identify the maximum tolerated dose 
(MTD) in subjects with any solid tumors (all comer) 
using an adaptive dose escalation design and expansion 
of cohort at MTD.
Study Part 2 will explore further the safety and PD of 
BAY 1163877 at the MTD identified in Part 1 in 
subjects with sqNSCLC, LAC, BC and SCCHN to seek 
any evidence of preliminary clinical responses. Part 2 
may start as soon as the MTD has been established in 
Part 1.
Study Part 3 will expand the safety database and in 
parallel will collect additional efficacy data and explore 
changes of selected immune parameters during 
treatment with BAY 1163877 at the MTD identified in 
Part 1 in subjects with sqNSCLC, LAC, and BC.11
                                                
11 Part 3 added by Amendment 7, see section 15.6.2.2


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Methodology
Eligible cancer subjects will be enrolled at multiple 
centers worldwide. In total, the “on study” period for 
the subjects comprises 3 phases:

Pre-treatment

FGFR expression / FGFR mutation testing

Screening 

Treatment 
Study Part 1 / dose escalation + MTD expansion 
(all comer):
Individual number of 21-day Cycles with 
BAY 1163877 monotherapy (tablet or solution) until 
disease progression or as long as clinical benefit is 
assumed by the investigator or until unacceptable 
toxicity occurs.
Study Part 1 /“tablet bridging cohort” 
(all comer):
In one of the dose escalation cohorts, administration of 
a single dose of BAY 1163877 using the tablet 
formulation on Cycle 1, Day -3 followed by solution 
formulation starting Cycle 1, Day 1 as described above.
Study Part 2 / MTD expansion (sqNSCLC + 
LAC + BC + SCCHN):
Individual number of 21-day Cycles with continuous 
BAY 1163877 monotherapy (tablet or solution) until 
disease progression or as long as clinical benefit is 
assumed by the investigator or until unacceptable 
toxicity occurs.
Study Part 3 / MTD expansion “Safety cohort”
(sqNSCLC + LAC + BC):
Individual number of 21-day Cycles with continuous 
BAY 1163877 monotherapy (tablet) until disease
progression or as long as clinical benefit is assumed by 
the investigator or until unacceptable toxicity occurs.12
                                                
12 Part 3 added by Amendment 7, see section 15.6.2.2


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Methodology 
(continued)
MTD expansion cohorts (study Part 1 and 
Part 2) / “food effect assessment”:
Approximately 8 subjects will receive single 
doses of BAY 1163877 on Cycle 1, Day -3 
(after consumption of a high-fat, high-calorie 
breakfast) and on Cycle 1, Day 1 (after an 
overnight fast of at least 8 hours) followed by 
treatment according to the schedule described 
above starting on Cycle 1, Day 3.
Note: Treatment with BAY 1163877 at MTD in Part 1 
(expansion cohort “all comer”), Part 2 (expansion 
cohort “sqNSCLC + LAC + BC + SCCHN” and 
Part 3 (expansion cohort “Safety cohort”, sqNSCLC 
+ LAC + BC13) can run in parallel.

Follow-up (FU)
End of Treatment (EOT) visit 0-14 days after 
last dose of BAY 1163877
Follow-up (FU) visit 30-35 days after last dose 
of BAY 1163877
At home, subjects will document the intake of study 
drug (date and time of dosing as well as the 
administered dose) on a compliance sheet / paper diary 
(source document to verify treatment compliance). The 
complete duration of the study (Part 1, Part 2 and Part 
3)13 depends on the number of dose-escalation steps in 
Part 1 and will be approximately 7 years.
                                                
13 Part 3 added by Amendment 7, see section 15.6.2.2


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Methodology 
(continued)
Determination of the MTD: An adaptive dose 
escalation design will be used to determine the 
MTD in study Part 1 (all comer). The MTD is 
defined as the highest dose that can be given such 
that not more than 20% of subjects experience a 
DLT during Cycle 1. The dose escalation will be
performed as follows:

Initially 3 subjects per dose level will be enrolled. In 
case 2 or more sites are conducting the dose 
escalation part, the initial enrolment of 4 subjects 
per dose level is optional.

The starting dose of BAY 1163877 is 50 mg given 
as a single dose on Cycle 1, Day 1, and twice daily 
(b.i.d.) from Cycle 1, Day 3 (100 mg /day)

The maximum dose escalation will be 2-fold.

Possible daily doses of BAY 1163877 starting from 
100 mg in increments of 100 mg.
If at least 1 subject out of 3 or 1 out of 4 in a cohort has 
DLTs or if at least 2 subjects report drug-related AEs 
(CTCAE v4.03) of Grade ≥ 2, any further dose 
escalation, de-escalation or cohort expansion will be 
decided in consultation between all investigator(s), and 
the sponsor (within the drug safety monitoring team = 
DSMT) after consideration of all available safety data 
of the previous cohorts. Any subsequent dose will be 
selected in order to determine the MTD. 
Model-based dose-response analysis of the DLT rates 
will be performed during these interim reviews in order 
to guide the dose decision (see details in Section 16.4).
The model-based dose selection procedure is 
considering data at all dose levels (not just at the last 
cohort). The dose predicted to yield 20% DLT rates will 
be reported from that model as a best candidate for the 
next cohort. 
The final decision about the next dose will be made by 
the sponsor in consultation with all investigators 
(DSMT). If the selected dose is larger than the last dose 
tested, then escalation will be pursued. If it is lower, a 
de-escalation step will occur. 


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Methodology 
(continued)
Without the occurrence of toxicities, dose escalation 
could be stopped and RP2D may be determined based 
on PK and/or PD results. The decision to continue 
treatment for an individual patient will be made by the 
investigator according to the criteria specified in the 
protocol (Section 8.4).
Cohort expansion will occur when a previously tested 
dose is selected again for the next cohort of 3 subjects. 
Expansions at any given dose up to a total of 9 subjects 
are allowed. In principle, the selection of a next dose 
level where the predicted DLT rate is close to 20% 
should insure that the next dose tested will remain safe. 
Nevertheless, the following constraint will be added in 
order to protect subject safety during the adaptive dose 
selection decisions:

If 2 out of 3 (or 2 out of 4), at least 4 out of 6 (or at 
least 5 out of 9) subjects experience DLTs at a given 
dose level, only lower doses will be given in all 
subsequent cohorts because the probability that the 
dose is above the MTD is very large (above 95.4%).

The dose-escalation procedure will be stopped as 
soon as: 
-
the MTD has been defined with good precision 
(i.e., the coefficient of variation for the MTD is 
lower than or close to 40%)
or
-
at any time when the selected dose level for the 
next cohort has already been given in 
9 subjects.
If the dose escalation stops, the sample size for the 
MTD cohort will be expanded up to a total of 
20 evaluable subjects (study Part 1 / MTD expansion 
cohort (all comer)). 
No intra-subject dose escalation is permitted. Dose 
interruptions and / or dose reductions may be required 
based on individual safety and tolerability.


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Methodology 
(continued)
Pharmacokinetics (PK): Single- and multiple-dose PK 
of BAY 1163877 will be evaluated in plasma samples 
collected on Cycle 1, Day -3 (up to 48 hours after 
dosing) in the “tablet bridging cohort”, and on Cycle 1, 
Day 1 (up to 48 hours after dosing) and on Cycle 1, 
Day 15 (up to 12 hours after dosing), respectively, in all 
subjects participating in Study Part 1 (all comer) and in 
at least 12 subjects participating in Study Part 2 
(sqNSCLC + LAC + BC + SCCHN). In all subjects 
participating in Study Part 3, multiple dose PK of BAY 
1163877 will be evaluated in plasma samples collected 
on Cycle 1, Day 15 (up to 12 hours after dosing).14
In approximately 8 subjects enrolled in MTD 
expansion cohorts (study Part 1 and Part 2), single 
dose PK of BAY 1163877 will be evaluated in 
plasma samples collected on Cycle 1, Day -3 (up to 
48 hours after dosing) and on Cycle 1, Day 1 (up to 
48 hours after dosing) for food effect assessment.
In the MTD expansion cohorts, in approximately 8 
subjects with moderately impaired renal function at 
baseline (glomerular filtration rate [GFR] of 30 to 
59 mL/min/1.73 m2 according to the modified diet in 
renal disease [MDRD] abbreviated formula), serial 
PK blood samples will be collected on Cycle 1 Day 1 
and Day 15.15
Plasma concentration of BAY 1163877 will be 
measured using a validated method.
In approximately 8 subjects enrolled in MTD expansion 
cohorts (study Part 1 and Part 2), urine will be collected 
for 24 hours after dosing on Cycle 1, Day 1 
(concurrently with plasma PK samples) and analyzed 
using validated method.
Exploratory monitoring of metabolites may also be 
performed in pooled plasma (most likely at the MTD or 
the therapeutic dose) and urine samples.
                                                
14 Part 3 added by Amendment 7, see section 15.6.2.2
15 Modified by Amendment 7, see section 15.6.2.2


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Methodology 
(continued)
Safety / tolerability: Safety will be assessed by close 
monitoring and timely assessment of adverse events 
(AEs), laboratory parameters (blood tests, urinalysis), 
vital signs (blood pressure, heart rate), subject’s 
medical condition (physical examination including 
weight), ophthalmological examination, general well-
being and activities of daily life (Eastern Cooperative 
Oncology Group (ECOG) performance status).16 Each 
subject will be regularly assessed in each cycle for 
potential AEs and disease related signs and symptoms. 
The CTCAE v4.03 will be used to grade toxicities / 
AEs.
Cardiovascular assessment: Blood pressure (BP) and 
heart rate (HR) will be measured at screening, 
frequently on PK profile days in Cycle 1, and once at all 
other visits during treatment and follow up.
Electrocardiogram (ECG): 12-lead ECG readings will 
be performed at screening, on Cycle 1, Days -3 and -2 
(“tablet bridging cohort” and “food effect assessment” 
only), on Cycle 1, Days 1, 2, and 15, thereafter on 
Day 1 of each subsequent Cycle, and at the EOT visit.
Pharmacodynamic (PD) biomarkers: In an attempt to 
demonstrate the mechanism of action of BAY 1163877,
biomarkers will be studied in tissue samples.
Biomarker analysis in tumor tissue
Biomarker analysis will be done at screening for subject 
stratification in the MTD expansion cohorts (Part 1: all 
comer; Part 2: sqNSCLC + LAC + BC + SCCHN; Part 
                                                
16 Amended by Amendment 7, see section 15.6.2.2


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Methodology 
(continued)
3: “Safety cohort” sqNSCLC + LAC + BC) according 
to FGFR expression levels / FGFR mutation using 
either an archival or fresh tumor biopsy material (see 
inclusion criteria).17
Analysis of phospho-extracellular signal-regulated 
kinase 1/2 levels, (p-ERK1/2) will be done at screening 
and on Cycle 2, Day 1 for all subjects of study Part 1 
and Part 2 who are willing to undergo a biopsy both at 
screening and on Cycle 2, Day 1.18 Both biopsies are 
mandatory for “all comer” subjects included in the 
MTD expansion cohort of Part 1.
Priming of immune response (only in Part 3 “Safety 
cohort”): Selected parameters of immune response will 
be measured in fresh tumor tissue at baseline and 
between Cycle 2, Day 1 and Cycle 2, Day 21 and 
peripheral blood at the following timepoints: at 
baseline; Cycle 1, Day 8; Cycle 2, Day 1; Cycle 2, Day 
15; and on the day of the second biopsy.19
Tumor response evaluation: Computed tomography 
(CT) or magnetic resonance imaging (MRI) of all 
anatomic regions involved with the disease will be 
performed at screening (baseline), at the end of Cycle 2 
and thereafter, every third cycle to assess tumor 
response using the Response Evaluation Criteria in 
Solid Tumors, Version 1.1. (RECIST v1.1)(1). 
Recommended Phase II dose (RP2D): The RP2D will 
be determined at the end of the study (after Part 2).
Type of control
The study is uncontrolled.
Number of subjects
Subjects will be enrolled in the pre-treatment phase of 
the study to recruit enough subjects with present high 
FGFR expression levels for the following study parts.

Study Part 1 / dose escalation (all comer): 
The total number of subjects will depend on the number 
of cohorts necessary to identify the MTD. Relative 
                                                
17 Part 3 added by Amendment 7, see section 15.6.2.2
18 ‘Study Part 1 and Part 2’ added by Amendment 7
19 Part 3 - Safety cohort - was added by Amendment 7, see section 15.6.2.2


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bioavailability of the tablet formulation in comparison 
to the solution formulation will be performed in all 
subjects enrolled in one of the dose escalation cohorts; 
pharmacokinetic data are needed in a minimum of 
3 subjects for relative bioavailability assessment. 

Study Part 1 / MTD expansion (all comer): 
Additional subjects will be enrolled to have 20 
evaluable “all comer” subjects treated at MTD.
Number of subjects
(continued)

Study Part 2 / MTD expansion (sqNSCLC + 
LAC + BC + SCCHN): 
Additional subjects will be enrolled to have 
20 evaluable subjects with sqNSCLC or LAC and a 
cohort of at least 30, up to a maximum of 50 evaluable 
subjects with BC and at least 8 subjects with SCCHN 
treated at MTD.20

Study Part 3 / MTD expansion “Safety cohort”
(sqNSCLC + LAC + BC):
Additional subjects will be enrolled to have 
approximately 20 subjects with sqNSCLC or LAC and 
approximately 20 subjects with BC treated at MTD.21
Primary variables
Determination of MTD
The primary variable for MTD determination will be 
the incidence of DLTs during the first 21 days of 
treatment (Cycle 1). 
The primary study outcome is the MTD being defined 
as the maximum dose at which the incidence of DLTs 
during Cycle 1 is below 20%.
Pharmacokinetics: (BAY 1163877)
On Cycle 1 Day -3 (“tablet bridging cohort” and 
“food effect assessment” only) and Cycle 1, Day 1:
Cmax, AUC(0-12), AUC(0-tlast), AUC and corresponding 
dose adjusted parameters (Cmax/D, AUC(0-12)/D 
AUC(0-tlast)/D, AUC/D and AUC).  
Amount of BAY 1163877 excreted renally during 0 to 
                                                
20 Modified by Amendment 6, see section 15.6.2.2
21 Part 3 - Safety cohort - was added by Amendment 7, see section 15.6.2.2


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12 h (AE,ur(0-12)), 12 to 24 h (AE,ur(12-24)) and 0 to 
24 h (AE,ur(0-24)) post-dose will be calculated at the 
MTD and also expressed as percent of dose 
administered.
For Cycle 1, Day 15: Cmax,md, Cmax/Dmd, AUC(0-12)md, 
AUC(0-12)/Dmd, AUC(0-tlast)md, and AUC(0-tlast)/Dmd.
Plan for statistical analysis
This is primarily a descriptive safety and tolerability 
trial. A confirmatory analysis is not intended. 
Quantitative data will be described by summary 
statistics. Frequency tables will be provided for 
qualitative data.
The incidence of subjects with DLTs during Cycle 1 
will be summarized by cohort and, as possible, modeled 
as a function of BAY 1163877 dose using Bayesian 
logistic regression to guide the dose selection.
PK data will be summarized by descriptive statistics. 
To investigate dose proportionality, bioavailability and 
food effect, ANOVA will be performed on the log-
transformed values of appropriate PK parameters and 
90% confidence intervals will be derived.


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Table of contents
1
Title page - amended......................................................................................................... 2
2
Synopsis - amended........................................................................................................... 5
3
Introduction - amended .................................................................................................. 32
4
Study objectives - amended............................................................................................ 35
5
Investigator(s) and other study participants - amended ............................................. 35
6
Study design - amended.................................................................................................. 36
6.1
Primary variable(s)..................................................................................................... 45
6.2
Justification of the design - amended......................................................................... 45
6.3
End of study ............................................................................................................... 46
7
Study population ............................................................................................................. 46
7.1
Eligibility.................................................................................................................... 47
7.1.1
Inclusion criteria.................................................................................................. 47
7.1.2
Exclusion criteria ................................................................................................ 49
7.1.3
Justification of selection criteria ......................................................................... 52
7.1.4
Justification for gender selection ........................................................................ 52
7.2
Withdrawal of subjects from study ............................................................................ 53
7.2.1
Withdrawal - amended........................................................................................ 53
7.2.2
Replacement........................................................................................................ 54
7.3
Subject identification.................................................................................................. 55
8
Treatment(s) .................................................................................................................... 55
8.1
Treatments to be administered - amended.................................................................. 55
8.2
Identity of study treatment ......................................................................................... 56
8.3
Treatment assignment ................................................................................................ 58
8.4
Dosage and administration......................................................................................... 58
8.4.1
Estimation of safe starting dose .......................................................................... 58
8.4.2
Selection and timing of dose for each subject - amended................................... 58
8.4.3
Dose modification and delays - amended ........................................................... 61
8.4.4
Dose-limiting toxicity (DLT).............................................................................. 64
8.5
Blinding...................................................................................................................... 65
8.6
Drug logistics and accountability............................................................................... 65
8.7
Treatment compliance................................................................................................ 66
8.8
Post-study therapy...................................................................................................... 66
8.9
Prior and concomitant therapy ................................................................................... 67
8.9.1
Drug-drug interactions relevant for BAY 1163877 ............................................ 67
8.9.2
Prohibited concomitant therapy .......................................................................... 67
8.9.3
Permitted concomitant therapy - amended.......................................................... 68
9
Procedures and variables ............................................................................................... 69
9.1
Schedule of procedures .............................................................................................. 69
9.1.1
Tabulated overview............................................................................................. 69
9.1.2
Timing of assessment.......................................................................................... 69


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9.2
Population characteristics........................................................................................... 83
9.2.1
Demographic....................................................................................................... 83
9.2.2
Medical history.................................................................................................... 83
9.2.3
Other baseline characteristics.............................................................................. 83
9.3
Efficacy ...................................................................................................................... 83
9.3.1
Tumor evaluation - response assessment (RECIST)........................................... 84
9.4
Clinical pharmacological parameters and procedures................................................ 85
9.4.1
Pharmacodynamics ............................................................................................. 85
9.4.2
Pharmacokinetics ................................................................................................ 86
9.4.3
Safety Variables .................................................................................................. 89
9.4.4
Biomarker investigations - amended................................................................... 89
9.5
Safety.......................................................................................................................... 94
9.5.1
Adverse events .................................................................................................... 94
9.5.2
Pregnancies ......................................................................................................... 99
9.5.3
Further safety variables..................................................................................... 100
9.5.4
Echocardiography / MUGA scan...................................................................... 101
9.6
Other procedures and variables................................................................................ 103
9.6.1
Diary.................................................................................................................. 103
9.7
Appropriateness of procedures / measurements....................................................... 104
10 Statistical measures and determination of sample size.............................................. 104
10.1
General considerations............................................................................................. 104
10.2
Analysis sets............................................................................................................. 104
10.3
Variables................................................................................................................... 105
10.4
Statistical and analytical plans ................................................................................. 105
10.4.1
Demographic and other baseline characteristics............................................... 105
10.4.2
Maximum tolerated dose................................................................................... 105
10.4.3
Adverse events .................................................................................................. 105
10.4.4
Safety parameters.............................................................................................. 105
10.4.5
Pharmacokinetic data ........................................................................................ 106
10.4.6
Pharmacodynamic data ..................................................................................... 107
10.4.7
Efficacy data...................................................................................................... 107
10.5
Planned interim analysis........................................................................................... 107
10.6
Further analysis described and reported under separate cover................................. 108
10.7
Determination of sample size - amended ................................................................. 108
11 Data handling and quality assurance.......................................................................... 108
11.1
Data recording - amended ........................................................................................ 108
11.2
Monitoring................................................................................................................ 110
11.3
Data processing ........................................................................................................ 111
11.4
Audit and inspection................................................................................................. 111
11.5
Archiving.................................................................................................................. 112
12 Premature termination of the study ............................................................................ 112
13 Ethical and legal aspects............................................................................................... 113
13.1
Ethical and legal conduct of the study ..................................................................... 113
13.2
Subject information and consent.............................................................................. 113


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13.3
Publication policy - amended................................................................................... 114
13.4
Compensation for health damage of subjects / insurance ........................................ 115
13.5
Confidentiality.......................................................................................................... 115
14 Reference list - amended............................................................................................... 116
15 Protocol amendments.................................................................................................... 120
15.1
Amendment 1........................................................................................................... 120
15.1.1
Overview of changes......................................................................................... 120
15.1.2
Changes to the protocol..................................................................................... 121
15.2
Amendment 2........................................................................................................... 162
15.2.1
Overview of changes......................................................................................... 162
15.2.2
Changes to the protocol..................................................................................... 162
15.3
Amendment 3........................................................................................................... 164
15.3.1
Overview of changes......................................................................................... 164
15.3.2
Changes to the protocol..................................................................................... 169
15.4
Amendment 4........................................................................................................... 249
15.4.1
Overview of changes......................................................................................... 249
15.4.2
Changes of protocol .......................................................................................... 250
15.5
Amendment 5........................................................................................................... 285
15.5.1
Overview of changes......................................................................................... 285
15.5.2
Changes of protocol .......................................................................................... 287
15.6
Amendment 7........................................................................................................... 323
15.6.1
Overview of changes......................................................................................... 323
15.6.2
Changes of protocol .......................................................................................... 324
16 Appendices..................................................................................................................... 357
16.1
Study flow chart - amended ..................................................................................... 357
16.2
Laboratory examinations - amended........................................................................ 367
16.3
Listing of instructions and manuals - amended........................................................ 374
16.4
Model-based dose-response analysis of the DLT rates............................................ 375
16.4.1
Statistical model................................................................................................ 375
16.4.2
Trial simulation details...................................................................................... 377
16.4.3
Simulation scenarios ......................................................................................... 377
16.4.4
Operational characteristics................................................................................ 378
16.4.5
Simulation results.............................................................................................. 379
16.5
National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 4.03 (CTCAE v4.03) .................................................................................. 382
16.6
Tumor node metastases (TNM) classification ......................................................... 383
16.7
Eastern Cooperative Oncology Group (ECOG) performance status ....................... 384
16.8
Response evaluation criteria in solid tumors (RECIST v1.1) - amended ................ 385
16.9
Estimation of renal function..................................................................................... 393
16.10 New York Heart Association (NYHA) classification.............................................. 394
16.11 CYP 3A4 inhibitors and inducers............................................................................. 395


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Table of text tables
Table 8-1:
Identity of test drug (IMP):  BAY 1163877 solution formulation ...............56
Table 8-2:
Identity of test drug (IMP):  BAY 1163877 tablet formulation ...................57
Table 8-3:
Scheme for dose-level reduction of BAY 1163877 in subjects with 
solid tumors ..................................................................................................62
Table 8-4:
Hematological criteria for dose delay and dose modification......................62
Table 8-5:
Non-hematological criteria for dose delay and dose modification...............62
Table 8-6:
Dose modifications of BAY 1163877 for liver toxicity - amended .............63
Table 8-7:
Dose modifications of BAY 1163877 for Increased Ca x PO4 -
amended........................................................................................................64
Table 9-1:
Pharmacokinetic parameters to be evaluated for BAY 1163877 .................88
Table 16-1: Study flow chart: Pre-Treatment – Study Part 1,  Part 2 and Part 3-
amended......................................................................................................358
Table 16-2:
Study flow chart: Treatment (Cycle 1, Day -3 to Day -1) – Study 
Part 1 and Part 2..........................................................................................361
Table 16-3:
Study flow chart: Treatment (Cycle ≥ 1) and Follow-up – Study Part 
1, Part 2 and Part 3 (continued) - amended ................................................363
Table 16-4: Parameters and time points of laboratory examinations performed at 
local laboratory or study site (safety laboratory) – Study Part 1,  Part 2 
and Part 3 - amended .................................................................................368
Table 16-5:
Parameters and time points for biomarker investigations 
in study Part 1 / dose escalation (all comer)...............................................370
Table 16-6: Parameters and time points for biomarker investigations in study 
Part 1 / MTD expansion (all comer)...........................................................371
Table 16-7: Parameters and time points for biomarker investigations 
in study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN) ....372
Table 16-8: Parameters and time points for biomarker investigations in study Part 3 / 
MTD expansion ”Safety cohort” (sqNSCLC + LAC + BC) ......................373
Table 16-9:
Prior probability distribution of MTD........................................................376
Table 16-10: ECOG Performance Status.........................................................................384
Table 16-11: Target and non-target lesion response - amended ......................................389
Table 16-12: Time-point response: Subjects with non-target disease only - amended....389
Table 16-13: Best overall response when confirmation of CR or PR is required............390
Table 16-14: New York Heart Association (NYHA) classification ................................394
Table 16-15: An overview of strong CYP3A4 inhibitors and inducers...........................395


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Table of text figures
Figure 6-1:
Schematic presentation of the treatment design - amended .........................38
Figure 16-1: 100 random observations (curves) from the prior distribution...................376
Figure 16-2: Dose versus DLT rates simulation scenarios..............................................378
Figure 16-3: Predicted mean + sd number of patients per dose by scenario...................381


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List of abbreviations
AUC(tlast-)
percentage of AUC from the last data point > LLOQ to infinity
AE
adverse event
AE,ur(0-12)
amount of drug excreted via urine during the collection interval 0 –
12 hours post administration
AE,ur(0-24)
amount of drug excreted via urine during the collection interval 0 –
24 hours post administration
AE,ur(12-24)
amount of drug excreted via urine during the collection interval 12 –
24 hours post administration
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANOVA
analysis of variance
anti-HCV
hepatitis C virus antibodies
anti-HIV
human immunodeficiency virus antibodies
AP
alkaline phosphatase
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the plasma concentration vs time curve from zero to 
infinity after single (first) dose
AUC(0-12)
AUC from time zero to 12 hours p.a. after first-dose administration
AUC(0-12)md
AUC(0-12) after multiple-dose administration
AUC(0-tlast)
AUC from time zero to the last data point > LLOQ
AUC/D
AUC divided by dose
AUCnorm
area under the curve divided by dose per kg body weight
b.i.d.
twice daily (bis in die)
BC
bladder cancer
BMI
body mass index
BP
blood pressure 
bpm
beats per minute
Ca
calcium
CI
confidence interval
CK
creatine phosphokinase
CLcr
creatinine clearance
Cmax
maximum drug concentration in plasma after first dose administration
Cmax,md
Cmax after multiple-dose administration


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Cmax,norm
maximum drug concentration in plasma after single dose 
administration divided by dose (mg) per kg body weight
Cmax/D
maximum drug concentration in plasma after single dose 
administration divided by dose 
CPK
creatine phosphokinase
CRA
clinical research associate / assistant
CRO
contract research organization
CRP
C-reactive protein
CSP
clinical study protocol
CSR
clinical study report
CT
computed tomography
CTCAE v 4.03
Common Terminology Criteria for Adverse Events (CTCAE), 
Version 4.03 (CTCAE v4.03: June 14, 2010) of the National Cancer 
Institute (NCI), U.S. Department of Health and Human Services, 
National Institutes of Health
Ctrough
drug concentration in plasma at the end of the dosing interval
CV
coefficient of variation
d
dose
Diary
paper diary
DLT
dose limiting toxicity 
DSMT
drug safety monitoring team
E(p|d)
posterior mean probability of DLT for dose d.
e.g.
exempli gratia, for example
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data collection / capture
eGFR
estimated glomerular filtration rate
EOS
end of study
EOT
end of treatment 
ERK
extracellular signal-regulated kinase 
FDA
Food and Drug Administration
FGF
fibroblast growth factor
FGF23
fibroblast growth factor 23
FGFR
fibroblast growth factor receptor
FGFR1/2/3/4
FGFR tyrosine kinases 1/2/3/4
FU
follow-up
GCP
good clinical practice
GFR
glomerular filtration rate


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GMP
good manufacturing practice
GOT
glutamic oxaloacetic transaminase (=AST)
GPT
glutamic pyruvic transaminase (=ALT)
Hb
hemoglobin
HBDH
lactate dehydrogenase-1 isoenzyme (hydroxybutyrate dehydro-
genase)
HBsAg
hepatitis B surface antigen
HDL
high-density lipoprotein
HDPE
high density polyethylene
HFSR
hand-foot skin reaction
HIV
human immunodeficiency virus
HR
heart rate
i.e.
id est, that is
IB
investigator’s brochure
ICH
International Conference of Harmonization
IEC
independent ethics committee
IMP
investigational medicinal product
INR
international normalized ratio (reagent-independent prothrombin 
ratio)
IRB
institutional review board
ISF
investigator site file
IVRS
Interactive voice response system
IWRS
Interactive web response system
kg
kilogram
K-ras
Kirsten rat sarcoma 2 viral oncogene homologue (cancer gene wild 
type)
L
liter
LAC 
lung adenocarcinoma 
LAP
leucine aminopeptidase
LDH
lactate dehydrogenase
LDL
low-density lipoprotein
LLOQ
lower limit of quantification
LPFV
last patient first visit
LPLV
last patient (subject) last visit
LVEF
left ventricular ejection fraction
MABEL
minimum anticipated biological effect level
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration


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MCV
mean corpuscular volume
md
multiple dose
MDRD
Modification of Diet in Renal Disease (equation) 
MedDRA
Medical Dictionary for Regulatory Activities 
mL
milliliter
mmHg
millimeter of mercury
MRI
magnetic resonance imaging
msec
millisecond
MTD
maximum tolerated dose
MUGA
multiple gated acquisition scan
NCA
non-compartmental analysis 
NCI
National Cancer Institute
NIMP
non-investigational medicinal product
NSCLC
non-small cell lung cancer 
NYHA
New York Heart Association
p.d.
post-dose
p.o.
per os (by mouth, orally)
PCHE
plasma cholinesterase
PD
pharmacodynamic
PD
progressive disease
PD-L1
programmed death-ligand 1
p-ERK
phospho-extracellular signal–regulated kinase
p-FGF
phospho-fibroblast growth factor
pFRS
p-FGF receptor substrate
PFS
progression-free survival
PK
pharmacokinetic(s)
PO4
phosphate
popPK
population PK (models)
PR
PR interval in ECG
PTF
peak trough fluctuation
PT-INR
international normalized ratio for prothrombin time
PTT
partial thromboplastin time
QA
quality assurance
QC
quality control
Qd
probability of dose d being the MTD
QRSD
QRS duration
QT
QT interval in ECG


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QTc
QT interval corrected for heart rate
RBC
red blood count
RECIST v1.1
Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 
ROS
Roll-over study
RP2D
recommended Phase II dose
SAE
serious adverse event
SAS
statistical analysis system
SCCHN
squamous cell carcinoma of the head and neck
sd
standard deviation 
SD
stable disease
sec
second
SIS / ICF
subject information sheet / informed consent form
SNR
screening number
SOP
standard operating procedure
SPC
summary of product characteristics
sqNSCLC
squamous non-small cell lung cancer 
SUSAR
suspected unexpected serious adverse reaction
t1/2
half-life associated with the terminal slope
Td
(tolerable) probability that the DLT rate is below 0.20, Pr(p <0.20| d), 
for a dose d
TEADR(s)
treatment-emergent drug-related adverse event(s)
TEAE(s)
treatment-emergent adverse event(s)
tlast
time of last plasma concentration above LLOQ
tmax
time to reach maximum drug concentration in plasma after single 
(first) dose
tmax,md
time to reach maximum drug concentration in plasma after multiple-
dose administration
TNM
tumor node metastasis (classification)
TSH
thyroid stimulating hormone (thyrotropin)
TTP
time to progression
ULN
upper limit of norm (upper limit of normal laboratory values)
USA
United States of America
V
apparent volume of distribution
vs.
versus
Vss/F
apparent volume of distribution at steady state after extravascular 
administration
Vz/F
apparent volume of distribution during terminal phase after oral 
administration


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WBC
white blood cell (count)
Definitions of terms
Progression-free 
survival 
(PFS)
Time (days) from the date of the first dose of study drug to the date 
of the first observed radiological disease progression or death, 
whatever comes first. 
PFS for subjects without tumor progression at the time of analysis 
will be censored at their last date of tumor evaluation.
Time to 
progression 
(TTP)
Time (days) from start of study treatment until objective tumor 
progression; TTP does not include deaths.


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3
Introduction - amended
Background information 
Fibroblast growth factors (FGF) and their corresponding receptor family (FGFR) drive 
crucial oncogenic signaling pathways including cell proliferation, survival and 
migration (1)(2). FGFRs are commonly altered in various human tumor diseases, 
including FGFR1 amplification in non-small cell lung cancer (e.g. sqNSCLC (3)(4)), 
squamous cell carcinoma of the head and neck (SCCHN (38)), or activating mutations of 
FGFR3 in bladder cancers (BC (5)(6)(7)). These changes contribute to tumor cell growth, 
sustained angiogenesis, invasion and metastasis and resistance against other therapies.
BAY 1163877 is an oral inhibitor of FGFR1, 2 and 3 and showed strong anti-tumor 
efficacy in pre-clinical models as a single agent as well as in combination with cytotoxic 
agents in FGFR pathway addicted tumor models. 
The targeted application form is oral and preclinical data suggest low clearance and low 
volume of distribution resulting in a daily dose of 300 to 800 mg.
Further details can be found in the investigator's brochure (IB), which contains
comprehensive information on the study drug. The IB in its most current version is 
available in the Study File.
Rationale of the study 
The target indications for BAY 1163877 in the expansion phase of this study are 
sqNSCLC, lung adenocarcinoma (LAC), BC and SCCHN. Preclinical data demonstrate a 
strong anti-tumor efficacy of BAY 1163877 in all four tumor types as a single agent. In 
human sqNSCLC, amplification of FGFR1 has been demonstrated in up to 21% of cases 
(8)(9)(10)(11), and FGFR1 amplification was found in 15 % of SCCHN cases (38) which 
is usually detected by FISH-based analysis of gene copy number alterations. Recent data 
from the literature, however, suggest that stratification via this approach may not be of 
sufficient sensitivity as a considerable number of subjects has been identified with low to 
intermediate gene copy numbers, rendering these subjects ineligible for targeted therapies 
with other FGFR inhibitors (12)(13). Analysis of responsive and non-responsive xenograft 
models revealed a strong correlation with total FGFR1, 2 and 3 mRNA expression levels 
that will be used as a stratification biomarker in the expansion phase of this trial. 
Additional genetic information needs to be confirmed as data from the literature (10)(14)
and in-house data confirmed a strong influence on tumor response through additional 
oncogenic mutations (e.g. in K-ras). In BC, activating mutations of FGFR3 have been 
described in up to 70% of cases (15)(6)(16) and will be used as an additional stratification 
marker if overall mRNA expression in these subjects is low. This stratification approach 
allows to minimize the risk for subjects who will potentially not benefit and increase the 
chance for generating early signs of clinical efficacy. Inhibition of FGFR1 leads to the 
upregulation of FGF23 in serum (17), which will be used as sensitive pharmacodynamic 
(PD) biomarker. Inhibition of extracellular signal-regulated kinase (ERK) phosphorylation 
will be assessed as an additional PD biomarker from tumor tissue.


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Preclinical data suggest a good tolerability and efficacy in these subject populations after 
continuous oral dosing with BAY 1163877. 22
It was shown that FGFR3 expression is inversely correlated to programmed death-ligand 1 
(PD-L1) expression and T cell infiltration in tumor tissue of patients with BC (40). This 
finding was confirmed in archival biopsy samples collected in study 16443. A similar 
correlation was detected in patients with sqNSCLC and LAC in study 16443.
It is assumed that a causal relationship between FGFR expression and T cell exclusion 
leads to low PD-L1 levels and decreased responsiveness towards inhibition of the PD-L1 
axis. Potentially, inhibition of FGFR can overcome this interaction and render tumors 
targetable by the immune system.
Immune responses and the tumor microenvironment are inadequately reflected in 
preclinical cancer models. We therefore aim to analyze selected immune parameters 
before and during BAY1163877 treatment in paired biopsies and in serum of biomarker-
selected patients. Fresh tumor tissue will be used to assess immune parameters indicating a 
T cell response against the tumor tissue. This will be done by performing gene expression 
profiling (nCounter PanCancer Immune Profiling Panel) and immunohistochemistry for 
CD8+ T cell infiltration and PD-L1 expression on the tumor tissue. Peripheral blood will 
be used to collect serum to determine cytokine levels (IL-6, IFN-gamma, and other 
cytokines if needed). Aim of the assessment of peripheral blood is to search for changes in 
this easily accessible specimen that reflect the immune response in the tumor tissue.
Guidance regarding selected adverse events of special interest is provided in Section 8.4.3. 
Additional details can be found in the IB.
Benefit-risk assessment 
BAY 1163877 is expected to demonstrate clinical benefit as additional treatment for 
subjects with refractory, locally advanced or metastatic solid tumors.
Taken all preclinical data together, BAY 1163877 has an acceptable safety profile with 
promising therapeutic efficacy. Subjects will be closely monitored for adverse events by 
the investigator for any adverse events starting from baseline visit till the end of the study 
visit to ensure the safety of subjects.
The subjects may not personally benefit from participation in the trial. They are the first to 
receive BAY 1163877 that may possibly become the standard of care. However, the 
therapy being tested is new, and the side effects in humans are unknown. Subjects 
participating in this trial will be seen frequently by qualified health care professional who 
provide care and closely monitor and evaluate the subject’s response to the study 
medication, in terms of its safety and effectiveness. Since there is often no alternative for 
subjects with advanced, refractory cancer, the risk–benefit ratio for finding the MTD may 
therefore be acceptable to the subjects.
                                                
22 The following section was added by Amendment 7, see section 15.6.2.3


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The study shall be discontinued in the event of new findings that indicate that a relevant 
deterioration of the risk - benefit relationship is probable. On the basis of the data 
available to date, the conduct of the study is regarded as justifiable.
In summary, this Phase I study of BAY 1163877 for the treatment of refractory, locally 
advanced or metastatic solid tumors is justifiable without exposing subjects to an undue 
risk.


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4
Study objectives - amended
The primary objectives are:

To determine the safety and maximum tolerated dose (MTD) of BAY 1163877 in 
subjects with advanced solid organ malignancies 

To characterize the pharmacokinetics (PK) of BAY 1163877
Secondary objectives include:

To evaluate biomarker status, pharmacodynamic (PD) parameters, and tumor 
response.

To assess the relative bioavailability of the tablet formulation in comparison to the 
solution formulation of BAY 1163877.
Exploratory objective:

To evaluate selected immune parameters.23
5
Investigator(s) and other study participants - amended
Sponsor’s Medical Expert
Name:
Title:
Address:
Bayer AG
Muellerstr, 178
13353 Berlin, Germany
Telephone No:
Coordinating Investigator for the Study
Name:
Title:
Address:
Germany
Telephone No:
Fax No:
                                                
23 Immune parameters added by Amendment 7, see section 15.6.2.4
24 The medical expert changed, see Amendment 7, section 15.6.2.5
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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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 (ISF).
Whenever the term ‘the 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 sheet before 
subject recruitment may start at the respective center. Likewise, all protocol amendments / 
integrated protocols must be signed and dated by the principal investigator 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 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.
6
Study design - amended
Design overview
This is a Phase I, first-in-human, open-label, non-randomized, multi-center, 2-part, dose-
escalation study of BAY 1163877 in sequential cohorts of subjects with refractory, locally 
advanced or metastatic solid tumors. The study will be conducted at multiple centers 
worldwide.
Study Part 1 will identify the maximum tolerated dose (MTD) in subjects with any solid 
tumors (all comer) using an adaptive dose escalation design and expansion of cohort at 
MTD.
Study Part 2 will explore further the safety and PD of BAY 1163877 at the MTD 
identified in Part 1 in subjects with sqNSCLC, LAC, BC and SCCHN to seek any 
evidence of preliminary clinical responses. Study Part 2 may start as soon as the MTD has 
been established in Part 1.
Study Part 3 will expand the safety database for patients on treatment with  BAY1163877 
at the MTD identified in Part 1 with sqNSCLC, LAC, and BC. In parallel, in Part 3 
additional efficacy data will be collected and changes of selected immune parameters will 
be assessed.
The complete duration of the study (Part 1, Part 2, and Part 3) depends on the number of 
dose-escalation steps in Part 1 and will be approximately 7 years. 25
                                                
25 Part 3 - Safety cohort - was added by Amendment 7, see section 15.6.2.6


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Planned sample size:
Subjects will be enrolled in the pre-treatment phase of the study to recruit enough subjects 
with present high FGFR expression levels for the following study parts.
Targeted / planned enrollment:

Study Part 1 / dose escalation (all comer): The total number of subjects will 
depend on the number of cohorts necessary to identify the MTD. Relative bioavailability 
of the tablet formulation in comparison to the solution formulation will be performed in all 
subjects enrolled in one of the dose escalation cohorts; pharmacokinetic data are needed in 
a minimum of 3 subjects for relative bioavailability assessment.

Study Part 1 / MTD expansion (all comer): Additional subjects will be enrolled to 
have 20 evaluable “all comer” subjects treated at MTD.

Study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN): additional 
subjects will be enrolled to have 20 evaluable subjects with sqNSCLC or LAC and at least 
30, up to a maximum of 50 evaluable subjects with BC and at least 8 subjects with 
SCCHN treated at MTD.
26

Study Part 3 / MTD expansion “Safety cohort” (sqNSCLC + LAC + BC): 
additional subjects will be enrolled to have approximately 20 subjects with sqNSCLC or 
LAC and approximately 20 subjects with BC treated at MTD.27
PK assessments will be performed in all subjects participating in study Part 1 / dose 
escalation and MTD expansion (all comer) and study Part 3/ MTD expansion “Safety 
cohort”. Additionally, PK assessments are planned in at least 12 subjects participating in 
study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN) such that valid PK 
data are available in 8 subjects and in approximately 8 subjects of the MTD expansion 
cohorts with impaired renal function at baseline.26 Food effect PK assessment is planned 
in approximately 8 subjects enrolled in the MTD expansion cohorts (study Part 1 and Part 
2). Subjects participating in “food effect assessment” in study Part 2 may be included in 
the total sample size of 12 if all protocol requirements are met.
All subjects participating in either of the 3 MTD expansion cohorts (Part 1, Part 2 and Part 
3 despite subjects with impaired renal function)28 will have 2 PK samples drawn for the 
purpose of exposure-response modelling on Day 1 of Cycles 2, 3, 4, and 5 (1 blood sample 
just before the morning dose of BAY 1163877 and 1 blood sample between 0.5 and 1.5 
hours post-dose). Subjects in Part 3 will provide one PK sample within 1 hour of biopsy 
collection in Cycle 2.29 The dose needs to be taken under supervision and the time 
                                                
26 Modified by Amendment 6, see section 15.6.2.6
27 Part 3 - Safety cohort - was added by Amendment 7, see section 15.6.2.6
28 Part 3 was added by Amendment 7, see section 15.6.2.6
29 PK sampling in Part 3 was added by Amendment 7, see section 15.6.2.6


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recorded.
Study periods: 
Figure 6-1: Schematic presentation of the treatment design - amended
§ The first study (screening) visit is scheduled within 7 days / within 28 days before administration of the first 
dose of BAY 1163877 (written informed consent for study treatment eligibility). 
Subjects recruited for Part 1,Part 2, or Part 3 MTD expansion cohorts have their first study visit before study 
(screening) visit to perform a biomarker analysis for subject stratification (mandatory written informed consent 
for FGFR expression / FGFR mutation testing). Those subjects who are eligible for participation in the MTD 
expansion cohort must additionally sign the informed consent for study treatment eligibility at the screening 
visit.30
# The first dose will be administered on Cycle 1, Day 1, except for subjects participating in relative bioavailability 
assessment (“tablet bridging cohort”) and “food effect assessment” who will receive the first dose on Cycle 1, 
Day -3.  
*Follow-up:  
- EOT (End of Treatment) visit within 0-14 days of last dose of BAY 1163877  
- FU (Follow-up) visit / contact at 30-35 days after last dose of BAY 1163877
In total, the “on study” period for all subjects comprises 3 phases (see Figure 6-1):

Pre-treatment 
-
Testing for FGFR expression and FGFR mutation (only for subjects recruited for 
Part 1, Part 2 or Part 3 MTD expansion cohorts)31
-
Screening

Treatment 
-
Study Part 1 / dose escalation + MTD expansion (all comer):
Individual number of 21-day Cycles with BAY 1163877 monotherapy (tablet or 
solution) until disease progression or as long as clinical benefit is assumed by the 
investigator or until unacceptable toxicity occurs. 
                                                
30 Part 3 was added by Amendment 7, see section 15.6.2.6
31 Part 3 was added by Amendment 7, see section 15.6.2.6
First study
Visit§
First dose
administration #
EOT visit
FU-visit / 
contact 
Pre-treatment
Treatment
Follow-up (FU)*
On study
Last dose 
administration 
Cycle X


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-
Study Part 1 / “tablet bridging cohort” (all comer):
In one of the dose escalation cohorts, administration of a single dose of 
BAY 1163877 using the tablet formulation on Cycle 1, Day -3 followed by 
solution formulation starting Cycle 1 Day 1 as described above. 
-
Study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN): 
Individual number of 21-day Cycles with continuous BAY 1163877 monotherapy 
(tablet or solution) until disease progression or as long as clinical benefit is 
assumed by the investigator or until unacceptable toxicity occurs. 
-
Study Part 1 (MTD expansion cohort) and Study Part 2 (sqNSCLC + LAC + BC + 
SCCHN) / “Food Effect Assessment”: 
Approximately 8 subjects will receive single doses of BAY 1163877 on Cycle 1, 
Day -3 (after consumption of a high-fat, high-calorie breakfast) and on Cycle 1, 
Day 1 (after an overnight fast of at least 8 hours) followed by treatment according 
to the schedule described above starting on Cycle 1, Day 3.
-
Study Part 3 / MTD expansion “Safety cohort” (sqNSCLC + LAC + BC): 
Individual number of 21-day Cycles with continuous BAY 1163877 monotherapy 
(tablet) until disease progression or as long as clinical benefit is assumed by the 
investigator or until unacceptable toxicity occurs. 32
Note: Treatment with BAY 1163877 at MTD in Part 1 (expansion cohort “all comer”),  
Part 2 (expansion cohort sqNSCLC + LAC + BC + SCCHN), and Part 3 (expansion cohort 
“Safety cohort”, sqNSCLC + LAC + BC) can run in parallel.32

Follow-up (FU)
-
End of Treatment (EOT) visit 0-14 days after last dose of BAY 1163877
-
Follow-up (FU) visit at 30-35 days after dose of BAY 1163877
The first screening visit is scheduled within 7 days / within 28 days before administration 
of the first dose of BAY 1163877. The informed consent form will be signed by the 
subject before or at the first screening visit (please refer to Section 13.2). The screening 
period ends just before start of treatment.
The treatment period starts on the day of the first administration of study treatment either 
on Cycle 1, Day 1 or on Cycle 1, Day -3 (“tablet bridging cohort” and “food effect 
assessment”) and ends with the last day when the study medication is administered in 
Cycle X. The length of treatment period may vary from subject to subject dependent on 
the number of individual treatment cycles. A Cycle for this study is defined as 21 days. 
There will be no break between cycles. 
When a subject starts new anti-cancer therapy, he / she is no longer considered “on study”.
An End of Treatment (EOT) visit will be performed for all subjects within 0-14 days after 
                                                
32 Part 3 - Safety cohort - was added by Amendment 7, see section 15.6.2.6


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administration of the last dose of BAY 1163877. The Follow-up visit for subjects who 
either discontinue prematurely or finish dosing with BAY 1163877 will be performed 30-
35 days after the last study drug treatment. There will be no long-term (survival) follow-
up (FU) period. 
Treatment: Subjects with PK assessment (all subjects of study Part 1 and 3 and at least 
12 subjects of study Part 2 and approximately 8 subjects of the MTD expansion cohorts 
with impaired renal function at baseline) will receive BAY 1163877 (tablet or solution) on 
a continuous schedule starting with single-dose administration on Cycle 1, Day 1, 
followed by a “drug-free day” (to enable single dose PK assessments, except for subjects 
in Part 3 who will receive BAY 1163877 twice daily continuously with no “drug free 
day”).33 Treatment with BAY 1163877 will resume on Day 3 of Cycle 1 if no protocol-
defined dose-limiting toxicities (DLTs) are reported. Starting on Cycle 1, Day 3, the study 
drug will be self-administered twice daily for the remaining 19 days of Cycle 1. For 
subsequent cycles, study drug will be administered twice daily for 21 days until disease 
progression or as long as clinical benefit is assumed by the investigator or until 
unacceptable toxicity occurs.
In one of the dose escalation cohorts in study Part 1 (“tablet bridging cohort”), relative 
bioavailability of the tablet formulation will be assessed by administration of a single dose 
of the tablet formulation on Cycle 1, Day -3. Starting with Cycle 1, Day 1, subjects 
enrolled in the “tablet bridging cohort” will continue with the solution formulation as 
described above. Depending on the results from the relative bioavailability assessment, 
subjects who initially start with solution formulation may be switched to tablet 
formulation in later cycles.
Approximately 8 subjects enrolled in the MTD expansion cohorts (study Part 1 and Part 2) 
will receive single doses of BAY 1163877 on Cycle 1, Day -3, after consumption of a 
high-fat, high-calorie breakfast and on Cycle 1, Day 1, after an overnight fast of at least 
8 hours followed by treatment according to the schedule described above starting on 
Cycle 1, Day 3.
Subjects without PK assessment in study Part 2 will receive BAY 1163877 (tablet or 
solution) twice daily from Cycle 1, Day 1 ongoing. 
At home, subjects will document the intake of study drug in a diary (see Section 8.7).
Subjects will continue receiving treatment until tumor progression, unacceptable toxicity, 
consent withdrawal, or subject withdrawal from the study at the discretion of the 
Investigator or his/her designated associate(s), see Section 7.2.1. As long as, in the 
judgment of the subject and the investigator, some benefit with evidence of tumor 
reduction or stable disease is being derived, dosing with BAY 1163877 may continue.
Determination of the maximum tolerated dose (MTD)
An adaptive dose escalation design will be used to determine the MTD in study Part 1 (all 
                                                
33 Part 3 was added by Amendment 7, see section 15.6.2.6


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comer). The MTD is defined as the highest dose that can be given such that not more than 
20% of subjects experience a DLT during Cycle 1.
Without the occurrence of toxicities, dose escalation could be stopped and RP2D may be 
determined based on PK and/or PD results. The decision to continue treatment for an 
individual subjects will be made by the investigator according to the criteria specified in 
the protocol (Section 8.4).
Each cohort will be evaluated after all subjects have completed the first 21 days of 
treatment (which will subsequently referred to as “Cycle 1”) or early discontinued.
Safety monitoring will occur by telephone conferences with participation of the 
investigators and the sponsor on a regular basis.
At the time of dose escalation the available clinical safety information is discussed in a 
telephone conference by the involved investigators and representatives from the Sponsor 
including the Study Medical Expert as well as representatives of other clinical and if 
required further contributing functions (drug safety monitoring team – DSMT). During 
this telephone conference it will be judged if dose escalation can proceed as planned 
according to the procedure outlined below. Dose escalation for subsequent cohorts will 
only be considered after full evaluation of at least Cycle 1 safety data from the previous 
cohort.
The National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
Version 4.03 (CTCAE v4.03) will be used to grade toxicities / adverse events. In general, 
the assessment of relationship between adverse events (AEs) and BAY 1163877 will be 
performed as described in Section 9.5.1.2.3.
The dose escalation will be performed as follows:

Initially 3 subjects per dose level will be enrolled. In case 2 or more sites are 
conducting the dose escalation part, the initial enrolment of 4 subjects per dose level is 
optional. 

The starting dose of BAY 1163877 is 50 mg given as a single dose on Cycle 1, 
Day 1, and twice daily (b.i.d.) from Cycle 1, Day 3 (100 mg / day).

The maximum dose escalation will be 2-fold.

Possible daily doses of BAY 1163877 starting from 100mg in increments of 
100mg.

The possible maximum dose of BAY 1163877 is considered to be 550 mg b.i.d. 
(1100 mg / day). Higher doses might be explored after discussions between sponsor and 
investigators.

If at least 1 subject out of 3 or 1 out of 4 in a cohort has DLTs or if at least 
2 subjects report drug-related AEs (CTCAE v4.03) of Grade ≥ 2, any further dose 
escalation, de-escalation or cohort expansion will be decided in consultation between all 
investigator(s), and the sponsor (within the DSMT) after consideration of all available 
safety data of the previous cohorts. Any subsequent dose will be selected in order to 
determine the MTD. 


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Model-based dose-response analysis of the DLT rates will be performed during these 
interim reviews in order to guide the dose decision (see details in Section 16.4). The 
model-based dose selection procedure is considering data at all dose levels (not just at the 
last cohort). The dose predicted to yield 20% DLT rates will be reported from that model 
as a best candidate for the next cohort. 
The final decision about the next dose will be made by the sponsor in consultation with all 
investigators (DSMT). 
If the selected dose is larger than the last dose tested, then escalation will be pursued. If it 
is lower, a de-escalation step will occur. 
Cohort expansion will occur when a previously tested dose is selected again for the next 
cohort of 3 subjects. 
Expansions at any given dose up to a total of 9 subjects are allowed. In principle, the 
selection of a next dose level where the predicted DLT rate is close to 20% should insure 
that the next dose tested will remain safe. 
Nevertheless, the following constraint will be added in order to protect subject safety 
during the adaptive dose selection decisions:
-
If 2 out of 3 (or 2 out of 4), at least 4 out of 6 (or at least 5 out of 9) subjects 
experience DLTs at a given dose level, only lower doses will be given in all 
subsequent cohorts because the probability that the dose is above the MTD is very 
large (above 95.4%).
-
The dose-escalation procedure will be stopped as soon as:
o
the MTD has been defined with good precision (i.e., the coefficient of variation for 
the MTD is lower than or close to 40%) 
or
o
at any time when the selected dose level for the next cohort has already been given 
in 9 subjects.
If the dose escalation stops, the sample size for the MTD cohort will be expanded up to a 
total of 20 evaluable subjects (study Part 1 / MTD expansion cohort (all comer)).
No intra-subject dose escalation is permitted. Dose interruptions and / or dose reductions 
may be required based on individual safety and tolerability.
Pharmacokinetics (PK):  Single- and multiple-dose PK of BAY 1163877 will be 
evaluated in plasma samples collected on Cycle 1, Day -3 in the “tablet bridging cohort”, 
and on Cycle 1, Days 1 and 15 in all subjects participating in Part 1 (all comer) and in at 
least 12 subjects participating in Part 2 (sqNSCLC + LAC + BC + SCCHN). In 
approximately 8 subjects enrolled in the MTD expansion cohorts (study Part 1 and Part 2), 
the effect of food on the PK of BAY 1163877 will be determined by comparing exposures 
on Cycle 1 Day -3 (administration after consumption of a high-fat, high-calorie breakfast) 
and Cycle 1 Day 1 (administration after an overnight fast of at least 8 hours), see 
Section 8.1.  In the MTD expansion cohorts, in approximately 8 subjects with moderately
impaired renal function at baseline (glomerular filtration rate [GFR] of 30 to 59 
mL/min/1.73 m2 according to the modified diet in renal disease [MDRD] abbreviated 
formula), serial PK blood samples will be collected on Cycle 1 Day 1 and Day 15. In all 


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subjects participating in Study Part 3/”Safety cohort”, multiple dose PK of BAY 1163877 
will be evaluated in plasma samples collected on Cycle 1, Day 15.34
Plasma concentration of BAY 1163877 will be measured using a validated method. 
In approximately 8 subjects enrolled in MTD expansion cohorts (study Part 1 and Part 2), 
urine will be collected for 24 hours after dosing on Cycle 1, Day 1 (concurrently with 
plasma PK samples) and analyzed using validated method.
Exploratory monitoring of metabolites may also be performed in pooled plasma samples 
(most likely at the MTD or the therapeutic dose) and urine samples. 
The time points for PK sampling and further details are provided in Section 9.4.2.1.
Safety / tolerability:  Drug safety will be monitored and evaluated continuously 
throughout the study, including a 30-day follow up period (time window +5 days) after 
administration of the last dose of BAY 1163877. 
Safety will be assessed by close monitoring and timely assessment of adverse events 
(AEs), laboratory parameters (blood tests, urinalysis), vital signs (blood pressure, heart 
rate), subject’s medical condition (physical examination including weight), 
ophthalmological examination, general well-being and activities of daily life (Eastern 
Cooperative Oncology Group (ECOG) performance status). 35
Each subject will be regularly assessed in each cycle for potential AEs and disease related 
signs and symptoms. The National Cancer Institute’s Common Terminology Criteria for 
Adverse Events, Version 4.03 (CTCAE v4.03) will be used to grade toxicities / AEs.
Subject data will be analyzed for evidence of cumulative toxicity with repeated cycles of 
therapy.
Women of childbearing potential must have a negative pregnancy test performed within 
7 days prior to first treatment with BAY 1163877 (i.e. 1 week before Cycle 1, Day 1 or 
Cycle 1, Day -3, if applicable). 
Cardiovascular assessment: Blood pressure (BP) and heart rate (HR) will be measured at 
screening, frequently on PK profile days in Cycle 1, and once at all other visits during 
treatment and follow up. The time points for monitoring BP and HR on the days of PK 
sampling and further details are provided in Section 9.4.1.1.
Assessment of immune priming (Part 3): Selected parameters of immune response will 
be measured in fresh tumor tissue at baseline and again between Cycle 2, Day 1 and Cycle 
2, Day 21; and in peripheral blood at the following timepoints: at baseline; Cycle 1, Day 
8; Cycle 2, Day 1; Cycle 2, Day 15; and on the day of the second biopsy.
Fresh tumor tissue will be used to assess immune parameters indicating a T cell response 
against the tumor tissue. This will be done by performing gene expression profiling 
                                                
34 Part 3 was added by Amendment 7, see section 15.6.2.6
35 Amended by Amendment 7, see section 15.6.2.6


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(nCounter PanCancer Immune Profiling Panel) and immunohistochemistry for CD8+ T 
cell infiltration and PD-L1 expression on the tumor tissue. Peripheral blood will be used to 
collect serum to determine cytokine levels (IL-6, IFN-gamma, and other cytokines if 
needed). Aim of the assessment of peripheral blood is to search for changes in this easily 
accessible specimen that reflect the immune response in the tumor tissue.36
Electrocardiogram (ECG): 12-lead ECG readings will be performed at screening, on 
Cycle 1, Days -3 and -2 (“tablet bridging cohort” and “food effect assessment”, only), on 
Cycle 1, Days 1, 2, and 15, thereafter on Day 1 of each subsequent Cycle, and at the EOT 
visit. In all Cycles  and at the EOT visit, ECG readings will be performed as single 
readings. The time points for ECG readings and further details are provided in 
Section 9.5.3.4.
Pharmacodynamic (PD) biomarkers: In an attempt to demonstrate the mechanism of 
action of BAY 1163877 biomarkers will be studied in tissue samples (for details see 
Section 9.4.4). 
Biomarker analysis in tumor tissue: Biomarker analysis will be done at screening for 
subject stratification in the MTD expansion cohorts (Part 1: all comer; Part 2: sqNSCLC + 
LAC + BC + SCCHN; Part 3: sqNSCLC + LAC + BC) according to FGFR expression 
levels / FGFR mutation using either an archival tumor tissue specimen or fresh tumor 
biopsy material (see Section 7.1.1, inclusion criteria).37
Analysis of phospho-extracellular signal-regulated kinase 1/2 levels, (p-ERK1/2) will be 
done at screening and on Cycle 2, Day 1 for all subjects of study Part 1 and Part 2 who are 
willing to undergo a biopsy both at screening and on Cycle 2, Day 1.38 Both biopsies are 
mandatory for “all comer” subjects included in the MTD expansion cohort of Part 1 
(please refer to Section 7.1.1 for details).
Tumor response evaluation: Computed tomography (CT) or magnetic resonance 
imaging (MRI) of all anatomic regions involved with the disease will be performed at 
screening (baseline), at the end of Cycle 2 and thereafter every third cycle to assess tumor 
response using the Response Evaluation Criteria in Solid Tumors, Version 1.1. 
(RECIST v1.1)(1).
Response evaluation according to RECIST v1.1 can be done up to 5 days after CT / MR 
scan. 
Recommended Phase II dose (RP2D): The dose recommended for Phase II studies with 
BAY 1163877 will be determined by the investigators and the sponsor (DSMT) at the end 
of this study (after Part 2) after having reviewed the data from all dose levels evaluated 
including PK data, overall incidence and severity of AEs, cardiac safety, and amount of 
MTD.
                                                
36 Part 3 - Safety cohort - was added by Amendment 7, see section 15.6.2.6
37 Part 3  was added by Amendment 7, see section 15.6.2.6
38 ‘Study Part 1 and Part 2’ added by Amendment 7 for clarification, see section 15.6.2.6


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6.1
Primary variable(s)
This is primarily a descriptive safety and tolerability Phase I study. The primary variable 
for MTD determination will be the incidence of DLTs during the first 21 days of treatment 
(Cycle 1). The primary study outcome is the MTD being defined as the maximum dose at 
which the incidence of DLTs during Cycle 1 is below 20%. 
Primary PK parameters are provided in Section 9.4.2.2. 
6.2
Justification of the design - amended
For study objectives please see Section 4.
The study will be conducted at multiple sites worldwide to ensure recruitment of a 
sufficient number of subjects with advanced solid organ malignancies. The sites must be 
specialized in tumor assessment according to RECIST 1.1 and must be well equipped to 
conduct the efficacy and safety evaluations required by the protocol.
Only subjects for whom in the opinion of the investigator, experimental therapy with 
BAY 1163877 may be beneficial are allowed to participate. Life expectancy in most of 
those subjects is expected to be about 3 months. Dosing with BAY 1163877 may continue 
without evidence of tumor reduction or stable disease as long as, in the judgment of the 
investigator, some benefit is being derived. The inclusion of a placebo control or blinding 
of the treatment is considered not applicable for the objectives of this dose-escalation 
study (identification of MTD / RP2D).
The open-label, non-randomized, dose-escalating design is the standard design to define 
the safety profile, MTD, PK, PD biomarker and tumor response profile in subjects with 
advanced malignancies.
Once DLTs are reported, the use of adaptive dose-selection decisions according to pre-
specified safety rules based on actual DLT observations is chosen because it permits a 
better determination of the MTD with reduced sample size, while limiting the number of 
subjects being treated with toxic doses.
The "all-comers" design in study Part 1 will allow for expedited accrual of subjects and 
evaluation of safety in subjects with varied solid tumor types (any solid tumors).
Study Part 3 / “Safety cohort” (sqNSCLC + LAC + BC)39
Preliminary safety data of patients with advanced cancer treated with BAY 1163877
showed a favorable safety profile (details can be found in the current version of the IB). 
However, sample size is still limited in selected indications (sqNSCLC, LAC, BC) and 
additional safety data  will be generated in Study Part 3 “Safety cohort”. In parallel, 
additional efficacy data will be collected and changes of selected immune parameters will 
be assessed in Part 3.
                                                
39 The following section was added by Amendment 7, see section 15.6.2.7


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It was shown that FGFR3 expression is inversely correlated to programmed death-ligand 1 
(PD-L1) expression and T cell infiltration in tumor tissue of patients with BC (40). This 
finding was confirmed in archival biopsy samples collected in study 16443. A similar 
correlation was detected in patients with sqNSCLC and LAC in study 16443.
Recently, the PD-1 and PD-L1 inactivating antibodies received accelerated approval by 
the FDA for patients with BC. It was demonstrated that patients with a low expression of 
PD-L1 had a smaller chance to respond to atezolizumab treatment. 
It is assumed that a causal relationship between FGFR expression and T cell exclusion 
leads to low PD-L1 levels and decreased responsiveness towards inhibition of the PD-L1 
axis. Potentially, inhibition of FGFR can overcome this interaction and render tumors 
targetable by the immune system.
Immune responses and the tumor microenvironment are inadequately reflected in 
preclinical cancer models. We therefore aim to analyze selected immune parameters 
before and during BAY1163877 treatment in paired biopsies and in serum of biomarker-
selected cancer patients. Fresh tumor tissue will be used to assess immune parameters 
indicating a T cell response against the tumor tissue. This will be done by performing gene 
expression profiling (nCounter PanCancer Immune Profiling Panel) and 
immunohistochemistry for CD8+ T cell infiltration and PD-L1 expression on the tumor 
tissue. Peripheral blood will be used to collect serum to determine cytokine levels (IL-6, 
IFN-gamma, and other cytokines if needed). Aim of the assessment of peripheral blood is 
to search for changes in this easily accessible specimen that reflect the immune response 
in the tumor tissue.
6.3
End of study
For each participating EU country, the end of the study according to the EU Clinical Trial 
Directive will be reached when the last visit of the last subject (LPLV) for all centers in 
the respective country has occurred. 
As for this study, the primary outcome will be analyzed at 6 months from last patient first 
visit (LPFV) or after LPLV, whatever comes first. 
The end of the study as a whole will be the date when the clean data base is available.
However, the LPLV date can also be reached based on the last patient stopping study 
treatment, switching to a roll-over study, or being switched to commercial drug supply 
with no cost to the patient. 
If the trial is stopped but benefits are observed for patients, further treatment options may 
be discussed and agreed between the investigator, sponsor and the patients.
See also Sections 8.2 and 8.8 for further details on the roll-over study.
7
Study population
Subjects with histologically or cytologically confirmed refractory, locally advanced or 
metastatic solid tumors are eligible. Subjects should have evaluable or measurable disease. 


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Subjects’ tumors must be refractory to standard treatment, have no standard therapy 
available or subjects who actively refused cytotoxic chemotherapy which would be 
regarded standard, and / or if, in the judgment of the investigator, experimental treatment 
is clinically and ethically acceptable.
7.1
Eligibility 
7.1.1 Inclusion criteria
7.1.1.1
Eligibility criteria for FGFR expression / FGFR mutation testing 
(only for MTD expansion cohorts of study Part 1, Part 2 and Part 3)
- amended40

Ability to understand and willingness to sign the written subject information sheet / 
informed consent form (SIS / ICF) for FGFR expression / FGFR mutation testing (see 
Section 13.2). Signed informed consent (IC) has to be obtained before any study specific 
procedure. 

Subjects with histologically or cytologically confirmed, refractory, locally 
advanced or metastatic solid tumors (all comer for study Part1; sqNSCLC, LAC, BC or 
SCCHN for Part 2; sqNSCLC, LAC, or BC for Part 3) who are not candidates for standard 
therapy. 40

Male or female subjects ≥18 years of age

Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or 2

Life expectancy of at least 3 months

Existence of archival or fresh tumor biopsy specimen for FGFR expression / FGFR 
mutation testing.
Besides these basic criteria, any criterion as outlined below under inclusion and exclusion 
criteria (Sections 7.1.1.2 and 7.1.2) already known to prohibit the patient’s participation in 
the study should be considered.  
7.1.1.2
Eligibility criteria for study treatment - amended
Screening for study treatment eligibility must be performed within 7 days / within 28 days 
prior to the first dose of study drug. Subjects must fulfill all of the following criteria 
before being included in the treatment phase (i.e, before receiving any dose of BAY 
1163877):

Ability to understand and willingness to sign the written SIS / ICF for study 
                                                
40 Part 3 - Safety cohort - was added by Amendment 7, see section 15.6.2.8


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treatment eligibility. Signed IC obtained before any (further) study specific procedure. 

Subjects with histologically or cytologically confirmed, refractory, locally 
advanced or metastatic solid tumors who are not candidates for standard therapy.
Subjects with any type of solid tumors (all comer) will be eligible for dose escalation and 
dose expansion at MTD in Part 1.

Subjects enrolled in the MTD expansion cohorts of Study Part 1, Part 2 and Part 3 
must present high FGFR expression levels based on archival or fresh tumor biopsy 
specimen analysis.
Bladder cancer subjects with low overall FGFR expression levels can be included if 
activating FGFR3 mutations are confirmed. 
(only for MTD expansion cohorts of study Part 1 (all comer), Part 2 (sqNSCLC + 
LAC +BC + SCCHN) and Part 3 (sqNSCLC + LAC + BC)).41

Subjects must have at least one measurable or evaluable lesion according to 
Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. A lesion in a 
previously irradiated area is eligible and to be considered as measurable disease as long as 
there is objective evidence of progression of the lesion prior to study enrollment. 

Subjects with resected primary tumors who have documented metastases are 
eligible.

Subjects consent to undergo a paired biopsy at screening and on Cycle 2, Day 1
(only for MTD expansion cohorts of study Part 1(all comer))
Note: Anticancer chemotherapy must have been stopped for at least 5 half-lives of the last 
applied therapy before the pre-treatment biopsy for biomarker (p-ERK1/2) studies is 
taken. Mitomycin C, nitrosoureas or monoclonal antibodies with anticancer activity (e.g. 
bevacizumab or cetuximab etc.) should not be given within 6 weeks of pre-treatment 
biopsy for biomarker (p-ERK1/2) studies.42

Subjects consent to undergo paired biopsies at screening and between Cycle 2, Day 
1 and Cycle 2, Day 21
(only for Study Part 3 / MTD expansion “Safety cohort” (sqNSCLC + LAC + BC)) 43

Male or female subjects ≥18 years of age

Life expectancy of at least 3 months

Recovery to National Cancer Institute’s Common Terminology Criteria for 
Adverse Events, version 4.03 (CTCAE v4.03) Grade 0 or 1 level or recovery to baseline 
preceding the prior treatment from any previous drug / procedure-related toxicity (subjects 
with persistent alopecia, anemia, and / or hypothyroidism can be included).
                                                
41 Part 3 was added by Amendment 7, see section 15.6.2.9
42 Amended by Amendment 7, see section 15.6.2.9
43 Part 3 - Safety cohort - was added by Amendment 7, see section 15.6.2.9


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
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or 2

Adequate bone marrow, liver and renal function as assessed by the following 
laboratory requirements conducted within 7 days of starting the study treatment:
- Absolute neutrophil count (ANC) ≥ 1,500/mm3
- Platelet count ≥ 75,000/mm3
- Total bilirubin ≤ 1.5 times the upper limit of normal (ULN). Documented Gilbert 
syndrome is allowed if total bilirubin is mildly elevated (< 6 mg/dL). 
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x 
ULN (≤ 5 x ULN for subjects with liver involvement of their cancer)
- Alkaline phosphatase limit ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver 
involvement of their cancer)
- Lipase ≤ 5 x ULN
- Not more than Child-Pugh score B7 hepatic impairment
- Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m2 according to the modified 
diet in renal disease (MDRD) abbreviated formula

International normalized ratio (INR) ≤ 1.5 x ULN and partial thromboplastin time 
(PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN. Subjects being treated 
with anticoagulant, e.g. warfarin or heparin, will be allowed to participate provided no 
prior evidence of an underlying abnormality in these parameters exists. Close monitoring 
of at least weekly evaluations will be performed until INR is stable based on a pre-dose 
measurement as defined by the local standard of care. 

Subjects with a history of hypertension should be on stable anti-hypertensive 
medicine for more than 7 days before start of study treatment.

Women of childbearing potential and men must agree to use adequate 
contraception before entering the program until at least 8 weeks after the last study drug 
administration. The investigator or a designated associate is requested to advise the subject 
on how to achieve an adequate birth control. Adequate contraception is defined in the 
study as any medically recommended method (or combination of methods) as per standard 
of care.

Women of childbearing potential must have a pregnancy test performed a 
maximum of 7 days before start of study treatment, and a negative result must be 
documented before start of study treatment.
7.1.2 Exclusion criteria
Subjects are to be excluded from the study if they display any of the following criteria:


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7.1.2.1
Exclusion criteria for FGFR expression / FGFR mutation testing 
(only for MTD expansion cohorts of study Part 1)

No archival biopsy available and no consent to obtain tumor biopsy. 

Subject still on anticancer treatment or in the washout period of a previous 
anticancer treatment (defined as 5 half-lives of the anticancer agent [or 6 weeks for 
mitomycin C, nitrosureas and monoclonal antibodies]) at the time the fresh biopsy would 
be obtained if no archival biopsy is available
7.1.2.2
Exclusion criteria for FGFR expression / FGFR mutation testing 
(only for MTD expansion cohorts of study Part 2 and Part 3) -
amended44

No archival biopsy available and no consent to obtain tumor biopsy.
7.1.2.3
Exclusion criteria - amended

FGFR testing shows low FGFR expression levels
(only for MTD expansion cohorts of study Part 1 (all comer), Part 2 (sqNSCLC + LAC + 
SCCHN) and Part 3 (sqNSCLC + LAC))

No consent for mandatory paired biopsies for biomarker (Part 1) or assessment of 
immune parameters (Part 3)
(only for MTD expansion cohorts of study Part 1 (all comer) and study Part 3 (sqNSCLC+ 
LAC + BC)45

FGFR expression / FGFR mutation testing shows low FGFR expression levels and
absence of activating mutation in FGFR3 gene 
(only for Part 2 and Part 3 (BC))
Medical and surgical history

Previous or concurrent cancer that is distinct in primary site or histology from the 
cancer being evaluated in this study except cervical carcinoma in situ, treated basal cell 
carcinoma or any cancer curatively treated > 3 years prior to start of study treatment

Previous treatment with anti-FGFR directed therapies (e.g. receptor tyrosine kinase 
inhibitors or FGFR-specific antibodies)

Symptomatic metastatic brain or meningeal tumors unless the subject is 
> 6 months from definitive therapy, has no evidence of tumor growth on an imaging study 
within 4 weeks prior to start of study treatment and is clinically stable with respect to the 
tumor at the start of study treatment. Also the subject must not be undergoing acute steroid 
therapy or taper (chronic steroid therapy is acceptable provided that the dose is stable for 
                                                
44 Part 3 was added by Amendment 715.6.2.11
45 Part 3 was added by Amendment 7, see section 15.6.2.11


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one month prior to and following screening radiographic studies).

History or current condition of an uncontrolled cardiovascular disease including 
congestive heart failure (CHF) > NYHA (New York Heart Association) Class 2, unstable 
angina (symptoms of angina at rest) or new-onset angina (within last 3 months) or 
myocardial infarction (MI) within past 6 months and cardiac arrhythmias requiring anti-
arrhythmic therapy (beta-blockers or digoxin are permitted)

History of human immunodeficiency virus (HIV) infection or chronic 
hepatitis B or C 

Active clinically infections (> CTCAE v4.03 Grade 2)

Seizure disorder requiring medication 

History of organ allograft

Evidence or history of bleeding diathesis or coagulopathy  

Any hemorrhage / bleeding event ≥CTCAE v4.03 Grade 3 within 4 weeks prior to 
the start of study medication

Serious, non-healing wound, ulcer or bone fracture

Known hypersensitivity to any of the study drugs, study drug classes, or excipients 
in the formulation

Unresolved toxicity higher than CTCAE v 4.03 Grade 1 (excluding alopecia, 
anemia and / or hypothyroidism) attributed to any prior therapy / procedure 

Any condition that is unstable or could jeopardize the safety of the subject and 
their compliance in the study

Any malabsorption condition

Pregnant or breast-feeding subjects
Medication, drug use and special behavioral patterns

Prior treatment with BAY 1163877. Subjects permanently withdrawn from study 
participation will not be allowed to re-enter the study.

Concomitant therapies that cannot be discontinued or switched to a different 
medication prior to study entry that are known to increase serum phosphate levels are not 
permitted within 4 weeks prior to start of study treatment). 

Anticancer chemotherapy or immunotherapy during the study or within 5-half-
lives prior to start of study treatment. Mitomycin C, nitrosoureas or monoclonal antibodies 
with anticancer activity (e.g. bevacizumab or cetuximab etc.) should not be given within 6 
weeks before starting to receive study treatment or within 6 weeks of pre-treatment biopsy 
for biomarker (p-ERK1/2) studies. Acute toxic effects of previous anticancer 
chemotherapy or immunotherapy have to be normalized completely (excluding alopecia). 
Anticancer therapy is defined as any agent or combination of agents with clinically proven 
anti-tumor activity administered by any route with the purpose of affecting the 


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malignancy, either directly or indirectly, including palliative and therapeutic endpoints.

Use of strong inhibitors of CYP3A4 and strong inducers of CYP3A4 should have 
been stopped 2 weeks before start of study treatment (see Section 16.11).

Radiotherapy to target lesions during study or within 3 weeks of start of study 
treatment. Palliative radiotherapy is allowed.

Use of systemic corticosteroids within 2 weeks of start of study treatment above 
the Cushing threshold 

Autologous bone marrow transplant or stem cell rescue within 4 months of start of 
study treatment 

Major surgery, open biopsy or significant traumatic injury within 4 weeks of start 
of study treatment

Subjects undergoing renal dialysis
Electrocardiogram (ECG), blood pressure, heart rate

Systolic / diastolic blood pressure ≤ 100/60 mmHg and heart rate ≥ 100/min 
(measured with the subject in a sitting position for at least 2 minutes).
Physical examination

Clinically relevant findings in the physical examination 
Laboratory examination

Positive pregnancy test

Deviations of the screened laboratory parameters from the defined ranges (see 
inclusion criteria) 
Other

Subjects unable to swallow oral medications

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)

Substance abuse, medical, psychological or social conditions that may interfere 
with the subject’s participation in the study or evaluation of the study results
7.1.3 Justification of selection criteria
The selection criteria are chosen to ensure that subjects with specific risks for 
administration of the study drugs and / or subjects with conditions which may have an 
impact on the aims of the study are excluded.
7.1.4 Justification for gender selection
As this is a Phase 1, dose-escalation trial, no specific gender distribution is necessary. 
The envisaged indication for BAY 1163877 is treatment of refractory, locally advanced or 


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metastatic solid tumors in males and females. The proportion of male and female subjects 
enrolled in this study depends only on the availability of eligible subjects at the study site. 
7.2
Withdrawal of subjects from study
7.2.1 Withdrawal - amended
Subjects will be withdrawn from the study for the following reasons:

Consent withdrawal
- At their own request or at the request of their legally acceptable representative
- At any time during the study and without giving reasons, a subject may decline to 
participate further. The subject will not suffer any disadvantage as a result.

Substantial non-compliance with study procedures
- Subject who is off study drug (BAY 1163877) longer than 8 consecutive days in 
Cycle 1 
- Subjects lost to follow-up

Violation of in- / exclusion criteria (subject no longer eligible for the study)
- If the subject develops conditions which would have prevented his / her entry into 
the study according to the in- / exclusion criteria, he / she must be withdrawn 
immediately if safety is concerned; in other cases, the investigator will decide 
whether there is a conflict with the study objectives.
- The development of a second malignancy that requires a different treatment.
- 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.
- Subjects with a positive urine beta-HCG test confirming pregnancy. Pregnancy 
will be reported under the same timelines as a serious adverse event.

Unacceptable toxicity
- If, in the investigator’s opinion, continuation of study would be harmful to the 
subject’s well-being
- Severe allergic reactions, such as exfoliate erythrodermia, anaphylaxis, or vascular 
collapse
- Any other potential adverse reaction deemed sufficiently serious to warrant 
discontinuation of treatment by the investigator or his designated associate(s).
- 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 


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or otherwise confound the results.
- Retinal detachment of grade 2 or higher according to CTCAE v4.03 46
- AST/ALT > 3xULN with concomitant bilirubin > 2xULN in the absence of 
another reason for these elevations46
- AST/ALT > 8xULN or AST/ALT > 5xULN for > 2 weeks if no other reason is 
found for these elevations46

Tumor progression
- Subjects with documented disease progression, unless the investigator (in 
consultation with the sponsor) deems that continued treatment is appropriate.
Patients may continue if they experience clinical benefit as assessed by the 
investigator, do not exhibit rapid disease progression and have stable performance 
status.  In addition, treatment beyond progression should not delay an imminent 
intervention to prevent serious complications of disease progression (e.g. CNS 
metastases).46

At specific request of the sponsor
In all cases, the reason for withdrawal must be recorded in the electronic case report form 
(eCRF) and the subject’s medical record.
A subject who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the subject has already been administered at least 1 dose of the study drug 
(BAY 1163877).
A subject who, for any reason (e.g. failure to satisfy the selection criteria), terminates the 
study before the time point used for the definition of “dropout” (see above) is regarded a 
“screening failure”.
Any subject removed from the study will remain under medical supervision until 
discharge or transfer is medically acceptable. 
Details for the premature termination of the study as a whole (or components thereof 
[e.g. centers, dose steps]) are provided in Section 12.
7.2.2 Replacement
Subjects who discontinue due to a DLT will NOT be replaced.
Subjects who discontinue during the first cycle of therapy (Cycle 1) due to any reason 
other than a DLT and / or related toxicity, and subjects who took less than 80% of the 
required study drug (BAY 1163877) in Cycle 1 (see Section 8.7) will be replaced to 
ensure 3 evaluable subjects per cohort for the determination of MTD and PK of 
BAY 1163877. Subjects who discontinue after the first cycle (Cycle 1) will not be 
                                                
46 Withdrawal criteria were added by Amendment 6, see section 15.6.2.12


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replaced.
Subjects enrolled in Study Part 1 / MTD expansion (all comer) with insufficient paired 
biopsy samples will be replaced to ensure at least 10 subjects with paired biopsy samples 
for p-ERK1/2 analysis.
7.3
Subject identification
Each subject who signs a consent form for the study will be assigned a unique 9-digit 
screening number (SNR) in ascending order of recruitment into the study at that center. 
The first 2 digits will refer to the country, the subsequent 3 digits to the site number, and 
the following 4 digits will be subject identifiers. 
This SNR will be entered into the electronic case record form (eCRF) regardless of 
whether the subject is actually treated with the study drug (BAY 1163877). 
Subjects who are not treated will be considered screening failures. The reason for 
screening failure should be recorded in the eCRF.
8
Treatment(s)
8.1
Treatments to be administered - amended
Investigational medicinal product (IMP) – test drug

BAY 1163877 drinking solution (test drug)

BAY 1163877 tablet (test drug)
Non-investigational product(s) (NIMP)
Not applicable
In study Part 1 / dose escalation + MTD expansion (all comer), twice daily dosing of 
BAY 1163877 follows the dose-escalation scheme described in Section 6 (Determination 
of the maximum tolerated dose (MTD)).
Study Part 1 starts with single-dose administration of 50 mg BAY 1163877 on Cycle 1, 
Day 1. After a “drug-free day” (Cycle 1, Day 2), multiple doses of BAY 1163877 will be 
given twice daily in an adaptive dose escalation manner, starting at a dose of 100 mg / day 
(50 mg b.i.d.), with possible dose steps of 100 mg / day. The dose-escalation design 
proceeds with cohorts of 3 subjects. Cohort expansion, increase or decrease in dose will be 
decided by the DSMT after consideration of all available safety data of the previous cohort 
(see Section 6). The dose decision will be guided by model-based dose-response analysis 
of the DLT rates (see Section 16.4).
In the “tablet bridging cohort”, relative bioavailability of the tablet formulation in 
comparison to the solution formulation will be assessed by administration of a single dose 
of the tablet formulation on Cycle 1, Day -3 in at least 3 subjects. Starting with Cycle 1, 
Day 1, subjects enrolled in this cohort will continue with the solution formulation as 
described above. 
In study Part 1 / MTD expansion (all comer), subjects will receive the MTD of 


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BAY 1163877 determined at the end of dose escalation.
For the “food effect assessment”, subjects will receive one single dose of BAY 1163877 
on Cycle 1, Day -3 immediately (within 5 min) after consumption of a high-fat, high-
calorie breakfast, and a second single dose BAY 1163877 on Cycle 1, Day 1 after an 
overnight fast of at least 8 hours. Further details are provided in Section 8.4.2.2.1.
In study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN), subjects will be 
treated with the MTD of BAY 1163877 determined in study Part 1. 
In study Part 3 / MTD expansion “Safety cohort” (sqNSCLC + LAC + BC), subjects will 
be treated with the MTD of BAY 1163877 determined in study Part 1. 47
8.2
Identity of study treatment
The details of the two formulations of BAY 1163877 planned to be used in this study are 
given in Table 8-1 (solution) and Table 8-2 (tablet). 
Table 8-1:
Identity of test drug (IMP):  BAY 1163877 solution formulation  
Generic name / brand name / INN
Not applicable
Substance code number(s)
BAY 1163877 as BAY 1213802
Material / (formulation) 
BAY1163877 HCl H2O SOL 1% 11 mL ORAL
Galenical form / formulation / vehicle and 
reconstitution, if applicable
Ready-to use solution for oral application
Composition
Active ingredients:  
BAY 1163877 as hydrochloride
Other ingredients:  
Hydroxypropylbetadex (solubilizer)
Sucralose (sweetener)
Sodium benzoate (preservative)
Hydrochloric acid (pH-adjustment agent)
Sodium hydroxide (pH-adjustment agent)
Purified water (solvent)
Strength (amount of drug per unit) or 
concentration
1% (10 mg of BAY 1163877 per 1 mL solution)
Type of packaging and content
Amber glass bottle with a withdrawable volume of 
11 mL corresponding to 110 mg BAY 1163877 
Marketing Authorization Holder if applicable
Not applicable  
                                                
47 Part 3 - Safety cohort - was added by Amendment 7, see section 15.6.2.13


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Table 8-2:
Identity of test drug (IMP):  BAY 1163877 tablet formulation 
Generic name / brand name / INN
Not applicable
Substance code number(s)
BAY 1163877 as BAY 1213802
Material / (formulation) 
BAY 1163877 HCL TAB 50.0 mg 363 COAT
BAY 1163877 HCL TAB 200.0 mg 364 COAT
Galenical form / formulation / vehicle and 
reconstitution, if applicable
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)*
* (contains hypromellose, macrogol, titanium
    dioxide,ferric oxide red)
Strength (amount of drug per unit) or 
concentration
50 mg BAY 1163877 per tablet
200 mg BAY 1163877 per tablet
Type of packaging and content
HDPE bottles with screw cap closure or blisters 
of Foil 25/45/60 µm oPA/Al/PP (4320 / 0257)
sealed to Foil 20 µm Al sealable to PP (4345 / 
0202)
Marketing Authorization Holder if applicable
Not applicable  
Labeling:  Study medication 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. Storage
conditions are provided on the label.
For all study drugs, a system of numbering in accordance with all requirements of good 
manufacturing practice (GMP) will be used, ensuring that each dose of study drug can be 
traced back to the respective bulk ware of the ingredients. Lists linking all numbering 
levels will be maintained by the sponsor’s clinical supplies Quality Assurance (QA) 
group.
A complete record of batch numbers and expiry dates of all study treatment as well as the 
labels will be maintained in the sponsor study file.
To reorder clinical drug supplies at least 2 weeks advance notice is required. The site 
should inform the responsible person for the drug reorder. Contact details of the 
responsible person are provided on the study team list. The responsible person will notify 
the site when the order for drug has been placed.


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All investigational drugs used during the trial will be stored at the site in accordance with 
instructions given by the clinical supplies delivering department, and will be inaccessible 
to unauthorized personnel. 
Study medication needs to be stored according to the label text. For special storage 
conditions see investigator site file (ISF) and trial master file (TMF).
In case patients are transferred to a roll-over study (ROS), drug formulation and / or 
dosage might change compared to this study depending on the course of the clinical 
development. 
8.3
Treatment assignment
After completion of the screening examinations, subjects who meet the entry criteria will 
be placed in the current cohort at the specified dose level. A random list is not necessary 
because this is a non-randomized open label clinical trial. All subjects will be assigned a 
unique screening number (SNR), whether or not they are treated after the first signed 
informed consent. For subject identification, see Section 7.3.
8.4
Dosage and administration
Please refer to Sections 8.1 and 8.2 for the dose, route of administration, formulation and 
duration of treatment. 
8.4.1 Estimation of safe starting dose
Study Part 1 / dose escalation (all comer)
The first cohort is treated at a starting dose of 100 mg / day of BAY 1163877 (50 mg 
b.i.d.) which is considered to be safe based on extrapolation from animal toxicological 
data. 
The dose level for each dose-escalation step will be defined primarily based on the results 
with regard to safety, tolerability, and, if available, PK of the previous dose steps. For this 
reason, an evaluation will be conducted after each dose step and the decision for the next 
step will be made by the study team. If necessary, the dose of the next step will be 
adopted. Details for the dose-escalating steps are given in Section 6 (Determination of the 
maximum tolerated dose (MTD)).
8.4.2 Selection and timing of dose for each subject - amended
Details for the dose-escalating steps in study Part 1 / dose escalation + MTD expansion 
cohort (all comer) as well as extent and duration of drug exposure of the individual subject 
are given in Section 6 (Determination of the maximum tolerated dose (MTD)). Safety
monitoring will occur by teleconferences with participation of the investigators and 
representatives of the sponsor on a regular basis (DSMT). Dose escalation for subsequent 
cohorts will only be considered after all subjects from the previous cohort have completed 
the first cycle or early discontinued.
Extent and duration of drug exposure of the individual subject in study Part 2 / dose 
expansion (sqNSCLC + LAC + BC + SCCHN) and study Part 3 / dose expansion “Safety 


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cohort” (sqNSCLC + LAC + BC) are given in Section 6.48
8.4.2.1
Dosing schedule - amended
BAY 1163877 will be given in cycles. Each cycle lasts 21 days. There will be no break 
between treatment cycles. 
Subjects will receive either the solution (IMP 1) or the tablet (IMP 2) formulation of 
BAY 1163877, except for subjects in the “tablet bridging cohort” who will receive both a 
single dose using the tablet formulation and multiple doses using the solution formulation. 
Study Part 1 / dose escalation + MTD expansion cohort (all comer):
Cycle 1 Day -3 (“tablet bridging cohort” only):
Single-dose administration of
BAY 1163877 tablet formulation on Cycle 1, Day -3; 
thereafter continuation with solution formulation 
starting on Cycle 1, Day 1 (see dosing schedule 
below)
Cycle 1:
Single-dose administration of BAY 1163877 on 
Cycle 1, Day 1 (in the morning)
No administration of BAY 1163877 on Cycle 1, 
Day 2 (“drug-free day”)
Twice daily administration of BAY 1163877 on 
Days 3-21
Cycle 2 and subsequent cycles:
Twice daily administration of BAY 1163877 on
Days 1-21. 
Study Part 2 / dose expansion (sqNSCLC + LAC + BC + SCCHN):

Subjects participating in PK assessments will follow the dosing regimen specified 
for study Part 1.

Subjects without PK assessment will receive BAY 1163877 twice daily from 
Cycle 1, Day 1 ongoing.
Study Part 1 (MTD expansion cohort) or Study Part 2 / “Food Effect Assessment”: 
Approximately 8 subjects will receive single doses of BAY 1163877 on Cycle 1, Day -3 
(after consumption of a high-fat, high-calorie breakfast) and on Cycle 1, Day 1 (after an 
overnight fast of at least 8 hours). BAY 1163877 will not be administered on Cycle 1, 
Day -2 and Day -1, in the evening of Cycle 1, Day 1 and on Cycle 1, Day 2. 
Study Part 3 / MTD expansion “Safety cohort” (sqNSCLC + LAC  + BC):

Subjects will receive BAY 1163877 twice daily from Cycle 1, Day 1 ongoing.49
                                                
48 Part 3 added by Amendment 7, see section 15.6.2.14
49 Part 3 - Safety cohort - was added by Amendment 7, see section 15.6.2.15


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Evidence of tumor progression, unacceptable toxicity, consent withdrawal or subject’s 
withdrawal from the study at the discretion of the Investigator may lead to termination of 
treatment (see Section 7.2.1).
8.4.2.2
Mode of administration
BAY 1163877 will be administered per os (p.o.). Subjects participating in “food effect 
assessment” will receive a single dose after consumption of high-fat, high-calorie meal 
(Cycle 1, Day -3) and a single dose after an overnight fast of at least 8 hours (Cycle 1, Day 
1) see Section 8.4.2.2.1.
The ready-to-use solution will be administered directly and undiluted via disposable 
syringe into the mouth of the subject. Immediately after administration, the subject has to 
drink a glass of water (approximately 200 mL / 7 ounces).
BAY 1163877 tablets should be taken with a glass of water (approximately 200 mL / 
7 ounces). Tablets should be swallowed intact and not chewed.
Subjects should not take additional doses of BAY 1163877 to compensate for a missed 
dose.
8.4.2.2.1 Food effect assessment
To assess the effect of food on the PK of BAY 1163877, a single dose of BAY 1163877 
will be administered immediately (within 5 minutes) after consumption of a high-fat, high-
calorie breakfast on Cycle 1, Day -3 followed by PK profiling in subjects participating in 
the MTD expansion cohorts of study Part 1 and Part 2.  
Examples of high-fat, high-calorie breakfast: 
A) 50 grams of smoked cooked ham, 30 grams of chicken liver sausage, 50 grams of 
rye bread, 7 ounces (210 mL) whole milk, 40 grams of butter, 30 grams of butter 
cheese and 17 Crispbread Wasa Mjölk
B) 2 eggs (fried), 2 strips of bacon, 2 slices of bread toast, 8 ounces (240 mL) whole 
milk and 3 teaspoons of butter (for frying and for toast) 
High-fat, high-calorie breakfast may be adapted depending on the country while 
maintaining similar fat and calorie content (approximately 50 % fat and 800 to 1000 
calories). Breakfast should be consumed within 25 minutes. No snack is permitted for 
4 hours after study drug administration.  
BAY 1163877 will not be administered on Cycle 1, Day -2 and Day -1.
A single dose of BAY 1163877 will be administered on Cycle 1, Day 1 after an overnight 
fast of at least 8 hours (water is allowed ad libitum) followed by PK profiling. No food or 
snack is permitted for 4 hours after drug administration, but water is allowed 1 hour after
dosing.  
Study drug will not be administered in the evening of Cycle 1, Day 1 and on Cycle 1, 
Day 2 (“drug-free day”). 
Starting with Cycle 1, Day 3, BAY 1163877 will be taken twice daily.


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8.4.2.3
Treatment duration
BAY 1163877 will be administered on a continuous schedule in at least one 21-day Cycle 
with no break between cycles until progression or as long as clinical benefit is assumed by 
the investigator or until unacceptable toxicity occurs.
For subjects in the “tablet bridging cohort” and “food effect assessment”, treatment starts 
on Cycle 1, Day -3.
For all other subjects, treatment starts on Cycle 1, Day 1.  
Further details on dosing schedule are provided in Section 8.4.2.1. 
8.4.3 Dose modification and delays - amended
Doses of study drug (BAY 1163877) may be delayed or reduced in case of clinically 
significant hematologic and other toxicities that are possibly, probably or definitely related 
to study drug therapy. Toxicities will be graded using the CTCAE v 4.03 (see 
Section 16.5). 
No intra-subject dose escalation will be permitted. However, the dose can be reduced or 
delayed for an individual subject based on toxicities that are related to study drug.
If a subject experiences a DLT during Cycle 1, the next dose of BAY 1163877 can be 
delayed for up to 21 days, but only in cases Grade 3 non-hematological toxicities persist 
no longer than 7 days.
All subjects who are re-treated following a DLT should undergo dose reduction (see Table 
8-3).
If the toxicity resolves to Grade 1, the next dosing of BAY 1163877 at 1 dose level 
below the current dose (see Table 6-3) can be considered, provided that this dose level has 
been evaluated during the dose escalation part of the study. Detailed dose adjustments for 
hematological toxicities are described in Table 8-4. If the subject was dosed at the starting 
dose level, the subject should be removed from the study. If the toxicity fails to resolve to 
Grade 1within 21 days after the planned treatment date, the subject will be removed 
from the study. Subjects who experience a Grade 4 non-hematological toxicity will be 
removed from the study. 
Drug-related adverse events of Grade 3 
For Grade 3 adverse event regarded as related to study drug, the next dosing of 
BAY 1163877 can be delayed for up to 21 days. If the toxicity fails to resolve to 
Grade 1 within 21 days after the scheduled dosing date, the subject will be removed 
from the study. If the toxicity resolves to Grade 1, the next dosing of BAY 1163877 at 1 
dose level below the current dose (see Table 8-5) can be considered, provided that this 
dose level has been evaluated during the dose escalation part of the study. Dose 
adjustments for toxicities are detailed in Table 8-3.
If the re-treatment reproduces the same toxicity grade, the next dosing of BAY 1163877 
can be delayed for up to 21 days until the toxicity has resolved to Grade 1. Re-treatment 
is possible at 1 dose level below the previous dose. 


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Subjects who experience a Grade 4 non-hematological toxicity will be removed from the 
study. If more than 2 dose reductions are required, treatment will be permanently 
discontinued. 
Table 8-3:
Scheme for dose-level reduction of BAY 1163877 in subjects with solid 
tumors
Dose level
Action
-1
1 dose below level of DLT occurrencea
-2
2 doses below level of DLT occurencea
-3
Discontinue study drug permanently
a
alternatively, treatment can be continued at an interim dose level with at least 3 subjects 
evaluated
Table 8-4:
Hematological criteria for dose delay and dose modification
Gradea
ANC
(109/L)
Platelets
(109/L)
Dose delay
Dose modification
1 - 2
1.0
50
Treat as scheduled
No change
3
<1.0 - 0.5
<50 - 25
Delayb until Grade 1
Decrease 1 dose levelc
4
<0.5
<25
Delayb until Grade 1
Decrease 1 dose levelc
a
Applies to all kinds of hematological toxicities; ANC and platelet count displayed as examples.
b
If no recovery after 21 days delay, treatment will be permanently discontinued.
c
Dose will not be re-escalated to original dose level after reduction for toxicity. If more than 
2 dose reductions are required, treatment will be discontinued.
Table 8-5:
Non-hematological criteria for dose delay and dose modification
Gradea
Dose delay
Dose modification
1 – 2
Treat as scheduled
No change
3
Delayb until Grade 1
Decrease 1 dose levelc
4
Discontinue study drug permanently
Discontinue study drug permanently
a
Excludes alopecia. A maximum duration of 48 hours of Grade 3 nausea or vomiting will be 
allowed and not be considered DLT. 
b
If no recovery after 21 days delay, treatment will be permanently discontinued.
c
Dose will not be re-escalated after dose reduction for toxicity. If more than 2 dose reductions 
are required, treatment will be permanently discontinued.
Liver toxicity
Dose modifications of BAY 1163877 for liver toxicity are presented in Table 8-6. Liver 
toxicity refers to ALT and / or AST and / or bilirubin increases and / or hepatic failure 
considered possibly related to BAY 1163877, and graded according to CTCAE v4.03. 


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Table 8-6:
Dose modifications of BAY 1163877 for liver toxicity - amended
Toxicity
Modification schedule
Grade 1-2
No modifications. Treat as scheduled and check 
AST, ALT and bilirubin weekly for at least 4 weeks.
Grade 3 
Hold BAY 1163877 until recovery to ≤grade 2 or 
baseline, 
then reduce 1 dose level and check AST, ALT and 
bilirubin weekly for at least 4 weeks.a
- 1st reappearance
Hold BAY 1163877 until recovery to ≤grade 2 or 
baseline,
then reduce 1 additional dose level and check AST, 
ALT and bilirubin weekly for at least 4 weeksa.
- 2nd reappearance
Withdraw subject from the study treatment.b
Grade 3 with ALT or AST > 8x ULN 
and a concomitant rise in bilirubin 
(of any degree compared to previous 
bilirubin level) 
or hepatic failure (of any degree)
In case of a negative risk-benefit assessment, 
consider permanent discontinuation at the first 
occurrenceb,c
OR
Hold BAY 1163877 until recovery to ≤grade 2 or 
baseline,
then reduce 1 dose level and check AST, ALT and 
bilirubin weekly for at least 4 weeksa.
-1st reappearance
Withdraw subject from study treatment.b
Grade 4 b
Withdraw subject from study treatment.b
a
Dose will not be re-escalated after dose reduction for toxicity50
b
In case of discontinuation, check AST, ALT, and bilirubin weekly until recovery to baseline 
or stabilization.
c
Subjects 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.
Patients with AST/ALT > 3xULN with concomitant bilirubin > 2xULN in the absence of 
another reason for these elevations have to permanently discontinue study drug.  
Permanent discontinuation also applies to patients with AST/ALT > 8xULN or AST/ALT 
> 5xULN for > 2 weeks if no other reason is found for these elevations.50
Increased Ca x PO451
Dose modifications of BAY 1163877 for . Ca x PO4 ≥ 70 mg²/dL² considered possibly 
related to BAY 1163877 are presented in Table 8-7.
                                                
50 Liver toxicity criteria amended by Amendment 6, see section 15.6.2.16
51 Section amended by Amendment 6, see section 15.6.2.16


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Table 8-7:
Dose modifications of BAY 1163877 for Increased Ca x PO4 -
amended
Toxicity
Modification schedule
Ca x PO4 (≥ 70 mg²/dL²)
Hold BAY 1163877, treat with phosphate
chelators and check twice weekly until recovery, to Ca x 
PO4 < 70 mg²/dL². 
Resume same dose level, continue phosphate chelators 
and check weekly for at least 4 weeks.
- 1st reappearance
Hold BAY 1163877, treat with phosphate 
chelators and check twice weekly until recovery to Ca x 
PO4 < 70 mg²/dL², 
then reduce 1 dose level, continue phosphate chelator and 
check weekly for at least 4 weeks.
- 2nd reappearance
Hold BAY 1163877 and check twice weekly until recovery 
to Ca x PO4 < 70 mg²/dL²,
then reduce 1 additional dose level, continue phosphate 
chelators and check weekly for at least 4 weeks.
- 3rd reappearance
Withdraw subject from study treatment.
In patients with hyperphosphatemia (Ca x PO4 ≥ 70 mg²/dL²), the serum phosphate and 
calcium levels have to be checked twice weekly until resolution (Ca x PO4 < 70 mg²/dL²).
In patients with hypocalcemia, an additional 12-lead ECG has to be obtained on the day of 
detection of hypocalcemia.
Retinal detachment
Patients that experience retinal detachment of grade 2 or higher according to CTCAE 
v4.03 have to be permanently discontinued from study treatment.  
8.4.4 Dose-limiting toxicity (DLT)
Adverse events which qualify as DLTs are causally related to study drug (while in turn not 
all related AEs are regarded as DLT). Dose-limiting toxicity will be defined as any of the 
following occurring during Cycle 1 of a dose level and regarded by the investigators and / 
or sponsor to be related to BAY 1163877. The CTCAE v 4.03 will be used to assess 
toxicities / adverse events (see Section 16.5).
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

Grade 3 hemorrhage associated with thrombocytopenia of ≥ Grade 3


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Non-hematological

Non-hematologic Grade 3 or Grade 4 toxicity (nausea and vomiting only if 
refractory to anti-emetics; excluding alopecia). A maximum duration of 48 hours of Grade 
3 nausea or vomiting will be allowed and not be considered DLT.

Serum calcium (albumin-corrected) x phosphate product > 70 mg²/dL² 
(5.6 mmol²/L²) despite the use of phosphate binders 
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 toxicity thought to be related to BAY 1163877 that, at the discretion of the 
investigator, or his designated associate(s), is thought to warrant withholding the drug. 
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 subject’s compliance.
For certain toxicities such as laboratory assessments without a clear clinical correlation 
(e.g. lipase increase without signs of a clinical pancreatitis), a discussion between the 
investigator and the sponsor may take place if that adverse event should be assessed as 
DLT necessitating dose reduction.
8.5
Blinding
The study is performed in a non-blinded design because this is considered adequate to 
meet the study objectives. 
8.6
Drug logistics and accountability
Study medication will be stored at the investigational site in accordance with good clinical 
practice (GCP) and GMP requirements and the instructions given by the clinical supplies 
department of the sponsor (or its affiliate / contract research organization (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 study file; the site-
relevant elements, of this information will be available in the ISF. The responsible site 
personnel will confirm receipt of study drug in writing and will use the study drug only 
within the framework of this clinical study and in accordance with this protocol. Receipt, 
distribution, return and destruction (if any) of the study drug must be properly documented 
according to the sponsor’s agreed and specified procedures.
Written instructions on medication destruction will be made available to affected parties as 
applicable.


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8.7
Treatment compliance
Treatment compliance
The first administration of study medication (BAY 1163877) will be done with a member 
of the site team. This person will ascertain and document that the subject receives the 
treatment as planned.
On the following days the subject will self-administer (or a caregiver will administer) 
BAY 1163877 after he / she has been informed about the correct dosing schedule. 
Plasma / serum concentrations will give additional information about the subjects’ 
treatment compliance.
At home, subjects will document the intake of study drug (date and time of dosing) as well 
as the administered dose on a compliance sheet / paper diary (source document to verify 
treatment compliance), see Section 9.6.1. 
The packages of study medication have to be brought back to the trial site for an additional 
control. 
Compliance will be evaluated by the investigational site based on drug accountability. 
The information recorded in the paper diary will be transferred into the eCRF taking into 
account each dose interruption and / or any individual changes in dosing. 
A compliance of at least 80% is required, meaning documented intake of at least 80% of 
the planned study medication (80 % = 32 doses or 16 days in Cycle 1 with PK assessment 
[Part 1 and Part 2 only] and 34 doses or 17 days in ≥ Cycles 2 and in Cycle 1 without PK 
assessment [including Part 3]). 52
Drug accountability
To have complete control over the distribution and use of the study medication, the drug 
accountability must be performed before new medication is handed out to the subject.
8.8
Post-study therapy
Further treatment at the end of the study will be 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 drug. 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 is established, the present study will end when all patients 
have transitioned into the roll-over study or discontinued from this study for another 
reason (e.g. consent withdrawn, lost to follow-up, death). Until the transition to the roll-
                                                
52 Modified by Amendment 7, see Section 15.6.2.17


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over study, patients will continue to follow all the procedures and visits required in the 
current version of the protocol.
8.9
Prior and concomitant therapy
For prior therapy, see Section 7.1.2 (Exclusion criteria “Medication, drug use and special 
behavioral patterns”). 
Medication other than the investigational product must not be taken during the study 
without consulting the investigator. 
All therapies that are considered necessary for the subject’s welfare and that are not 
expected to interfere with the evaluation of the study drug may be given at the discretion 
of the investigator. 
Disease-specific anti-neoplastic therapies, including kinase inhibitors, chemotherapy, 
radiation therapy, or surgical intervention, are not allowed during study treatment.
All concomitant medications (including start / stop dates, total daily dose, and indication) 
must be recorded in the subject’s source documentation and in the eCRF. Concomitant use 
of contrast media needs not to be recorded unless the subjects experiences and AE and 
there is a reasonable possibility that the event might have been caused by exposure to 
contrast media.
8.9.1 Drug-drug interactions relevant for BAY 1163877
Oxidative metabolism of BAY 1163877 is mainly catalyzed by CYP3A4 and CYP1A1 
and to a lesser extent by CYP2C9. Therefore, drugs and herbal preparations that are strong 
inhibitors and inducers of CYP3A4 are not permitted during the study. Currently, there are 
no known approved drugs or herbal preparations that are strong CYP1A1 inhibitors or 
inducers. However, it should be noted that CYP1A1 is induced in smokers. The subjects 
who are current smokers and those with recent history of smoking may have lower 
plasma concentrations of BAY 1163877.
Initial in vitro study results with BAY 1163877 indicate minor mechanism-based 
(irreversible) inhibition potential towards CYP 3A4. Since several commonly used drugs 
are metabolized by CYP 3A4, subjects should be proactively closely monitored for side 
effects of these comedications due to potentially increased systemic exposure. 
In general, subjects should be closely monitored for side effects of all concomitant 
medications regardless of elimination pathway, especially those with narrow therapeutic 
index. If possible, narrow therapeutic index drugs that are CYP3A4 substrates should be 
avoided (see Section 16.11).
No data are available to evaluate the interaction between BAY 1163877 and radiation.
8.9.2 Prohibited concomitant therapy
Concomitant therapy with the following medication is NOT allowed:

Anticancer chemotherapy or immunotherapy during the study or within 5-half-
lives prior to start of study treatment. Antibody treatment should not be given within 6 


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weeks before starting to receive study treatment. Acute toxic effects of previous anticancer 
chemotherapy or immunotherapy have to be normalized completely (excluding alopecia, 
anemia and / or hypothyroidism). Anticancer therapy is defined as any agent or 
combination of agents with clinically proven anti-tumor activity administered by any route 
with the purpose of affecting the malignancy, either directly or indirectly, including 
palliative and therapeutic endpoints.

Mitomycin C, nitrosoureas or monoclonal antibodies with anticancer activity (e.g. 
bevacizumab or cetuximab etc.) should not be given within 6 weeks before starting to 
receive study treatment or within 6 weeks of pre-treatment biopsy for biomarker (p-
ERK1/2) studies in case of performed biopsy procedure 

Bone marrow transplant or stem cell rescue.

Investigational anti-tumor agents or anti-neoplastic chemo / hormonal / 
immunotherapy.

Radiotherapy to target lesions (palliative radiotherapy is allowed)

CYP3A4 inhibitors and inducers: BAY 1163877 is mainly metabolized by 
CYP3A4 and CYP1A1 and to a lesser extent by CYP2C9. Therefore, concomitant use of 
strong inhibitors of CYP3A4 and strong inducers of CYP3A4 are not permitted for 2 
weeks prior to start of study treatment or during the study. Concomitant use of moderate 
and weak CYP3A4 inducers should be avoided as clinically significant decrease in plasma 
concentrations of BAY 1163877 cannot be ruled out. Strong CYP3A4 inhibitors and 
inducers are shown in Section 16.11.

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.

If possible, narrow therapeutic index drugs that are CYP3A4 substrates (e.g. 
alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, 
sirolimus, and tacrolimus) should be avoided

Fluconazole is considered a moderate to strong inhibitor of CYP 2C9 and should 
be avoided, if possible.

Therapies that are known to increase serum calcium and / or phosphate levels, 
especially calcium, phosphate, vitamin D, parathyroid hormone (parathormone).
Therapeutic monitoring should be performed consistent with the local clinical standard of 
care following dose modification of the investigational agent. In general, subjects should 
be closely monitored for side effects of all concomitant medications regardless of path of 
elimination.
8.9.3 Permitted concomitant therapy - amended

Subjects may receive supportive care for any underlying illness, including 
dexamethasone, G-CSF and other hematopoietic growth factors to treat acute toxicities, 


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such as febrile neutropenia, when clinically indicated or at the investigator’s discretion. 

Additional concomitant medications such as low dose heparin, gonadotropin 
releasing hormone agonist or antagonist, antihistamines and intravenous fluid supply are 
permitted, if clinically indicated

In view of the maximum dose of 800 mg b.i.d., a risk for clinically relevant drug 
interaction due to inhibition of BCRP and/or P-gp in the intestine for drugs with a low 
bioavailability limited by P-gp and BCRP cannot be ruled out.  However, based on the 
maximum achievable plasma BAY 1163877 concentration, risk of clinically relevant drug 
interaction due to systemic inhibition of BCRP and P-gp is regarded as low.53

Subjects taking narrow therapeutic index medications should be monitored 
proactively.

Antiemetic therapy is allowed.

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). 
9
Procedures and variables
9.1
Schedule of procedures
Time deviations from the given time points will be documented as protocol deviations, if 
applicable. Respective time windows for visits are specified in the flow chart (see 
Section 16.1).
9.1.1 Tabulated overview
See study flow charts in Section 16.1.
9.1.2 Timing of assessment
If not stated otherwise, the measures listed in the following sections will be performed by 
or under the supervision of an investigator.
The same imaging or measuring method must be used for all tests required at baseline 
(screening) and follow-up.
                                                
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9.1.2.1
Pre-treatment
9.1.2.1.1 FGFR expression / FGFR mutation testing (MTD expansion cohorts 
only) - amended
A separate subject information sheet / informed consent form (SIS / ICF) for FGFR 
expression / FGFR mutation testing must be signed by all subjects recruited for study
Part 1, Part 2 or Part 3 MTD expansion cohort (see Section 13.2).54
The following activities / examinations will be performed prior to FGFR expression / 
FGFR mutation testing:

Signed informed consent for FGFR expression / FGFR mutation testing  

Inclusion criteria limited to FGFR expression / FGFR mutation testing (see 
Section 7.1.1.1) 

ECOG performance status assessment

Demographic data 

Documentation of the primary diagnosis (refractory, locally advanced or metastatic 
solid tumor) using the complete pathological report

Complete medical /oncological history, TNM classification (see Section 9.2.3)

Obtain archival tumor tissue sample for FGFR expression / FGFR mutation testing
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 

Toxicity / AE assessment and recording only in case an invasive procedure will be 
performed to obtain tumor material after subjects´ informed consent
All subjects enrolled into the study will be listed on a subject enrollment log provided by 
the sponsor’s representatives.
9.1.2.1.2 Screening - amended
Pre-study examinations will be performed within 7 days / within 28 days before first 
administration of BAY 1163877 (i.e. before Cycle 1, Day 1). Due to the fact that not all 
subjects may fulfill the inclusion / exclusion criteria, a higher number of subjects, than 
needed to be valid for the evaluation of the study, will be asked to participate in the pre-
study (screening) examination. As soon as fulfillment of all criteria is confirmed, the 
subject is included into the trial. In case all subjects are equally qualified, decision will be 
made by the sponsor or sponsor representative casting lots. 
                                                
54 Part 3 added by Amendment 7, see section 15.6.2.19


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Study specific required screening examinations will only be performed after having 
received the subject’s written IC for study treatment eligibility. The subject 
information sheet / informed consent form (SIS / ICF) for study treatment eligibility must 
be signed by all subjects including those subjects presenting FGFR expression / FGFR 
mutation who have signed the SIS / ICF for FGFR expression / FGFR mutation testing 
before (see Section 9.1.2.1.1)
The following examinations will be performed prior to the first study drug administration:
Within 28 Days Prior to First Dose of BAY 1163877  

Signed informed consent for study treatment eligibility (within 28 days or earlier), 
see Section 13.2.

Inclusion / exclusion criteria

Demographic data (already collected for subjects of Part 1, Part 2 or Part 3 MTD 
expansion cohorts, see Section 9.1.2.1.1) 55

Documentation of the primary diagnosis (refractory, locally advanced or metastatic 
solid tumor) using the complete pathological report (already done for subjects of Part 1,
Part 2 MTD expansion cohorts or Part 3, see Section 9.1.2.1.1)

Complete medical / oncological history, TNM classification (see Section 9.2.3) 
(already done for subjects of Part 1, Part 2 or Part 3 MTD expansion cohorts, see Section 
9.1.2.1.1)

Concomitant diseases and NYHA grading

Review of baseline toxicities

Baseline characteristics (smoking habits / history, alcohol consumption )

Previous and concomitant treatment (medication history up to 4 months prior to 
start of study treatment, see Section 7.1.2)

Physical examination with complete review of body systems (see Section 9.5.3.1) 

ECOG performance status assessment (also for subjects of Part 1, Part 2 or Part 3 
MTD expansion cohorts, see Section 9.1.2.1.1)

Single 12-lead ECG reading (see Section 9.5.3.4)

Send subject to consultant ophthalmologist for ophthalmological examination (see 
Section 9.5.3.2). New onset of cataract or other abnormalities affecting lens or cornea lead 
to the exclusion of the subject. 

CT scans of the chest, abdomen and pelvis; CT scans of other metastatic lesions as 
applicable or MRI and documentation of lesion(s) according to RECIST, v1.1. CT/MRI 
                                                
55 Part 3 added here and in the following by Amendment 7, see section 15.6.2.20


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scans prior screening can be used for documentation according to RECIST, v1.1, if scans 
were done the latest 28 days prior to first dose of BAY 1163877 (see Section 9.3.1)

Virology tests, for details see Table 16-4

Obtain pre-treatment biopsy: 
-
optional for subjects in the dose escalation cohorts of study Part 1 (all comer)
-
mandatory for all subjects in the MTD expansion cohort of Part 1 (all comer).
-
optional for subjects in the MTD expansion cohort of Part 2 (sqNSCLC + LAC + 
BC + SCCHN)
-
mandatory for all subjects in the study Part 3 / MTD expansion “Safety cohort”
(sqNSCLC + LAC + BC)56
-
Note 1: A biopsy is mandatory for all subjects in the MTD expansion cohort of 
Part 1, Part 2 and Part 3 for whom no archival biopsy is available for FGFR 
expression / FGFR mutation testing. Additional biopsy is not requested if a biopsy 
was already obtained for FGFR expression / FGFR mutation testing prior to the 
screening visit (see Section 9.1.2.1.1). 57
-
Note 2: Anticancer chemotherapy must have been stopped for at least 5 half-lives 
of the last applied therapy before the pre-treatment biopsy for biomarker (p-
ERK1/2) studies is taken. Mitomycin C, nitrosoureas or monoclonal antibodies 
with anticancer activity (e.g. bevacizumab or cetuximab etc.) should not be given 
within 6 weeks of pre-treatment biopsy for biomarker (p-ERK1/2) studies.58
Within 7 Days Prior to First Dose of BAY 1163877 

Update of inclusion / exclusion criteria

Review of baseline toxicities

Update of concomitant therapy

Body weight and height, calculation of BMI 

Vital signs (body temperature, respiration rate, blood pressure, heart rate)

Blood and urine collection for safety laboratory tests. In case of abnormal results 
caused by intercurrent diseases, short-term treatable conditions or other temporary health 
disorders, the investigator may decide to repeat the respective screening parameter(s). As a 
rule, up to 2 repetitions are acceptable, for details see Table 16-4

Only for females of childbearing potential:  Urine pregnancy test (the negative 
                                                
56 Part 3 - Safety cohort - was added by Amendment 7, see section 15.6.2.20
57 Part 3 was added by Amendment 7, see section 15.6.2.20
58 Amended for clarification by Amendment 7, see section 15.6.2.20


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result must be documented before start of study drug treatment)

Calculation of eGFR (see Section 16.9)

Documentation of lesion(s) according to RECIST v1.1

Adverse events before start of treatment (results of physical examination)

Only for subjects in Part 3: peripheral blood sample collection for determination of 
cytokine levels in serum. 59
9.1.2.2
Randomization
Not applicable (see Section 8.3).
9.1.2.3
Treatment - amended
For subjects in the “tablet bridging cohort” and “food effect assessment”, the treatment 
phase starts on Cycle 1, Day -3, followed by Cycle 1 (21 days) and a variable number of 
subsequent Cycles (each of 21 days duration) with no break between Cycles.
For all other subjects, the treatment phase comprises Cycle 1 (21 days) and a variable 
number of subsequent Cycles (each of 21 days duration) with no break between Cycles. 
There will be both visits and possible overnight stays at the study site. 
Patients with an estimated GFR in the range 30 mL/ min to 60 mL/min should be carefully 
monitored for signs of increased toxicity.60
9.1.2.3.1 Cycle 1- amended
For “tablet bridging cohort” or “food effect assessment” only:
Day -3 to Day -1 (possible overnight stay)
Day -3

Update of concomitant therapy

Physical examination

Ask subject for changes in vision

Cardiovascular assessment (BP and HR) 

Measurement of body temperature and body weight

Triplicate 12-lead ECG readings (see Section 9.5.3.4).
                                                
59 Part 3 was added by Amendment 7, see section 15.6.2.20
60 Added by Amendment 6, see section 15.6.2.21


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
ECOG performance status

Blood and urine collection for safety laboratory tests (repetitions for controls may 
be necessary), for details see Table 16-4

Calculation of eGFR (see Section 16.9)

Single oral administration of BAY 1163877 tablet formulation (“tablet bridging 
cohort” only)

Single oral administration of BAY 1163877 tablet formulation immediately after 
consumption of high-fat, high-calorie meal as specified in Section 8.4.2.2.1 (“food effect 
assessment” only)

PK sampling 

Toxicities / AE assessment and recording (if applicable)
Day -2 

No administration of BAY 1163877 (“drug-free day”)

Update of concomitant therapy

Physical examination

Ask subject for changes in vision

Cardiovascular assessment (BP and HR) 

Measurement of body temperature 

Triplicate ECG readings (see Section 9.5.3.4) 

ECOG performance status

PK sampling  

Toxicities / AE assessment and recording (if applicable)
Day -1

No administration of BAY 1163877 (“drug-free day”)

Update of concomitant therapy

Physical examination

Ask subject for changes in vision

Cardiovascular assessment (BP and HR) 

Measurement of body temperature 

ECOG performance status

PK sampling  


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
Toxicities / AE assessment and recording (if applicable)
Days 1-3 (possible overnight stay)
Day 1

Update of concomitant therapy

Physical examination

Ask subject for changes in vision

Cardiovascular assessment (BP and HR) 

Measurement of body temperature and body weight (measurement of weight not 
required for subjects in the “tablet bridging cohort” and for subjects with “food effect 
assessment”)

Single 12-lead ECG reading (see Section 9.5.3.4)

ECOG performance status

Blood and urine collection for safety laboratory tests (repetitions for controls may 
be necessary), for details see Section 16.2.

Calculation of eGFR (see Section 16.9)

PK sampling (all subjects of study Part 1 and at least 12 subjects of study Part 2
and approximately 8 subjects of the MTD expansion cohorts with impaired renal function 
at baseline)61

Urine collection for PK analysis (to be performed in approximately 8 subjects in 
Part 1 or Part 2 MTD expansion cohorts, see Section 9.4.2.1)

Dispense of study medication (BAY 1163877) and diary
Oral administration of BAY 1163877 (single dosing for subjects with PK
assessment, twice daily dosing for subjects without PK assessment and for subject 
in Part 3)62
Oral administration of a single dose of BAY 1163877 after at least 8 hours of 
     overnight fast as specified in Section 8.4.2.2.1 (“food effect assessment” only)

Toxicities / AE assessment and recording (if applicable)
                                                
61 Modified by Amendment 7, see section 15.6.2.22
62 Part 3 added by Amendment 7, see section 15.6.2.22


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Day 2 
No administration of BAY 1163877 (“drug-free day”) for subjects with PK 
assessment (all subjects of study Part 1 and at least 12 subjects with PK assessment in 
study Part 2 and approximately 8 subjects with PK assessment in the MTD expansion 
cohorts with impaired renal function at baseline [including “food effect assessment”])63

Twice daily administration of BAY 1163877 for subjects without PK assessment 
(remaining subjects of study Part 2) and for subjects of Part 364

Update of concomitant therapy

Physical examination

Ask subject for changes in vision

Cardiovascular assessment (BP and HR) 

Measurement of body temperature 

Single ECG reading (see Section 9.5.3.4)

ECOG performance status

PK sampling (all subjects of study Part 1 and at least 12 subjects of study Part 2
and approximately 8 subjects of the MTD expansion cohorts with impaired renal function 
at baseline) 65

Toxicities / AE assessment and recording (if applicable)
Day 3 

Update of concomitant therapy

Physical examination

Ask subject for changes in vision

Cardiovascular assessment (BP and HR) 

Measurement of body temperature 

ECOG performance status

Only for subjects included in study Part 1/ dose escalation (all comer): Blood 
(serum) samples collection for biomarker investigations, see Table 16-5

PK sampling (all subjects of study Part 1 and at least 12 subjects of study Part 2
andapproximately 8 subjects of the MTD expansion cohorts with impaired renal function 
                                                
63 Modified by Amendment 7, see section 15.6.2.22
64 Part 3 added by Amendment 7, see section 15.6.2.22
65 Modified by Amendment 7, see section 15.6.2.22


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at baseline)66

Dispense of study medication (BAY 1163877) and diary 
Oral administration of BAY 1163877 

Toxicities / AE assessment and recording (if applicable)
                                                
66 Modified by Amendment 7, see section 15.6.2.22


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Day 8 ± 1 (Visit)

Update of concomitant therapy

Physical examination

Ask subject for changes in vision

Cardiovascular assessment (BP and HR) 

Measurement of body temperature 

ECOG performance status

Blood and urine collection for safety laboratory tests (repetitions for controls may 
be necessary), for details see Section 16.2.

Only for subjects in Part 3: Collection of peripheral blood for determination of 
cytokine levels67

Calculation of eGFR (see Section 16.9)

Dispense of study medication (BAY 1163877) and diary
Oral administration of BAY 1163877 

Toxicities / AE assessment and recording (if applicable)
Days 15 (Visit)

Update of concomitant therapy

Physical examination

Ask subject for changes in vision

Cardiovascular assessment (BP and HR) 

Measurement of body temperature 

ECG reading (see Section 9.5.3.4)

ECOG performance status

Blood and urine collection for safety laboratory tests (repetitions for controls may 
be necessary), for details see Section 16.2.

Calculation of eGFR (see Section 16.9)

PK sampling (all subjects of study Part 1, 3 and at least 12 subjects of study Part 2
and approximately 8 subjects of the MTD expansion cohorts with impaired renal function 
                                                
67 Added by Amendment 7, see section 15.6.2.22


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at baseline)68

Dispense of study medication (BAY 1163877) and diary
Oral administration of BAY 1163877 

Toxicities / AE assessment and recording (if applicable)
9.1.2.3.2 Subsequent Cycles (Cycles 2-12) - amended
Day 1 (Visit)

Update of concomitant therapy

Physical examination

Ask subject for changes in vision

Cardiovascular assessment (BP and HR) 

Measurement of body temperature and body weight

12-lead ECG, single reading (see Section 9.5.3.4)  

ECOG performance status

Blood and urine collection for safety laboratory tests (repetitions for controls may 
be necessary), for details see Section 16.2.

Only for subjects in Part 3 in Cycle 2: peripheral blood sample collection for 
determination of cytokine levels. 69

Calculation of eGFR (see Section 16.9)

Only on Day 1 of Cycles 2, 3, 4 and 5: Blood (plasma) sample collection for 
exposure-response modeling at pre-dose and between 0.5 and 1.5 hours post-dose in all 
subjects participating in the MTD expansion cohorts of study Part 1, Part 2, and Part 3
(not in subjects with impaired renal function) , see Table 16-3. The dose needs to be taken 
under supervision and the time recorded. 70

Only on Day 1 of Cycle 2: Obtain second biopsy: mandatory for all subjects in the 
MTD expansion cohort of Part 1 (all comer), voluntary for subjects in the dose escalation 
cohorts of study Part 1 (all comer) and in the MTD expansion cohort of Part 2, and send to 
laboratory, see Section 16.2.70

Mandatory for all subjects in study Part 3 / MTD expansion “Safety cohort”
(sqNSCLC + LAC + BC): Between Day 1 and Day 21 of Cycle 2: Obtain second biopsy
                                                
68 PK sampling in part 3 added by Amendment 7, see section 15.6.2.22
69 Part 3  was added by Amendment 7, see section 15.6.2.23
70 Modified by Amendment 7, see section 15.6.2.23


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and send to laboratory, see Section 16.2; obtain peripheral blood for determination of 
cytokine levels. Subjects in Part 3 will provide one PK sample within 1 hour of biopsy
collection in Cycle 2. 71

Dispense of study medication (BAY 1163877) and diary
Administration of BAY 1163877  

Toxicities / AE assessment and recording (if applicable)
Day 8 ± 1 and Day 15 ± 1 (Visits)

Update of concomitant therapy

Physical examination

Ask subject for changes in vision

Cardiovascular assessment (BP and HR) 

ECOG performance status

Blood and urine collection for safety laboratory tests (repetitions for controls may 
be necessary), for details see Section 16.2.

Only for subjects in Part 3 on Day 15 in Cycle 2: peripheral blood sample 
collection for determination of cytokine levels.72

Calculation of eGFR (see Section 16.9)
Oral administration of BAY 1163877 

Toxicities / AE assessment and recording (if applicable)
End of Cycle 2 and every 2nd subsequent Cycle (i.e., end of Cycles 2, 4, 6, 8, 10, 12)

Send subject to consultant ophthalmologist for ophthalmological examination and 
review certificate
End of Cycle 2 and every 3rd subsequent Cycle (i.e., end of Cycles 2, 5, 8, 11)

CT scans of the chest, abdomen and pelvis; CT scans of other metastatic lesions as 
applicable or MRI and documentation of response according to RECIST, v1.1 (see 
Section 9.3.1)
9.1.2.3.3 Subsequent Cycles (Cycles ≥13)
Day 1 (Visit)

Update of concomitant therapy
                                                
71 Part 3 - Safety cohort - was added by Amendment 7, see section 15.6.2.23
72 Added by Amendment 7, see section 15.6.2.23


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
Physical examination

Ask subject for changes in vision

Cardiovascular assessment (BP and HR) 

Measurement of body temperature and body weight

12-lead ECG, single reading (see Section 9.5.3.4)  

ECOG performance status

Blood and urine collection for safety laboratory tests (repetitions for controls may 
be necessary), for details see Section 16.2

Calculation of eGFR (see Section 16.9)

Oral administration of BAY 1163877 

Toxicities / AE assessment and recording (if applicable)
Day 11 (Visit)

Update of concomitant therapy

Physical examination

Ask subject for changes in vision

Cardiovascular assessment (BP and HR) 

ECOG performance status

Blood and urine collection for safety laboratory tests (repetitions for controls may 
be necessary), for details see Section 16.2.

Calculation of eGFR (see Section 16.9)

Oral administration of BAY 1163877 

Toxicities / AE assessment and recording (if applicable)
End of Cycle 14 and every 2nd subsequent Cycle (i.e., end of Cycles 14, 16, 18, …)

Send subject to consultant ophthalmologist for ophthalmological examination and 
review certificate
End of Cycle 14 and every 3rd subsequent Cycle (i.e., end of Cycles 14, 17, 21, …)

CT scans of the chest, abdomen and pelvis; CT scans of other metastatic lesions as 
applicable or MRI and documentation of response according to RECIST, v1.1 (see 
Section 9.3.1)


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9.1.2.3.4 Follow-up
An End of Treatment (EOT) visit will be performed within 0-14 days after the last study 
drug administration. 
A follow-up (FU) visit will be performed 30-35 days after the last study drug 
administration. This will be a visit for subjects who have not started a new treatment. For 
subjects who have started a new antitumor treatment, only a phone call will be made. 
There will be no long-term (survival) follow-up period.
The following examinations will be done
Within 0-14 Days of Last Study Drug Administration (EOT Visit)

Update of concomitant therapy

Return of study medication and diary

Physical examination

Ask subject for changes in vision

Cardiovascular assessment (BP and HR) 

Measurement of body temperature and body weight

12-lead ECG, single reading (see Section 9.5.3.4)  

ECOG performance status

Blood and urine collection for safety laboratory tests (repetitions for controls may 
be necessary), for details see Section 16.2.

Calculation of eGFR (see Section 16.9)

Send subject to consultant ophthalmologist for ophthalmological examination and 
review certificate

Toxicities / AE assessment and recording (if applicable)
At 30-35 days after last study drug administration: FU (Visit / Phone call)
If FU-visit:

Physical examination

Ask subject for changes in vision

Cardiovascular assessment (BP and HR) 

Toxicities / AE assessment and recording (if applicable)
If FU-phone call* 
Toxicities / AE assessment and recording (if applicable)
*For subjects who have started a new antitumor treatment.


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9.2
Population characteristics
9.2.1 Demographic
The following information will be collected and summarized as part of the demographic 
and baseline characteristics for all subjects enrolled in this study: age, gender, ethnic 
group. The subjects of all races / ethnicity can participate in the study provided that they 
meet all eligibility criteria.
9.2.2 Medical history
Medical history findings (i.e. previous diagnoses, diseases or surgeries) meeting all criteria 
listed below will be collected:

Not pertaining to the study indication

Start before signing of the informed consent

Considered relevant to the study
Detailed instructions on the differentiation between medical history and AEs can be found 
in Section 9.5.1.1.
9.2.3 Other baseline characteristics  
Other baseline characteristics to be obtained include 

Tumor stage according to the International Union Against Cancer (UICC), Tumor 
Node Metastasis (TNM) Classification of Malignant Tumors, 7th edition (UICC-TNM 
v 7, see Section 16.6).

Presence of visceral or non-visceral metastases in subjects with metastatic disease

Prior therapy received for locally advanced or metastatic solid tumors:
-
Neoadjuvant therapy:  Treatment (e.g. chemotherapy, radiation therapy, and 
hormone therapy) given as a first step to shrink a tumor before the main treatment, 
usually surgery.
-
Adjuvant therapy:  Additional cancer treatment given after the primary treatment 
to lower the risk of cancer recurrence (e.g., chemotherapy, radiation therapy, 
hormone therapy, targeted therapy, or biological therapy). 
-
Any other anticancer therapy (to be specified in the eCRF)

Smoking habits and alcohol consumption.
9.3
Efficacy
Efficacy will be assessed by determining tumor response to therapy as a secondary 
endpoint.
For each subject, the investigator will designate at least 1 and up to 5 measurable (if 
appropriate) or non-measurable lesions for response assessment. The most appropriate 


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measures to evaluate the tumor status of a subject should be used. The investigator must 
enter a statement in the subject’s medical records clearly defining the basis of his / her 
decision on subject disease status. 
The following standard assessments should be performed to evaluate the response of the 
tumors:

Tumor response assessment for measurable lesions (CT / MRI scan) according to 
RECIST, v1.1, see Section 9.3.1
All records and films of responding subjects (complete response, partial response, and 
stable disease) must be available for eventual extramural review of the tumor.
All measurable and evaluable disease will be assessed by the identical method as used at 
baseline. All measurements should be recorded in metric notation, using a ruler or 
calipers. 
9.3.1 Tumor evaluation - response assessment (RECIST)
In measurable lesions (i.e., at the primary site, visceral or nodal [in lymph nodes ≥1,5 cm] 
lesions), the objective response will be assessed by CT / MRI scan at the EOT visit and 
documented according to the revised RECIST guideline, Version 1.1 (RECIST, v1.1), see 
Section 16.8. The assessment will be done by the investigators. No central evaluation is 
planned for this study.
CT / MRI scans will be performed at the following time points:

Screening (within 28 days prior to the first dose of BAY 1163877)

At the end of Cycle 2 and every third subsequent Cycle (beginning with Cycle 5)
Results for these evaluations will be recorded with as much specificity as possible so that 
pre- and post-treatment results will provide the best opportunity for evaluation of tumor 
response. 
A zero should be recorded when a lesion has completely resolved. Otherwise, 
disappearance of a lesion cannot be differentiated from a missing value.
The occurrence and location of new lesions should be recorded in the eCRF and the 
subject’s medical records.
In general, the subject’s best response assignment will depend on the achievement of both 
measurement and confirmation criteria (see Section 16.8). 
If radiographic changes are believed by the investigator to be secondary to drug induced 
inflammation and not tumor progression, the investigator may postpone a diagnosis of 
progressive disease (PD) until the next radiographic evaluation in the study.
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. For a response 
to be scored as complete response (CR) or partial response (PR), the response must be 
confirmed by a repeat CT scan (with contrast) or MRI scan (with and without contrast) 
performed not earlier than 4 weeks after the response was first determined. 


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9.4
Clinical pharmacological parameters and procedures
9.4.1 Pharmacodynamics
9.4.1.1
Cardiovascular assessment
To assess a possible pharmacodynamic effect of BAY 1163877 on cardiovascular 
function, a blood pressure (BP) / heart rate (HR) profile will be recorded by an automated 
device as follows: 
- Subject seated for at least 2 minutes before measurement with their arms bared and 
supported at heart level.
- At screening, BP must be measured in both arms to see whether there is a difference 
in blood pressure readings between the subject’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) 
- When blood pressure measurement and PK sample collection are scheduled at the 
same time point, subject’s blood pressure will be measured before collection of the 
PK sample.
BP and HR will be measured at the following time points:

Screening (one measurement within 7 days before start of treatment)

Cycle 1, Day -3 to Day -1 (“tablet bridging cohort” and “food effect assessment” 
only)
-
before and 0.5, 1, 2, 3, 4, 6, 8, 12 (Day -3), 24 (Day -2) and 48 (Day -1) hour(s) 
after single-dose administration 

Cycle 1, Day 1 and Day 2
before and 0.5, 1, 2, 3, 4, 6, 8, 12 (Day 1), and 24 (Day 2) hour(s) after single-dose 
administration 

Cycle 1, Day 3
-
before and 1, and 2 hour(s) after morning dose

Cycle 1, Day 8 (one measurement)

Cycle 1, Day 15
-
before and 0.5, 1, 2, 3, 4, 6, 8 and 12 hour(s) after morning dose (12-hour 
measurement before evening dose)

Cycle ≥ 2 and follow up
-
each visit (one measurement)

Follow up
EOT visit (one measurement)


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FU-visit (one measurement)
If a reduction of systolic BP below 90 millimeters of mercury (mmHg) or an increase in 
HR above 120 beats per minute (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, subject’s blood pressure will be measured before collection of the PK sample.
Details about ECGs readings are provided in Section 9.5.3.4. 
9.4.1.2
Assessment of immune priming73
Assessment of immune response will be done at screening and during treatment for 
subjects in the “Safety cohort” (Part 3: sqNSCLC + LAC + BC). For gene expression 
profiling (nCounter PanCancer Immune Profiling Panel) and immunohistochemistry for 
CD8+ T cell infiltration and PD-L1 expression a fresh tumor biospy (e.g. obtained by 
endoscopic or ultrasound guided biopsy) will be collected as follows:

Study Part 3 / “Safety cohort” (sqNSCLC + LAC + BC):
Screening:  Biopsy is mandatory
Between Cycle 2, Day 1 and Cycle 2, Day 21:  Biopsy is mandatory
Peripheral blood will be collected for determination of cytokine levels (IL-6, IFN-gamm, 
and others if needed) at the following timepoints: at baseline; Cycle 1, Day 8; Cycle 2, 
Day 1; Cycle 2, Day 15; and on the day of the second biopsy.
9.4.2 Pharmacokinetics
9.4.2.1
Drug measurements - amended
Pharmacokinetics of BAY 1163877 will be evaluated on Cycle 1, Day -3 (“tablet bridging 
cohort” and “food effect assessment”, only), on Cycle 1, Day 1 after single-dose 
administration, and on Cycle 1, Day 15 after multiple-dose administration of 
BAY 1163877 at the respective dose level achieved during dose escalation.
Pharmacokinetic assessments will be performed in all subjects enrolled in Part 1 (dose 
escalation and MTD expansion (all comer) cohorts). The plan is to perform 
pharmacokinetic assessments in at least 12 subjects in Part 2 MTD expansion cohort 
(sqNSCLC + LAC + BC + SCCHN) such that valid PK data are available in 8 subjects. 
“Food effect assessment” will be performed in approximately 8 subjects enrolled in the 
MTD expansion cohorts (study Part 1 and Part 2). In the MTD expansion cohorts
pharmacokinetic assessments will be performed in approximately 8 subjects with 
moderately impaired renal function at baseline (glomerular filtration rate [GFR] of 30 to 
59 mL/min/1.73 m2 according to the modified diet in renal disease [MDRD] abbreviated 
                                                
73 Whole section - immune priming - was added by Amendment 7, see section 15.6.2.24


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formula). In all subjects participating in study Part 3/ MTD expansion “Safety cohort”, 
multiple dose pharmacokinetics (on Cycle 1 Day 15) will be performed.74
Blood (plasma) samples for PK assessment of BAY 1163877 will be collected at the 
following time points:

Cycle 1, Day -3 (“tablet bridging cohort” and “food effect assessment” only): 
single-dose PK 
-
pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 and 48 hour(s) post-dose

Cycle 1, Day 1: single-dose PK 
-
pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 and 48 hour(s) post-dose (48-hours sample 
before administration of morning dose on Day 3)

Cycle 1, Day 15: multiple-dose PK
-
pre-dose (before morning dose), and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose 
(12-hours sample before administration of evening dose)

Cycles 2-5, Day 1: exposure-response modeling (not in subjects with impaired 
renal function)
-
pre-dose (before supervised dose administration), and 1 (0.5) hour post-dose

Cycle 2: Subjects in Part 3/ MTD expansion “Safety cohort” will provide one PK 
sample within 1 hour of biopsy collection in Cycle 2.75
In consultation with the investigators, if needed, up to three additional samples may be 
collected during the study.
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. Sampling times outside the suggested intervals 
will not be considered as protocol deviations. It is of importance that the actual date and 
time of blood sampling is documented in the eCRF and subject`s source document 
because PK calculations will be based on the actual sampling times relative to dosing 
times.
When blood pressure measurement and PK sample collection are scheduled at the same 
time point, subject’s blood pressure will be measured before collection of the PK sample.
24-hour urine collection: In approximately 8 subjects of the MTD expansion cohorts 
(study Part 1 and Part 2), on Cycle 1 Day 1, complete urine output will be collected over 
                                                
74 Modified and Part 3 added by Amendment 7, see section 15.5.2.2015.6.2.25
75 Part 3 added by Amendment 7, see section 15.5.2.2015.6.2.25


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24 hours post administration in 0 to 12 hour and 12 to 24 hour intervals concurrently with 
plasma PK samples. For each subject, within each collection interval, the collected urine 
will be combined and the total volume of the combined urine will be determined. 
A representative aliquot of the pooled urine will be used to determine the concentration of 
BAY 1163877.
Plasma and urine concentrations of BAY 1163877 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 
(most likely at the MTD or the therapeutic dose) and in urine samples. 
9.4.2.2
Pharmacokinetic evaluation
PK parameters will be calculated by non-compartmental analysis (NCA) according to 
current Bayer guidelines using WinNonlin software, in the latest version. PK parameters 
from NCA will be evaluated only for those subjects meeting the PK validity criteria 
(Section 10.2). Based on plasma concentration versus time results, the following 
parameters are planned to be calculated (see Table 9-1): 
Table 9-1:
Pharmacokinetic parameters to be evaluated for BAY 1163877
Symbol
Definition
AUC(tlast-)
percentage of AUC from the last data point > LLOQ to infinity
AUC
area under the plasma concentration vs. time curve from zero to infinity 
after first dose
AUC(0-12)
AUC from time zero to 12 hours after first-dose administration
AUC(0-12)/D
AUC(0-12) divided by dose
AUC(0-tlast)
Area under the concentration-time curve from time zero to the last data 
point > LLOQ
AUC(0-tlast)/D
AUC(0-tlast) divided by dose
AUC/D
AUC divided by dose
Cmax
maximum drug concentration in plasma after first dose administration
Cmax/D
maximum drug concentration in plasma at steady state divided by dose 
(mg)
Md
multiple dose
t1/2
half-life associated with the terminal slope
tlast
time of last plasma concentration above LLOQ
tmax
time to reach maximum drug concentration in plasma after single (first) 
dose


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Primary PK parameters (plasma): BAY 1163877

Cycle 1, Day -3 (“tablet bridging cohort” and “food effect assessment” only) 
and Cycle 1, Day 1 single dose: Cmax, Cmax/D, AUC(0-12), AUC(0-12)/D,
AUC(0-tlast), AUC(0-tlast)/D, AUC, and AUC/D
AUC may not be calculated if it is not possible to estimate half-life.

Cycle 1, Day 15 multiple dose: Cmax,md, Cmax/Dmd, AUC(0-12)md, AUC(0-12)/Dmd,
AUC(0-tlast)md, and AUC(0-tlast)/Dmd. 
Secondary PK parameters (plasma): BAY 1163877

tmax, tlast, t1/2 of Cycle 1, Day -3 (“tablet bridging cohort” only) and Cycle 1, Day 1 
and tmax,md and tlast,md of Cycle 1, Day 15.
Other PK parameters (plasma): BAY 1163877

%AUC(tlast-)
Additional parameters, e.g. apparent oral clearance (CL/F) and apparent volume of 
distribution at steady state after extravascular administration (Vss/F), may be estimated, if 
appropriate.
Pre-dose plasma concentrations (if additionally collected) will be used for monitoring 
purpose only.
Amount of BAY 1163877 excreted renally during 0 to 12 h (AE,ur(0-12)), 12 to 24 h 
(AE,ur(12-24)) and 0 to 24 h (AE,ur(0-24)) post-dose will be calculated at the MTD and also 
expressed as percent of dose administered.
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.
These samples collected on Day 1 of Cycles 2 through 5 at pre-dose and between 0.5 and 
1.5 hours post-dose will document a longitudinal exposure under steady state condition. 
No detailed dosing history is required before the pre-dose sample, but the dose that 
separates the pre- and post-dose sample needs to be taken under supervision and the time 
recorded. The longitudinal exposure data will be used in exposure-response modeling of 
adverse events and clinical responses.
9.4.3 Safety Variables
Please refer to Section 9.5.3
9.4.4 Biomarker investigations - amended
Concentrations of FGF23 will be measured by a validated ELISA assay. Instructions for 
sample collection, processing, storage and shipment will be described in a separate 
document (e.g. lab manual). 


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Pharmacodynamic (PD) biomarkers:
In an attempt to demonstrate the mechanism of action of BAY 1163877, biomarkers will 
be studied in tissue samples.
Biomarker analysis in TUMOR TISSUE
Biomarker analysis will be done at pre-screening for subject stratification in the MTD 
expansion cohorts (Part 1: all comer; Part 2: sqNSCLC + LAC + BC + SCCHN; Part 3
sqNSCLC + LAC + BC) according to FGFR expression levels / FGFR mutation using 
either an archival tumor tissue specimen or fresh tumor biopsy material (see Section 7.1.1: 
Inclusion criteria, and Section 9.4.4.1: Predictive marker investigation).76 For analysis of 
phospho-extracellular signal-regulated kinase 1/2 levels, (p-ERK1/2) a tumor biospy (e.g. 
obtained by endoscopic or ultrasound guided biopsy) will be collected as follows: 

Study Part 1 / dose escalation (all comer):
-
Screening:  Biopsy is optional* (p-ERK1/2) 
-
Cycle 2, Day 1:  Biopsy is optional* (p-ERK 1/2)

Study Part 1 / MTD expansion (all comer):
-
Screening:  Biopsy is mandatory (p-ERK1/2) 
-
Cycle 2, Day 1:  Biopsy is mandatory (p-ERK1/2)

Study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN):
Screening:  Biopsy is optional* (p-ERK1/2) 
Cycle 2, Day 1:  Biopsy is optional* (p-ERK1/2)
*Optional biopsy: Only for subjects who agreed on biopsy both at screening and on Cycle 2, Day 1.
Anticancer chemotherapy must have been stopped for at least 5 half-lives of the last 
applied therapy before the pre-treatment biopsy for biomarker (p-ERK1/2) studies is 
taken.77 Mitomycin C, nitrosoureas or monoclonal antibodies with anticancer activity (e.g. 
bevacizumab or cetuximab etc.) should not be given within 6 weeks of pre-treatment 
biopsy for biomarker (p-ERK1/2) studies.
The evaluation of FGFR pathway mutations is planned retrospectively for subject in the 
MTD expansion cohorts. 
Tumor response evaluation: Computed tomography (CT) or magnetic resonance imaging 
(MRI) of all anatomic regions involved with the disease will be performed at screening 
(baseline), at the end of Cycle 2 and thereafter, every third cycle to assess tumor response 
using the Response Evaluation Criteria in Solid Tumors, Version 1.1. (RECIST v1.1)(1). 
Response evaluation according to RECIST v1.1 can be done up to 5 days after CT / MR 
                                                
76 Part 3 added by Amendment 7
77 Modified by Amendment 7, see section 15.6.2.26


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scan.  
Rationale for serum FGF23, phosphate and calcium measurements as PD biomarker
The phosphaturic hormone fibroblast growth factor 23 (FGF23) controls phosphate 
homeostasis by regulating renal expression of sodium-dependent phosphate co-
transporters (18). Multiple FGF receptors (FGFRs) can act as receptors for FGF23 when 
bound by the co-receptor Klotho expressed in the renal tubular epithelium. FGFRs also 
regulate skeletal FGF23 secretion (19). Activation of FGFR-FGF23 signaling, e.g. by 
administration of an FGFR1 activating antibody (20) or by administration of recombinant 
FGF23 to mice (21) leads to hypophosphatemia. Likewise, inhibition of renal FGFR 
signaling e.g., by administration of pan-FGFR kinase inhibitor leads to an enhanced 
reabsorption of phosphate in the kidney and thus to an increase of serum phosphate levels. 
This increase of phosphate levels in turn activates FGF23 synthesis in the bone leading to 
higher serum levels of FGF23 (22). The FGF23/FGFR/Klotho complex also limits renal 
vitamin D synthesis and thus intestinal calcium uptake (23)(24). FGFR inhibitor treatment 
may therefore lead to increased serum calcium levels. Hence, modulation of circulating 
FGF23, and the incidence of hyperphosphatemia and elevated serum calcium levels are 
potential biomarkers for effective systemic FGFR inhibition (25). A dose-dependent 
hyperphosphatemic effect accompanied by an increase of serum FGF23 levels was 
observed in all animal species after BAY1163877 administration including mouse, rat and 
monkeys. Similar effects have also been observed with competitor compounds in 
preclinical models (26)(22) and in clinical trials (28)(29).
Rationale for the immunohistochemical quantification of tumor p-ERK levels as PD 
biomarker
Activation of the FGFR signaling pathway leads to enhanced cell proliferation – an effect 
that is mediated at least in part by Extracellular Regulated Kinases 1&2 (ERK1/2) (27). In 
a large set of human tumor cell lines, the phosphorylation of p-ERK1/2 was increased 
upon stimulation of the FGFR signaling pathway with the FGFR ligand bFGF, whereas 
pre-treatment of the cells with pan-FGFR inhibitor BAY 1163877 strongly reduced p-
ERK1/2 phosphorylation levels and inhibited cell proliferation. In line with this, treatment 
of tumor-bearing xenograft mice with pan-FGFR-inhibitor BAY 1163877 leads to a 
reduced phosphorylation of tumor ERK1/2 in sensitive models, whereas no effect or only 
a weak effect on tumor p-ERK1/2 levels was observed in xenograft mouse models that 
were largely insensitive to BAY 1163877-treatment. Quantification of tumor p-ERK1/2 
levels in biopsy samples from study participants pre- and post-treatment with 
BAY 1163877 may thus serve as an early predictor of clinical efficacy of the drug, as has 
been described for many kinase inhibitors in first-in-man trials including competitor 
compound dovitinib (28)(29).
9.4.4.1
Predictive marker investigations - amended
Prediction Biomarker:
For subjects to be enrolled in study Part 1 / MTD expansion (all comer), subjects to be 
enrolled in Study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN) and 
subjects to be enrolled in Study Part 3 MTD expansion (sqNSCLC + LAC + BC) 


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biomarker analysis will be done prior study start (subject stratification) on either a fresh or 
archival tumor biopsy sample to confirm high fibroblast growth factor receptor (FGFR) 
expression levels / FGFR mutation (see Section 7.1.1: Inclusion criteria). 78
Rationale for the quantification of tumor FGFR-1 -2- and -3 levels 
Amplification of the FGFR1 8p12 gene locus has been observed in up to 20 % of
sqNSCLC subjects (8)(9)(11). FGFR1 gene amplification is so far one of the most 
frequently observed molecular alteration in sqNSCLC (30). In SCCHN, the FGFR1 gene 
was amplified in about 15 % of all cases (38). In vitro experiments with BAY 1163877 
and published data with competitor compounds revealed equal sensitivity to proliferation 
inhibition by either adenocarcinoma or squamous subtype-derived lung cancer cell lines. 
In-house quantification of FGFR1-3 mRNA expression levels in patient-derived lung 
cancer tumors revealed a high FGFR1, 2 or 3 mRNA expression levels also in cases of 
lung adenocarinomas. In line with this, a recent publication confirmed a strong expression 
of FGFR1 mRNA also in adenocarcinoma biopsy samples in the absence of FGFR1 
amplification (39). Therefore, we suggest to include lung adenocarcinoma patients into 
Part 2 of the study. Mutations in FGFR-encoding genes are rare in sqNSCLC subjects 
(< 2%), whereas in bladder cancer, up to 70% of all cases reveal mutations within FGFR3 
gene (31). The molecular consequences of FGFR gene amplifications are not always clear: 
In bladder cancer, activating FGFR3 mutations with higher kinase activity have been 
described (32) but also cases in which FGFR3 amplification leads to higher target 
expression levels in tumor (33). 
Recent publications investigating the correlation between FGFR1 gene amplification in 
sqNSCLC and their correlation with target expression level (mRNA or protein expression) 
revealed, a high proportion of subjects with FGFR1 overexpression in tumor that do not 
have an FGFR1 gene amplification and even in those subjects with a high FGFR1 gene 
copy number, a relevant subset of subjects does not reveal high FGFR1 target 
overexpression (12)(13).
In line with this literature data on subject biopsy samples, preclinical in vivo data with 
competitor compound AZD4547 and in vitro data with competitor compound BGJ398 
revealed that a correlation with response-to-treatment (tumor weight inhibition or 
proliferation inhibition) correlated only weakly with gene amplification status and that up 
to 50 % of tumor cells did not respond to FGFR inhibitor treatment despite having FGFR 
genetic alterations (10)(34). In house data revealed that the best correlation with anti-
tumor efficacy upon BAY1163877-treatment in preclinical cancer models was observed 
for total-FGFR mRNA tumor expression levels - including lung and bladder cancer, and 
head and neck squamous cell cancer models. This may at least in part be explained by the 
parallel expression of more than one FGFR isoform in xenograft tumors which could not 
be investigated on protein level by immunohistochemistry due to the lack of isoform-
specific, sensitive anti-FGFR antibodies. Parallel quantification of FGFR1/2/3 mRNA 
                                                
78 Part 3 added by Amendment 7


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levels in fresh frozen xenograft tumors (by RT-PCR) and in archival tissue samples 
derived thereof (by RNA in situ hybridization) indicated a high degree of correlation 
between both methods. Thus, quantification of FGFR1/2/3 mRNA levels in archival tissue 
samples is technically feasible. We therefore consider to stratify sqNSCLC, LAC, BC and 
SCCHN subjects to be enrolled in study Part 2 and Part 3 / MTD expansion by the 
quantification of total FGFR mRNA expression levels in archival tissue samples in order 
to exclude subjects that are unlikely to benefit from BAY1163877 therapy due to low 
overall FGFR target expression levels.79
Rationale for the detection of genetic alterations in FGFR encoding genes and in 
FGFR pathway downstream signaling molecules
In subjects included in study Part 1 / MTD expansion (all comer) and Part 2 / MTD 
expansion (sqNSCLC + LAC + BC + SCCHN) and Part 3 / MTD expansion “Safety 
cohort” (sqNSCLC + LAC + BC), genetic testing of tumor tissue may be necessary if a 
subject lacks a treatment response to BAY 1163877 despite FGFR overexpression in 
tumor. Such a lack of anti-tumor response upon BAY 1163877-treatment has been 
observed in some preclinical models despite high total FGFR mRNA tumor levels and 
may be attributable to a constitutively active FGFR downstream signaling pathway e. g.
due to K-ras mutations. Existence of such FGFR downstream pathway activating 
mutations in the case of lack of response to BAY 1163877 treatment - despite high total 
FGFR mRNA tumor expression levels - should be evaluated retrospectively in subjects 
enrolled in study Part 1 / MTD expansion (all comer) and Part 2 / MTD expansion 
(sqNSCLC + LAC + BC + SCCHN) and Part 3 / MTD expansion “Safety cohort”
(sqNSCLC + LAC + BC).80
Furthermore, in some animal models with bladder cancer cell lines bearing an activating 
mutation in FGFR3 gene, a good anti-tumor response upon BAY 1163877-treatment was 
observed despite rather low overall total FGFR mRNA expression levels in tumor cells. 
We therefore consider genetic testing for FGFR3-activating mutations in bladder cancer 
subjects prior to treatment start - in case they lack high FGFR mRNA expression levels in 
tumor. 
                                                
79 Part 3 added by Amendment 7
80 Part 3 added by Amendment 7


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9.5
Safety
9.5.1 Adverse events
9.5.1.1
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 
subject or clinical investigation subject after providing written informed consent for 
participation in the study. 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 subject should not be recorded as AE (however, the condition for which the 
surgery is required may be an AE). 

The clinical manifestation of any failure of expected pharmacological action 
(tumor progression) is not recorded as an AE. If, however, the event fulfills any of the 
criteria of an SAE, it must be recorded and reported as such unless otherwise specified in 
the protocol. 
In the following differentiation between medical history and AEs, the term “condition” 
may include abnormal e.g. physical examination findings, symptoms, diseases, laboratory 
values, ECG.

Conditions that started before signing of informed consent 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.
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 subject 
was at risk of death at the time of the event, it does not refer to an event which 
hypothetically might have caused death if it were more severe.
c) Requires insubject hospitalization or prolongation of existing hospitalization


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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 
(i.e. elective or scheduled surgery arranged prior to the start of the study)
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 
dependant on clinical judgment. In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedence.
a) Results in persistent or significant disability / incapacity
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions.
b) Is a congenital anomaly / birth defect
c) Is another medically important serious event as judged by the investigator
All SAEs occurring after the IC for study treatment eligibility has been obtained, until 
the end of the follow-up period must be handled via this process. All serious 
diagnoses, symptom(s), sign(s) or finding(s) that have a start date after signing the IC 
must be recorded as SAEs. This also includes all serious events with a start date during 
the pre-treatment period for subject stratification (FGFR expression / FGFR mutation 
testing period), in case an invasive procedure was performed to obtain tumor 
material. A condition that was present before signing the IC for study treatment 
eligibility and worsens after signing the IC must also be recorded as an SAE if the 
serious criteria are met.
9.5.1.2
Classifications for adverse event assessment
All AEs will be assessed and documented by the investigator according to the categories 
detailed below.
9.5.1.2.1 Seriousness
For each AE, the seriousness must be determined according to the criteria given in 
Section 9.5.1.1
9.5.1.2.2 Intensity
The intensity / severity of an AE will be graded using the CTCAE v4.03, see Section 16.5. 
For events not listed in the CTCAE v4.03 the following scale will be used:
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Grade 2 = Moderate AE, sufficiently discomforting to interfere with normal activities
Grade 3 = Severe AE, prevents normal activities
Grade 4 = Life-threatening and / or disabling AE
Grade 5 = Results in death (fatal)
9.5.1.2.3 Causal relationship
The assessment of the causal relationship between an AE and the administration of 
treatment is a clinical decision based on all available information at the time of the 
completion of the eCRF. 
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 clear alternative explanation, e.g. mechanical bleeding at 
surgical site.
or
2.
Non-plausibility, e.g. the subject 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 there is a reasonable suspicion that the AE is 
associated with the use of the study treatment.
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):

Subject’s response after de-challenge or subjects response after re-challenge should 
be considered in the 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 subject may have.

Concomitant medication or treatment:
The other drugs the subject is taking or the treatment the subject receives should be 
examined to determine whether any of them may be suspected to cause the event in 
question.

The pharmacology and pharmacokinetics of the study treatment:
The pharmacokinetic properties (absorption, distribution, metabolism and excretion) of the 


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study treatment, coupled with the individual subject’s pharmacodynamics should be 
considered.
9.5.1.2.4 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.”
9.5.1.2.5 Action taken with study treatment
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below.
-
Drug withdrawn
-
Drug interrupted
-
Dose reduced
-
Dose not changed
-
Dose increased
-
Not applicable
-
Unknown
9.5.1.2.6 Other specific treatment(s) of AE
-
None
-
Remedial drug therapy
-
Other
9.5.1.2.7 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
9.5.1.3
Assessments and documentation of adverse events
AEs observed, mentioned upon open questioning by a member of the investigator team or 
spontaneously reported by the subject, will be documented (see Section 11.1 for details). 


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AEs will be documented event based (using the CTCAE v4.03 guidelines). The 
observation phase for AEs will start with signing the first Informed Consent and will end 
in general with the last visit of follow-up. All AEs identified after first IC during the pre-
treatment period for subject stratification (FGFR expression / FGFR mutation testing 
period) will not be documented in the eCRF, in case no invasive procedure will be 
performed to obtain tumor material. Adverse events should be collected past 30-35 days 
after the study treatment stop for all AEs that were ongoing at the end of treatment as well 
as new SAEs (information may be obtained via phone call). The investigator is 
responsible for the grading of each category mentioned in Section 9.5.1.2.
Adverse events should be followed until resolution or stabilization unless, in the 
investigator’s opinion, the condition is unlikely to resolve due to the subject’s underlying 
disease.
If any subject dies within 30-35 days of last dose of study drug, the investigator will 
inform the sponsor and record the cause of death in detail within 24 hours on a SAE form.
A laboratory test abnormality considered clinically relevant, e.g. causing the subject to 
withdraw from the study, requiring treatment or causing apparent clinical manifestations, 
or judged relevant by the investigator, should be reported as an AE. Each event should be 
described in detail along with start and stop dates, severity, relationship to investigational 
product, action taken and outcome.
An isolated laboratory abnormality that is assigned grade 4, according to CTCAE v4.03 
definition, is not reportable as an SAE; unless the Investigator assesses that the event 
meets standard ICH criteria for an SAE. CTCAE v4.03 Grade 4 baseline laboratory 
abnormalities that are part of the disease profile should not be reported as an SAE, 
specifically when they are allowed or not excluded by the protocol inclusion/exclusion 
criteria. If an Investigator is in doubt about the applicable reporting obligations, he/she 
should consult with the study monitor for the Sponsor. CTCAE v4.03 Grade 4 laboratory 
abnormalities will be documented in the laboratory data and will be reviewed on a regular 
basis.
For all SAEs the sponsor has to carry out a separate assessment for expectedness, 
seriousness and causal relationship to study drug.
9.5.1.4
Reporting of serious adverse events
The definition of serious adverse events (SAEs) is given in Section 9.5.1.1.
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 ISF. This information will be updated as needed.
All SAEs occurring during the observation period defined in Section 9.5.1.3 must 
immediately (within 24 hours of the investigator’s awareness) be reported to the recipient 
detailed in the Key Study Personal List. An SAE form must also be completed within 
24 hours of the investigator awareness and forwarded to the designated recipient. Each 
SAE must be followed up until resolution or stabilization by submission of updated 


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reports to the designated recipient.
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 Independent Ethics Committees (IECs) / Institutional Review Boards 
(IRBs) about all relevant events (e.g. SAEs, <suspected, unexpected, serious adverse 
reactions (SUSARs)>) will be performed by the sponsor (or delegate) and / or by the 
investigator according to all applicable regulations.
Notification of the authorities 
The processing and reporting of all relevant events (e.g. SUSARs) to the authorities will 
be done by the sponsor according to all applicable regulations.
Sponsor’s notification of the investigational site
The sponsor will inform all investigational sites about reported relevant events (e.g. fatal 
or life-threatening SUSARs) according to all applicable regulations.
9.5.1.5
Expected adverse events
Expected adverse drug reactions (ADRs)
Overview listings of frequent events that have occurred so far in the clinical development 
of BAY 1163877 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.
9.5.2 Pregnancies
The investigator must report to the sponsor any pregnancy occurring in a study subject 
during the subject’s participation in this study. The report should be submitted within the 
same timelines as a SAE, although a pregnancy per se is not considered a SAE.
For a study subject, the outcome of the pregnancy should be followed up carefully, and 
any abnormal outcome of the mother or the child should be reported.
Bayer usually does not gather information of drug exposure via father, however, if those 
cases are reported, all efforts should 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.


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9.5.3 Further safety variables
9.5.3.1
Physical examination including weight
The physical examination (by means of inspection, palpation, auscultation) will be 
performed according to the schedule summarized in the flow chart of Section 16.1. This 
includes review of all organ systems, examination of pertinent organ systems, and vital 
signs.
For this examination, the investigator will assess / examine the following:
- General appearances
- Skin
- Eyes
- Ears, nose and throat
- Head and neck
- Lungs
- Heart
- Abdomen
- Lymph nodes
- Musculoskeletal system (including
  extremities and spine)
- Neurological findings
If indicated by the subject’s history, the following will be examined by specialists, if 
applicable:
- Genito-urinary system
- Gynecological organs
- Rectum
Depending on criteria of relative timing (before or after signing IC), the findings of the 
physical examination have to be recorded as medical / surgical history or as an AE.
Body weight will be measured in the morning by a member of the investigator’s team 
under the following conditions:
-
Fasting state of the subject, empty bladder, without shoes, in underwear
Subject’s body height in centimeter (cm) will be measured only at screening. 
Subject’s body mass index (BMI) is calculated at screening by dividing the subject’s 
weight by the square of his or her height (kg/cm2).
A skin check for detection of hand-foot skin reaction (HFSR) will be performed by a 
physician at each study visit.
9.5.3.2
Ophthalmological examination
A complete ophthalmologic examination will be performed by an ophthalmologist, at 
screening, during treatment (every second cycle) and at the EOT visit. The exam will 
include previous eye history and any ophthalmic symptoms, best corrected visual acuity, 
dilated ophthalmoscopy and optical coherence tomography for the measurement of central 
foveal thickness. The ophthalmologist will describe examination findings on an 
examination worksheet provided by the investigational site. Any findings qualifying as an 
adverse event will be recorded accordingly.
Additionally, the investigator will ask the subject for changes in vision at each site visit.


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9.5.3.3
Vital signs
Systolic / diastolic blood pressure, respiration rate and heart rate will be measured by a 
member of the investigator’s team (cardiovascular assessment, see Section 9.4.1.1).
Body temperature will be measured by a member of the investigator’s team according to 
the following method: sublingual, using an electronic thermometer with digital display 
and recorded in the eCRF in degree Celsius (°C).
9.5.3.4
Electrocardiogram (ECG)
For the assessment of possible drug effects on QT/ QTc interval duration at pre-defined 
time points at screening and in Cycle 1, standard 12-lead ECGs will be recorded in 
triplicates in selected subjects dosed with 50 mg and higher until implementation of 
Amendment 5. The triplicate ECGs will be recorded in close sequence and not more than 
2 minutes apart. 
Subjects will have a single ECG recording in all subsequent cycles.
12-lead ECG readings will be performed in the supine position at the following time 
points:

Screening (single ECG readings)

Cycle 1, Day -3 and Day -2 (triplicate ECG readings [“tablet bridging cohort” and 
“food effect assessment” only])
-
before and 2, 3 (Day -3) and 24 (Day -2) hours after single-dose administration

Cycle 1, Day 1 and Day 2 (single ECG reading)
-
before and 2, 3 (Day 1) and 24 (Day 2) hours after single-dose administration

Cycle 1, Day 15 (single ECG reading)
-
before morning dose, and 2 and 3 hours thereafter 

Cycle ≥ 2, Day 1 (single ECG readings)
-
after morning dose

EOT visit (single ECG reading)
The study number, SNR, visit and the date of the ECG are noted on every ECG. All ECGs 
recorded during the study will be evaluated by a physician. He / she will document the 
diagnosis(-ses) including an overall assessment of the findings and their clinical relevance 
in the eCRF. 
9.5.4 Echocardiography / MUGA scan
An echocardiography or MUGA (multiple gated acquisition) scan is to be done at 
screening (within 7 days prior to first study drug administration) to ensure that only 


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subjects with adequate cardiac function (LVEF ≥ 50%) participate in this study. This is no 
longer needed after implementation of Amendment 5. 81
9.5.4.1
ECOG Performance status
Subject’s ability to manage activities of daily living will be appraised utilizing the 
performance status scale by USA Eastern Cooperative Oncology Group (ECOG), see 
Section 16.7. The subject’s ECOG performance score will be estimated according to the 
schedule summarized in the flow chart of Section 16.1. An ECOG Performance Status 
score of 0, 1 or 2 is required for study inclusion (see Section 7.1.1).
9.5.4.2
Laboratory examinations - amended
Section 16.2 provide the parameters and time points for the laboratory examinations to 
be performed during the study. 
Blood and urine samples for the safety laboratory tests, biomarker investigations, and gene 
expression profiling and cytokine levels will be collected by a member of the 
investigator’s team.82
The laboratory test results will be made promptly available to the investigator except for 
the biomarker parameters and cytokine levels, which will be analyzed in batches where 
appropriate.
Detailed information about the handling and labeling of the samples will be provided in a 
separate document (e.g. Laboratory Manual).
The following laboratory analyses (safety laboratory tests) will be performed by the local 
laboratory or at the study site (see Section 16.2):
Blood tests:
-
Hematology and biochemistry parameters (for details see Section 16.2)
Serum creatinine concentration will be used to estimate the subject’s 
glomerular filtration rate (eGFR) at screening utilizing the Modification of 
Diet in Renal Disease (MDRD) equation, see Section 16.9.
Coagulation parameters  (for all subjects).
Virology tests 
Urine tests: 
Macroanalysis
Urinalysis (dip stick and laboratory analysis), for details see Section 16.2.
                                                
81 Section 9.5.4 deleted by Amendment 5, see section 15.5.2.24
82 Cytokines added by Amendment 7, see section 15.6.2.28


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Microscopic analysis: to be performed if the appearance of urine is turbid, or if 
protein, leukocytes, erythrocytes, or nitrite are out of normal range.
Urine pregnancy test (only in woman of childbearing potential). 
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 in the eCRF).
The following laboratory analyses will be performed by analysis laboratories: 
Tumor biopsies: 
-
Quantification of tumor p-ERK levels pre- and post-treatment by 
immunohistochemistry
In this clinical trial, tumor biopsies will be examined using immunohistochemistry 
in order to examine the relationship between tumor p-ERK and response to 
BAY 1163877 therapy. Paired tumor biopsies should be obtained prior to study 
treatment and on Cycle 2, Day 1 (at the end of Cycle 1) for analysis of p-ERK in 
tumor tissue. 
-
Quantification of tumor FGFR1, 2 and 3 mRNA levels
In this clinical trial tumor biopsies will be examined for FGFR1, FGFR2 and 
FGFR3 mRNA levels from biopsy samples / archival biopsy samples.
-
Retrospective evaluation of mutations in either FGFR encoding genes or in FGFR 
downstream pathway genes from biopsy samples / archival tissue samples.
-
Gene expression profiling (nCounter PanCancer Immune Profiling Panel) 
-
Immunhistochemistry for CD8+ T cell infiltration and PD-L1 expression
Peripheral Blood:
-
Collection of serum to determine cytokine levels (IL-6, IFN-gamma, and others if 
needed)83
Subjects with BC with low overall FGFR expression levels can only be included in study 
Part 2 or Part 3 if an activating mutation in FGFR3 gene has been confirmed at screening. 
9.6
Other procedures and variables
9.6.1 Diary
Subject paper diaries in local language will be provided to the study sites, to document the 
following information:
Daily oral administration of BAY 1163877 (amount of drug and time of dosing) by 
the subject
                                                
83 Gene expression profiling, immunohistochemistry and blood cytokines added in Part 3, see section 15.6.2.28


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Confirmation of diary check by the investigator’s team and clinical research 
assistant (CRA)
The daily records of study drug intake will be transferred to the database in accordance 
with the data entry guidelines.
The subject will be told to start the diary with the first oral administration of the study 
drug on Cycle 1 / Day 1. The subject has then to keep the diary until the end of the 
treatment period. The subject will be told to bring the diary along to each visit. The diaries 
will be checked at each visit for completeness and plausibility by a member of the 
investigator’s team (see Section 8.7). Care should be taken that the (handwritten) entries 
are clearly legible.
9.7
Appropriateness of procedures / measurements
All efficacy and safety parameters, as well as the methods to measure them, are standard 
variables / methods in clinical studies and / or clinical and gynecological practice. They 
are widely used and generally recognized as reliable, accurate and relevant.
10 Statistical measures and determination of sample size
10.1 General considerations 
Statistical analysis will be performed using SAS (statistical analysis system); 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 change versus baseline. Graphical illustrations will be provided 
where appropriate. Frequency tables will be provided for qualitative data. Due to the 
exploratory character of this study, no confirmatory analysis will be done. 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.
10.2 Analysis sets
All subjects who received at least one dose of the study medication will be included in the 
safety evaluation. All subjects who completed Cycle 1 or discontinued during Cycle 1 due 
to an adverse event or DLT will be included in the MTD evaluation. All subjects who 
have received at least one dose of BAY 1163877 and who have post-baseline efficacy data 
available will be included in the efficacy evaluations.
All subjects with valid pharmacokinetic data will be included in the evaluation of 
pharmacokinetic concentrations and parameters.
Subjects to be included in the relative bioavailability evaluation (“tablet bridging cohort”) 
should have evaluable pharmacokinetic data on both Cycle 1, Day -3 and Cycle 1, Day 1.


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10.3 Variables
Variables (primary and secondary) are specified in Section 9.4.
10.4 Statistical and analytical plans
10.4.1 Demographic and other baseline characteristics
Summary statistics (arithmetic mean, standard deviation, median, minimum and maximum 
for quantitative variables) will be presented by treatment arm. Frequency tables for 
qualitative data will be provided. Medical history findings will be summarized using 
MedDRA (Medical Dictionary for Regulatory Activities) terms. 
10.4.2 Maximum tolerated dose
Individual listings and treatment summaries of dose limiting toxicities with CTCAE v4.03 
code and grade will be presented.
The incidence of subjects with DLTs during Cycle 1 will be summarized by treatment and, 
as possible, modeled as a function of BAY 1163877 dose using Bayesian logistic 
regression. The moderately-informative independent priors used during the interim 
analysis (see Section 16.4 for details) as well as non-informative priors will be used for 
this analysis in order to assess sensitivity of the estimates. Parameter estimates and model 
predictions will be reported with 90% credibility sets. The MTD will be computed as a 
derived function of model parameters as:
MTD = (log(0.2/0.8)-intercept) / slope.
The posterior distribution of the MTD will be summarized in tabular and graphical 
formats.
10.4.3 Adverse events
Individual listings of adverse events will be provided. The incidence of treatment-
emergent adverse events (TEAEs) and treatment-emergent drug-related adverse events 
(TEADRs), respectively, will be summarized by cohort in frequency tables using worst 
CTCAE v4.03 grade. Frequency tables will also be provided for the changes of worst 
CTCAE v4.03 grade after start of treatment versus baseline. In addition analysis will be 
done using MedDRA terms.
10.4.4 Safety parameters
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 by cohort for the original data as well as for the difference to 
baseline. Frequency tables will be provided for qualitative data.
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 by cohort in frequency tables. The incidence of laboratory toxicities will be 
summarized by worst CTCAE v4.03 grade and by cohort. Frequency tables will be 


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provided for the changes of worst CTCAE v4.03 grade after start of treatment versus 
baseline.
10.4.5 Pharmacokinetic data
The concentration-times courses of all analytes will be tabulated for each cohort. 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 by treatment using both linear and semilogarithmic scale. The amount and 
percent of drug excreted into urine will be graphically illustrated for the sampling interval 
as well as for the whole sampling period (bar-charts for the individual data and the 
arithmetic mean including standard deviation).
Pharmacokinetic characteristics (tmax and 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. Amount and percent of drug excreted in urine 
will be described by arithmetic statistics, minimum, maximum and median.
To investigate dose proportionality, an explorative analysis of variance (ANOVA), 
including the factor cohort, will be performed on the log-transformed values of 
appropriate PK parameters calculated from single (where applicable) and multiple dose 
PK profiles.
In order to evaluate the relative bioavailability of the tablet formulation, tablet Cmax/D, 
AUC(0-tlast)/D and AUC/D on Cycle 1, Day -3 will be compared to solution Cmax/D, 
AUC(0-tlast)/D, AUC/D on Cycle 1, Day 1 for all analytes. If needed, additional PK 
parameters may be used for relative bioavailability assessment. The logarithms of these 
PK parameters will be analyzed using analysis of variance (ANOVA) including subject 
and formulation effects. Based on these analyses, point estimates (LS-means) and 
exploratory 90% confidence intervals for the ratios (tablet/solution) of Cmax/D, 
AUC(0-tlast)/D, AUC/D will be calculated by retransformation of the logarithmic data 
using the intra-individual standard deviation of the ANOVA.
In order to evaluate the food effect, BAY 1163877 Cmax and AUC(0-tlast) on Cycle 1, 
Day -3 and Cmax and AUC(0-tlast) on Cycle 1, Day 1 will be compared. The logarithms of 
Cmax and AUC(0- tlast) will be analyzed using ANOVA including subject and food effects. 
Based on these analyses, point estimates (LS-means) and exploratory 90% confidence 
intervals for the ratios (high-fat, high-calorie meal / fasting) of Cmax and AUC(0- tlast) will 
be calculated by retransformation of the logarithmic data using the intra-individual 


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standard deviation of the ANOVA.
10.4.6 Pharmacodynamic data
Cardiovascular parameters will be described by the following summary statistics: 
arithmetic mean, standard deviation, median, minimum and maximum. These summary 
statistics will be presented by cohort for the original data as well as for the difference to 
baseline.
Graphical displays of individual data as well as mean values with standard deviation will 
be included for absolute values as well as change from baseline.
10.4.7 Efficacy data
Efficacy data, such as best tumor response, 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.
The efficacy analysis will include descriptive analyses on response rate, progression-free 
survival (PFS) and time to progression (TTP). 
Response as defined by RECIST v.1.1: complete response (CR), partial response (PR), 
stable disease (SD), progressive disease (PD), see Section 16.8.
Progression-free survival (PFS) is defined as the time (days) from the date of the first 
dose of study drug to the date of the first observed radiological disease progression or 
death, whatever comes first. PFS for subjects without tumor progression at the time of 
analysis will be censored at their last date of tumor evaluation.
Time to progression (TTP) is defined as the time from start of study treatment until 
objective tumor progression; TTP does not include deaths.
10.5 Planned interim analysis
Safety data will be reviewed on an ongoing basis during study Part 1 / dose escalation (all 
comer). Bayesian dose-response and / or PK / PD modeling of DLTs rates and CTCAE 
v4.03 gradings may be performed after selected cohorts 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 cohort expansion during the adaptive dose escalation part. This 
group will also determine when to implement predefined stopping rules.
No interim analysis is planned during dose expansion at MTD in study Part 1 (MTD 
expansion cohort “all comer”), study Part 2 (MTD expansion cohort “sqNSCLC + LAC + 
BC + SCCHN”) or study part 3 (MTD expansion cohort “Safety cohort”).84
                                                
84 Part 3 - Safety cohort - was added by Amendment 7, see section15.6.2.29


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10.6 Further analysis described and reported under separate cover
In order to evaluate the exposure-response during 4 cycles, two blood samples will be 
collected on Day 1 of Cycles 2-5, one before and one after a supervised dose. The 
resulting longitudinal exposure data will be modeled together with occurrences of selected 
adverse events and documented clinical responses. Also longitudinally measured PD 
biomarkers will be modeled with this exposure data. Exposure-response models and 
simulations after alternative dosing schedules will be reported in a separate document.
10.7 Determination of sample size - amended
This is primarily a descriptive safety and tolerability Phase I trial. No formal sample size 
estimation is performed. The actual sample size required to adequately determine the 
MTD depends on the initial dose, rate of dose escalation and the observed dose-toxicity 
and dose / exposure-pharmacological relationships. Simulation studies have been 
performed to quantify the operational characteristics (i.e., precision of the MTD, sample 
size, number of subjects being over / under dosed) of the adaptive dose-escalation design 
under a number of plausible dose-DLT relationship scenarios. Results are provided in 
Section 16.4. Based on experience the chosen sample size of 3-9 subjects per cohort is 
considered to be sufficient to fulfill the objectives of the study. 
In study Part 1 / MTD expansion (all comer), additional subjects will be included in order 
to gain more information about biomarkers (p-ERK1/2) in at least 20 evaluable subjects 
with any solid tumors.
In study Part 2 / MTD expansion, additional subjects will be included in order to obtain 
further safety and PK data at the MTD level in at least 20 subjects with sqNSCLC or
LAC, at least 30, up to a maximum of 50 evaluable subjects with BC and at least 8 
subjects with SCCHN.85
In study Part 3 / MTD expansion “Safety cohort”, additional subjects will be included to 
expand the safety database, to collect additional efficacy data, and to assess changes of
immune parameters during treatment at the MTD level in approximately 20 subjects with 
sqNSCLC or LAC, and approximately 20 subjects with BC. 86
11 Data handling and quality assurance
11.1 Data recording - amended
It is the expectation of the sponsor that all data entered into the eCRF has source 
documentation available at the study site. Entries into the eCRF should be made as soon as 
possible.
A Source Document Checklist will be used at site to identify the source data for all points 
                                                
85 Modified by Amendment 7, see section 15.6.2.30
86 Part 3 - Safety cohort - was added by Amendment 7, see section 15.6.2.30


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collected.
A CRO (Linical, formerly part of Nuvisan) provides the investigational site with access to 
an internet / web-based electronic data capture (EDC) computer system (termed 
“Inform”). Oracle has developed this system as a secured data entry tool that cannot be 
modified by investigative sites. The customized application for this protocol was 
developed by Linical and validated according to Lincical “Standard Operating 
Procedures”. Edit checks and data logic checks are done at the point of entry and are 
validated by Linical. All data entered into the system is transferred to a secure server 
maintained by Linical. 
Access to the Inform EDC system at the site, at Linical and at Bayer is password 
protected. Study access is granted to site personnel only after they have been trained in 
the use of the Inform EDC System by Linical personnel or after a web-based training, 
either at the investigational site or at the investigators’ meeting. Linical and Bayer 
personnel are also required to complete the training program before they are allowed to 
access the system. All Inform EDC system training history is documented and maintained 
by Linical.
The Inform EDC System contains a system-generated audit trail that captures any changes 
made to a data field, including who made the change, and the date and time it was 
made. This information is available both at the investigator’s site and at Linical. 
Data entries made in the Inform EDC screens are supported by source documents 
maintained for all subjects enrolled in this study. 

Results from pharmacokinetic analyses
The results of drug concentration measurements will be provided as electronic data 
files and transferred to Data Management, where the information necessary for 
evaluation will be added (e.g. administration and sampling time points, demographic 
data). This data set will be evaluated by the responsible pharmacokineticist. The 
complete pharmacokinetic evaluation will then be retransferred to Data 
Management.
Results from biomarker analyses
The results of biomarker analyses will be provided by the laboratories as electronic data 
files and transferred to Data Management, where the data is mapped into the database.
Results from ECG measurement
A part of the ECG analyses will be performed by Nabios. Nabios will send the electronic 
data files to Data Management, where the data is mapped into the database.

Data recorded during the FGFR expression / FGFR mutation testing period (MTD 
expansion cohorts only)
Limited data will be recorded for all subjects in the FGFR expression / FGFR 
mutation testing period as described below: 
-
Subject number


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-
Demographic data
-
Cancer classification including primary diagnosis (all comer for study Part 1; 
sqNSCLC, LAC, BC or SCCHN for Part 2; sqNSCLC, LAC or BC for Part 3), 
complete medical / oncological history data and TNM classification87
-
Life expectancy
-
ECOG Performance Status
-
Information on existence of an archival tumor biopsy specimen
-
Details on collection of fresh tumor material (if applicable)
-
Adverse event(s) only in case an invasive procedure will be performed to obtain 
tumor material after informed consent

Data recorded from “only screened subjects (screening failures)” including pre-
screening
For screening failures, all items listed below must be documented within the eCRF:
-
Subject number
-
Date of informed consent
-
Date of birth
-
Gender
-
Reason for discontinuation
-
Date of Last Visit
For screening failures with an SAE, the following information has to be added:
-
Adverse event(s)
-
Concomitant medication
-
Medical history
-
Other information related to the SAE (e.g. laboratory results)
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:
                                                
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Data are authentic, accurate and complete
Safety and rights of subjects are being protected
Study is conducted in accordance with the currently approved protocol 
-
Any other study agreements, GCP, and all applicable regulatory requirements are 
met.
The investigator and the head of the medical institution (where applicable) agrees to allow 
the monitor direct access to all relevant documents.
11.3 Data processing
The data collection tool for this study will be the validated electronic system by Oracle 
Inform©. Subject data necessary for analysis and reporting will be entered/ transmitted into 
a validated database that will follow the sponsor’s requirements. Clinical data 
management will be performed in accordance with applicable sponsor’s standards and 
data cleaning procedures. This is applicable for data recorded in the eCRF as well as for 
data from other sources (e.g. ECG). 
For data coding (e.g. AEs, medication), Linical will transfer the verbatim terms and 
internationally recognized and accepted dictionaries will be used by the sponsor. 
Bioanalytical results for pharmacokinetic evaluation will electronically be transferred 
from the Bioanalytical Department to Data Management using a predefined uniform file 
format. Data Management will include these data in the corresponding SAS data 
repository. Data Management will create a transfer file containing the bioanalytical 
results, demographic data, dosing data, and actual dosing and sample collection times and 
will electronically send this file to Bayer, Clinical Sciences. Clinical Sciences will 
calculate all pharmacokinetic parameters indicated in this protocol as described in 
Section 9.4.2.2. The finalized evaluation will electronically be transferred to Data 
Management where all data will be included in the corresponding SAS data repository. All 
electronic file transfer processes will follow validated procedures.
11.4 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 investigational 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.


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11.5 Archiving
Essential documents shall be archived safely and securely in such a way that ensures that 
they are readily available upon authorities’ request.
Subject (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. 
The investigator / institution notifies the sponsor if the archival arrangements change (e.g. 
relocation or transfer of ownership).
The ISF is not to be destroyed without the sponsor’s approval.
The investigator’s contract will contain all regulations relevant for the investigational site.
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); 
(If dose Level 1 is not tolerated, the trial will end.)
-
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 study 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.

All affected institutions (e.g. IEC(s) / IRB(s); competent authority(ies); study 
center(s)) 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 
given by the sponsor for destruction.

In case of a partial study closure, ongoing subjects, including those in post study 
follow-up, must be taken care of in an ethical manner
Details for individual subject's withdrawal can be found in Section 7.2.1.


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13 Ethical and legal aspects
13.1 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 under 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).
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 clinical study protocol (CSP) 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 study subjects 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 / sponsor. Any deviations from the protocol must be explained and documented by 
the investigator.
Details on discontinuation of the entire study or parts thereof can be found in Section 12.
13.2 Subject information and consent
All relevant information on the study will be summarized in 2 separate integrated subject 
information sheet and informed consent forms (SIS / ICFs) provided by the sponsor or the 
study center. 
SIS / ICF for FGFR expression / FGFR mutation testing
For subject stratification in the MTD expansion cohorts (Part 1: all comer; Part 2: 
sqNSCLC + LAC + BC + SCCHN, Part 3: sqNSCLC + LAC + BC), a separate SIS / 
ICF will be provided to subjects for FGFR expression / FGFR mutation testing. This 
separate SIS / ICF gives brief information on the study conduct, details on the tissue 
sample required to be taken to perform the tests along with information on possible 
risks. 88
SIS / ICF for study treatment eligibility
All subjects who have interest to participate in this study (including those who are 
confirmed presenting the appropriate FGF receptor level, or - for bladder cancer 
subjects - who are confirmed carrying the FGFR mutation) will be provided the SIS / 
ICF for screening of study treatment eligibility no longer than 28 days prior to start of 
                                                
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study treatment. 
Samples of the 2 SIS /ICFs are provided as a document separate to this protocol.
Based on the subject information sheet(s), the investigator or designee will explain all 
relevant aspects of the study to each subject 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 IEC / IRB has been 
obtained.
Each subject will have ample time and opportunity to ask questions and will be informed 
about the right to withdraw from the study at any time without any disadvantage and 
without having to provide reasons for this decision.
Only if the subject voluntarily agrees to sign the informed consent form(s) and has done 
so, may he / she enter the study. Additionally, the investigator and other information 
provider (if any) will personally sign and date the form(s). The subject will receive a copy 
of the signed and dated form(s).
The signed informed consent statement(s) is (are) to remain in the ISF or, if locally 
required, in the subject’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 subject’s clinical record must clearly show that 
informed consent was obtained prior to these procedures.
The informed consent form(s) and any other written information provided to subjects will 
be revised whenever important new information becomes available that may be relevant to 
the subject’s consent, or there is an amendment to the protocol that necessitates a change 
to the content of the subject information and / or the written informed consent form(s). 
The investigator will inform the subject of changes in a timely manner and will ask the 
subject to confirm his / her participation in the study by signing the revised informed 
consent form(s). Any revised written informed consent form and written information must 
receive the IEC / IRB’s approval / favorable opinion in advance of use.
13.3 Publication policy - amended89
The sponsor is interested in the publication of the results of every study it performs. All 
relevant aspects regarding publication will be part of the contract between the sponsor and 
the investigator / institution.
The sponsor has committed to the global industry position on disclosure of information 
about clinical trials. The information regarding the CSP is made publicly available on the 
internet at www.clinicaltrials.gov.
                                                
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All data and results and all intellectual property rights in the data and results derived from 
the trial will be the property of the Bayer AG, who may utilize the data in various ways, 
such as for submission to government regulatory authorities or disclosure to other 
investigators. The investigator, whilst free to utilize data derived from the trial for 
scientific purposes, must discuss any publication with Bayer AG prior to release and 
obtain written consent of Bayer AG on the intended publication. Bayer AG recognizes the 
right of the investigator to publish the results upon completion of the trial. However, the 
investigator must send a draft manuscript of the publication or abstract to Bayer AG 
30 days in advance of submission in order to obtain approval prior to submission of the 
final version for publication. This will be reviewed promptly and approval will not be 
withheld unreasonably. In case of a difference of opinion between Bayer AG and the 
investigator(s), the contents of the publication will be discussed in order to find a solution 
that satisfies all parties.
13.4 Compensation for health damage of subjects / insurance
The sponsor maintains clinical trial insurance coverage for this study in accordance with 
the laws and regulations of the country in which the study is performed.
13.5 Confidentiality
All records identifying the subject will be kept confidential and, to the extent permitted by 
the applicable laws and / or regulations, will not be made publicly available.
Subject names will not be supplied to the sponsor. Only the subject number will be 
recorded in the eCRF, and if the subject 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. The subjects 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 subject’s identity will remain confidential.
The investigator will maintain a list to enable subjects to be identified.


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Turner N, Grose R. Fibroblast growth factor signalling: from development to cancer. 
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Knowles MA. Role of FGFR3 in urothelial cell carcinoma: biomarker and potential 
therapeutic target. World J Urol. 2007;25(6):581-93 
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Knowles MA. Novel therapeutic targets in bladder cancer: mutation and expression 
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Dutt A, Ramos AH, Hammermann PS, Mermel C, Cho J, Sharifnia T, Chande A, 
Tanaka KE, Stransky N, Greulich H, Gray NS, Meyerson M. Inhibitor-sensitive 
FGFR1 amplification in human non-small cell lung cancer. PLoS One. 
2011;6(6):e20351 
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Schildhaus HU, Heukamp LC, Merkelbach-Bruse S, Riesner K, Schmitz K, Binot E, 
Paggen E, Albus K, Schulte W, Ko YD, Schlesinger A, Ansén S, Engel-Riedel W, 
Brockmann M, Serke M, Gerigk U, Huss S, Göke F, Perner S, Hekmat K, Frank KF, 
Reiser M, Schnell R, Bos M, Mattonet C, Sos M, Stoelben E, Wolf J, Zander T, 
Buettner R. Definition of a fluorescence in-situ hybridization score identifies high-
and low-level FGFR1 amplification types in squamous cell lung cancer. Mod Pathol. 
2012;25(11):1473-80 
(10) Zhang J, Zhang L, Su X, Li M, Xie L, Malchers F, Fan S, Yin X, Xu Y, Liu K, 
Dong Z, Zhu G, Qian Z, Tang L, Zhan P, Ji Q, Kilgour E, Smith PD, Brooks AN, 
Thomas RK, Gavine PR. Translating the therapeutic potential of AZD4547 in 
FGFR1-amplified non-small cell lung cancer through the use of patient-derived 
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(11) Heist RS, Mino-Kenudson M, Sequist LV, Tammireddy S, Morrissey L, Christiani 
DC, Engelman JA, Iafrate AJ. FGFR1 amplification in squamous cell carcinoma of 
the lung. J Thorac Oncol. 2012;7(12):1775-80
(12) Kim HR, Kim DJ, Kang DR, Lee JG, Lim SM, Lee CY, Rha SY, Bae MK, Lee YJ, 
Kim SH, Ha SJ, Soo RA, Chung KY, Kim JH, Lee JH, Shim HS, Cho BC. 
Fibroblast growth factor receptor 1 gene amplification is associated with poor 
survival and cigarette smoking dosage in patients with resected squamous cell lung 
cancer. J Clin Oncol. 2013;31(6):731-37. 
(13) Kohler LH, Mireskandari M, Knösel T, Altendorf-Hofmann A, Kunze A, Schmidt 
A, Presselt N, Chen Y, Petersen I. FGFR1 expression and gene copy numbers in 
human lung cancer. Virchows Arch. 2012;461(1):49-57
(14) Guagnano V, Kauffmann A, Wöhrle S, Stamm C, Ito M, Barys L, Pornon A, Yao Y, 
Li F, Zhang Y, Chen Z, Wilson CJ, Bordas V, Le Douget M, Gaither LA, Borawski 
J, Monahan JE, Venkatesan K, Brümmendorf T, Thomas DM, Garcia-Echeverria C, 
Hofmann F, Sellers WR, Graus-Porta D. FGFR genetic alterations predict for 
sensitivity to NVP-BGJ398, a selective pan-FGFR inhibitor. Cancer Discov. 
2012;2(12):1118-33
(15) Dodurga Y, Tataroglu C, Kesen Z, Satiroglu-Tufan NL. Incidence of fibroblast 
growth factor receptor 3 gene (FGFR3) A248C, S249C, G372C, and T375C 
mutations in bladder cancer. Genet Mol Res. 2011;10(1):86-95
(16) Kompier LC, Lurkin I, van der Aa MNM, van Rhijn BWG, van der Kwast TH, 
Zwarthoff EC. FGFR3, HRAS, KRAS, NRAS and PIK3CA mutations in bladder 
cancer and their potential as biomarkers for surveillance and therapy. PLoS One. 
2010;5(11): e13821 
(17) Yu X, White KE. Fibroblast growth factor 23 and its receptors. Ther Apher Dial. 
2005;9(4):308-12
(18) Gattineni J, Bates C, Twombley K, Dwarakanath V, Robinson ML, Goetz R, 
Mohammadi M, Baum M. FGF23 decreases renal NaPi-2a and NaPi-2c expression 
and induces hypophosphatemia in vivo predominantly via FGF receptor 1. Am J 
Physiol Renal Physiol. 2009;297(2):282–91
(19) Hu MC, Shiizaki K, Kuro-o M, Moe OW. Fibroblast growth factor 23 and Klotho: 
physiology and pathophysiology of an endocrine network of mineral metabolism. 
Annu Rev Physiol. 2013;75:503-33
(20) Wu AL, Feng B, Chen MZ, Kolumam G, Zavala-Solorio J, Wyatt SK, Gandham 
VD, Carano RA, Sonoda J. Antibody-mediated activation of FGFR1 induces FGF23 
production and hypophosphatemia. PLoS One. 2013;8(2):e57322
(21) Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, Fujita T, 
Nakahara K, Fukumoto S, Yamashita T 2004 FGF23 is a potent regulator of vitamin 
D metabolism and phosphate homeostasis. J Bone Miner Res 19:429–435.


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(22) Wöhrle S, Bonny O, Beluch N, Gaulis S, Stamm C, Scheibler M, Müller M, Kinzel 
B, Thuery A, Brueggen J, Hynes NE, Sellers WR, Hofmann F, Graus-Porta D. FGF 
receptors control vitamin D and phosphate homeostasis by mediating renal FGF23 
signaling and regulating FGF23 expression in bone. J Bone Miner Res. 
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(23) Kocełak P, Olszanecka-Glinianowicz M, Chudek J. Fibroblast growth factor 23--
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(24) Yang L, Isoda F, Yen K, Kleopoulos SP, Janssen W, Fan X, Mastaitis J, Dunn-
Meynell A, Levin B, McCrimmon R, Sherwin R, Musatov S, Mobbs CV. 
Hypothalamic Fkbp51 is induced by fasting, and elevated hypothalamic expression 
promotes obese phenotypes. Am J Physiol Endocrinol Metab. 2012;302(8):987-91
(25) Brooks AN, Kilgour E, Smith PD. Molecular pathways: fibroblast growth factor 
signaling: a new therapeutic opportunity in cancer. Clin Cancer Res. 
2012;18(7):1855-62
(26) Wöhrle S, Henninger C, Bonny O, Thuery A, Beluch N, Hynes NE, Guagnano V, 
Sellers WR, Hofmann F, Kneissel M, Graus Porta D. Pharmacological inhibition of 
fibroblast growth factor (FGF) receptor signaling ameliorates FGF23-mediated 
hypophosphatemic rickets. J Bone Miner Res. 2013 Apr;28(4):899-911
(27) Liang G, Liu Z, Wu J, Cai Y, Li X. Anticancer molecules targeting fibroblast 
growth factor receptors. Trends Pharmacol Sci. 2012;33(10):531-41
(28) Kim KB, Chesney J, Robinson D, Gardner H, Shi MM, Kirkwood JM. Phase I/II 
and pharmacodynamic study of dovitinib (TKI258), an inhibitor of fibroblast growth 
factor receptors and VEGF receptors, in patients with advanced melanoma. Clin 
Cancer Res. 2011;17(23):7451-61
(29) Angevin E, Lopez-Martin JA, Lin CC, Gschwend JE, Harzstark A, Castellano D, 
Soria JC, Sen P, Chang J, Shi M, Kay A, Escudier B. Phase I study of dovitinib 
(TKI258), an oral FGFR, VEGFR, and PDGFR inhibitor, in advanced or metastatic 
renal cell carcinoma. Clin Cancer Res. 2013;19(5):1257-68
(30) Lim SM, Kim HR, Shim HS, Soo RA, Cho BC. Role of FGF receptors as an 
emerging therapeutic target in lung squamous cell carcinoma. Future Oncol. 
2013;9(3):377-86
(31) Di Martino E, Tomlinson DC, Knowles MA. A decade of FGF receptor research in 
bladder cancer: past, present, and future challenges. Adv Urol. 2012;2012:429213
(32) Bourdin J, Sastre-Garau X, Chopin D, Thiery JP, Radvanyi F. Frequent activating 
mutations of FGFR3 in human bladder and cervix carcinomas. Nature Genetics. 
1999;23(1):18–20
(33) Tomlinson DC, Baldo O, Harnden P, Knowles MA. FGFR3 protein expression and 
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(34) Guagnano V, Kauffmann A, Wöhrle S, Stamm C, Ito M, Barys L, Pornon A, Yao Y, 
Li F, Zhang Y, Chen Z, Wilson CJ, Bordas V, Le Douget M, Gaither LA, Borawski 
J, Monahan JE, Venkatesan K, Brümmendorf T, Thomas DM, Garcia-Echeverria C, 
Hofmann F, Sellers WR, Graus-Porta D. FGFR genetic alterations predict for 
sensitivity to NVP-BGJ398, a selective pan-FGFR inhibitor. Cancer Discov. 
2012;2(12):1118-33
(35) Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R,  Dancey J, 
Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, 
Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: 
Revised RECIST guideline (Version 1.1). European Journal of Cancer 45: 228-47
(36) Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, 
Carbone PP. Toxicity and Response Criteria of the Eastern Cooperative Oncology 
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(37) Tibaldi F, Beck B, Bedding A. Implementation of a Phase 1 Adaptive Clinical Trial 
in a Treatment of Type 2 Diabetes. Drug Information Journal. 2008;42(05):455-465
(38) von Mässenhausen A, Franzen A, Heasley LE, Perner S. FGFR1 as a novel 
prognostic and predictive biomarker in squamous cell cancers of the lung and the 
head and neck area. Ann Transl Med. 2013;1(3). doi: 10.3978/j.issn.2305-
5839.2013.06.08
(39) Wynes MW, Hinz TK, Gao D, Martini M, Marek LA, Ware KE, Edwards MG, 
Böhm D, Perner S, Helfrich BA, Dziadziuszko R, Jassem J, Wojtylak S, Sejda A, 
Gozgit JM, Bunn PA Jr, Camidge DR, Tan AC, Hirsch FR, Heasley LE. FGFR1 
mRNA and protein expression, not gene copy number, predict FGFR TKI sensitivity 
acroll all lung cancer histologies. Clin Cancer Res, 2014 April 25 [Epup ahead of 
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(40) Sweis RF, Spranger S, Bao R, Paner GP, Stadler WM, Steinberg G, Gajewski TF.
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Urothelial Bladder Cancer. Cancer Immunol Res. 2016 Jul;4(7):563-8. doi: 
10.1158/2326-6066.CIR-15-0274. Epub 2016 May 17.90
                                                
90 Reference 40 was added by Amendment 7


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15 Protocol amendments
15.1 Amendment 1
Date of amendment: 31 Oct 2013
15.1.1 Overview of changes
Modification 1: Use of a further drug formulation (tablet)
Rationale for introducing Modification 1 
Studies have demonstrated the stability of a tablet formulation of BAY 1163877 which 
was developed for ease of administration. The switch from solution to tablet formulation 
is planned after relative bioavailability assessment of the tablet formulation planned in one 
of the dose escalation cohorts (“tablet bridging cohort”).
List of all CSP sections affected by Modification 1:
-
Synopsis
-
Section 2
-
Section 4 
-
Section 6.1 
-
Section 6.2 
-
Section 6.4.2.1 
-
Section 6.4.2.2
-
Section 6.4.2.3
-
Section 7.1.2.3
-
Section 7.1.2.3.1
-
Section 7.4.1.1
-
Section 7.4.2.1
-
Section 7.4.2.2
-
Section 7.5.3.4
-
Section 8.2
-
Section 8.4.5 
-
Section 14.1
-
Section 14.2
Modification 2: Completion of listing of primary variables
Rationale for introducing Modification 2 


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In the original protocol, the primary PK parameters listed in Section 7.4.2.2 were not 
mentioned as primary variables.
List of all CSP sections affected by Modification 2:
-
Synopsis
-
Section 4.1
Modification 3: Addition of criteria for dose modification of BAY 1163877
Rationale for introducing Modification 3 
Criteria for dose modifications of BAY 1163877 for liver toxicity and tissue 
mineralization were not provided in the original protocol. 
List of all CSP sections affected by Modification 3:
-
Section 6.4.3 
Modification 4: Minor corrections
Rationale for introducing Modification 4 
Minor text modifications and corrections of omissions or terminology were done for 
clarification and to ensure correct and consistent wording. 
List of all CSP sections affected by Modification 4:
-
List of abbreviations
-
Section 6.4.2 
-
Section 6.7
-
Section 7.4.4
-
Section 14.2
15.1.2 Changes to the protocol
In this section, all affected protocol sections are detailed; the sequence of the sections 
follows the structure of the original protocol. In the display of modifications, the “old 
text” refers to the protocol version preceding this amendment. Deletions are crossed out in 
the “old text”. Additions are underlined in the “new text”. Corrections of typing errors, 
omissions or terminology (minor corrections) are not highlighted in this amendment.
Synopsis
This section was changed as a result of Modifications 1 and 2.
Old text:
Title
…
Short title
…


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Clinical study phase
…
Project number
…
Study objective(s)
…
Test drug(s) 
…
Name of active ingredient 
…
Formulation 
Ready-to use solution for oral application (10 mg 
BAY 1163877 per 1 mL solution)
Dose(s)
…
Route of administration
…
Duration of treatment
Duration and dosing schedule for subjects participating 
in PK assessments (all subjects of study Part 1 and at 
least 12 subjects of study Part 2):
Subjects will receive BAY 1163877 on a 
continuous schedule starting with single-dose 
administration on Cycle 1, Day 1, followed by a 
“drug-free day” (to enable single dose PK 
assessments). Treatment with BAY 1163877 
will resume on Day 3 of Cycle 1 if no protocol-
defined dose-limiting toxicities (DLTs) are 
reported. Starting on Cycle 1, Day 3, the study 
drug will be self-administered twice daily for the 
remaining 19 days of Cycle 1. For subsequent 
cycles, study drug will be administered twice 
daily for 21 days each Cycle.
Duration and dosing schedule for subjects of study 
Part 2 without PK assessment: 
Duration of treatment
(continued)
Subjects will receive BAY 1163877 twice daily 
from Cycle 1, Day 1 ongoing.
Evidence of tumor progression, …
Reference drug (s)
…
Indication
…


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Diagnosis and main criteria for 
inclusion
…
Study design
…
Methodology
Eligible cancer subjects will be enrolled at multiple 
centers in Europe and Asia. In total, the “on study” 
period for the subjects comprises 3 phases:

Screening (minimum 7 days, maximum 28 days)

Treatment 
Study Part 1 / dose escalation + MTD expansion 
(all comer):
Individual number of 21-day Cycles with 
BAY 1163877 monotherapy until disease 
progression or as along as clinical benefit is 
assumed by the investigator or until 
unacceptable toxicity occurs
Study Part 2 / MTD expansion (sqNSCLC + 
BC): 
Individual number of 21-day Cycles with continuous 
BAY 1163877 monotherapy until disease progression 
or as along as clinical benefit is assumed by the 
investigator or until unacceptable toxicity occurs. 
Note: Treatment with BAY 1163877at MTD…
…
Pharmacokinetics (PK): Single- and multiple-dose PK 
of BAY 1163877 will be evaluated in plasma on 
Cycle 1, Day 1 (up to 48 hours after dosing) and on 
Cycle 1, Day 15 (up to 12 hours after dosing), 
respectively, in all subjects participating in Study Part 1 
(all comer) and at least 12 subjects participating in 
Study Part 2 (sqNSCLC + BC).


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Methodology
(continued)
Plasma concentration of BAY 1163877…
…
Cardiovascular assessment: Blood pressure (BP) and 
heart rate (HR) will be measured at screening, 
frequently on PK profile days in Cycle 1 (see above)
and once at all other visits during treatment and follow 
up. 
Electrocardiogram (ECG): 12-lead ECG readings will 
be performed at screening, on Cycle 1, Day 1 (before, 2, 
3 and 24 hours after single dosing) and Day 15 (before, 
2 and 3 hours after dosing), and on Day 1 of each 
subsequent Cycle (once after morning dose). 
At screening and in Cycle 1, ECG readings should 
be done in triplicate. The triplicate ECGs will be 
recorded in close sequence and not more than 2 minutes 
apart. In all subsequent Cycles (Cycle ≥ 2), ECG 
readings will be performed as single readings.
…
Type of control
…
Number of subjects
Up to 111 subjects will be enrolled in the screening 
phase of the study.

Study Part 1 / dose escalation (all comer): 
The total number of subjects will depend on the number 
of cohorts necessary to identify the MTD.

Study Part 1 / MTD expansion (all comer): ... 
Primary variable
The primary variable for MTD determination will be 
the incidence of DLTs during the first 21 days of 
treatment (Cycle 1). 
The primary study outcome is the MTD being defined 
as the maximum dose at which the incidence of DLTs 
during Cycle 1 is below 20%.
Plan for statistical analysis
…The incidence of subjects with DLTs during Cycle 1 
will be summarized by cohort and, as possible, modeled 
as a function of BAY 1163877 dose using Bayesian 
logistic regression to guide the dose selection.
New text:


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Title
…
Short title
…
Clinical study phase
…
Project number
…
Study objective(s)
…
Test drug(s) 
…
Test drug(s) 
…
Name of active ingredient 
…
Formulation IMP 1
Ready-to use solution for oral application 
(10 mg BAY 1163877 per 1 mL solution)
Formulation IMP 2
Tablet (50 mg tablet and 200 mg tablet)
Dose(s)
…
Route of administration
…
Duration of treatment
Duration and dosing schedule for subjects participating 
in PK assessments (all subjects of study Part 1 and at 
least 12 subjects of study Part 2):
Subjects will receive BAY 1163877 (tablet or 
solution) on a continuous schedule starting with 
single-dose administration on Cycle 1, Day 1, 
followed by a “drug-free day” (to enable single 
dose PK assessments). Treatment with BAY 
1163877 will resume on Day 3 of Cycle 1 if no 
protocol-defined dose-limiting toxicities (DLTs) 
are reported. Starting on Cycle 1, Day 3, the 
study drug will be self-administered twice daily 
for the remaining 19 days of Cycle 1. For 
subsequent cycles, study drug will be 
administered twice daily for 21 days each Cycle.
Duration and dosing schedule of subjects enrolled for 
tablet relative bioavailability assessment (“tablet 
bridging cohort”) of study Part 1: 


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Duration of treatment
(continued)
Subjects will receive a single dose of tablet 
formulation on Cycle 1, Day -3, and then continue 
with the solution formulation starting on Cycle 1, 
Day 1, according to the schedule described above. 
Duration and dosing schedule for subjects of study 
Part 2 without PK assessment: 
Subjects will receive BAY 1163877 (tablet or 
solution) twice daily from Cycle 1, Day 1 ongoing.
Evidence of tumor progression, …
Reference drug (s)
…
Indication
…
Diagnosis and main criteria for 
inclusion
…
Study design
…
Methodology
Eligible cancer subjects will be enrolled at multiple 
centers in Europe and Asia. In total, the “on study” 
period for the subjects comprises 3 phases:

Screening (minimum 7 days, maximum 28 days)

Treatment 
Study Part 1 / dose escalation + MTD expansion 
(all comer):
Individual number of 21-day Cycles with 
BAY 1163877 monotherapy (tablet or solution) until 
disease progression or as along as clinical benefit is 
assumed by the investigator or until unacceptable 
toxicity occurs
Study Part 1 /“tablet bridging cohort” 
(all comer):
In one of the dose escalation cohorts, administration of 
a single dose of BAY 1163877 using the tablet 
formulation on Cycle 1, Day -3 followed by solution 
formulation starting Cycle 1, Day 1 as described above.
Study Part 2 / MTD expansion (sqNSCLC + 
BC):
Individual number of 21-day Cycles with continuous 
BAY 1163877 monotherapy (tablet or solution) until 
disease progression or as along 


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Methodology 
(continued)
as clinical benefit is assumed by the investigator 
or until unacceptable toxicity occurs. 
Note: Treatment with BAY 1163877 at MTD …
….
Pharmacokinetics (PK): Single- and multiple-dose PK 
of BAY 1163877 will be evaluated in plasma samples 
collected on Cycle 1, Day -3 (up to 48 hours after 
dosing) in the “tablet bridging cohort”, and on Cycle 1, 
Day 1 (up to 48 hours after dosing) and on Cycle 1, 
Day 15 (up to 12 hours after dosing), respectively, in all 
subjects participating in Study Part 1 (all comer) and in
at least 12 subjects participating in Study Part 2 
(sqNSCLC + BC).
Plasma concentration of BAY 1163877…
…
Cardiovascular assessment: Blood pressure (BP) and 
heart rate (HR) will be measured at screening, 
frequently on PK profile days in Cycle 1, and once at all 
other visits during treatment and follow up. 
Electrocardiogram (ECG): 12-lead ECG readings will 
be performed at screening, on Cycle 1, Days -3 and -2 
(“tablet bridging cohort” only), on Cycle 1, Days 1, 2, 
and 15, thereafter on Day 1 of each subsequent Cycle,
and at the EOT visit. 
At screening and in Cycle 1, ECG readings should 
be done in triplicate. The triplicate ECGs will be 
recorded in close sequence and not more than 2 minutes 
apart. In all subsequent Cycles (Cycle ≥ 2) and at the 
EOT visit, ECG readings will be performed as single 
readings.
…
Type of control
…
Number of subjects
Up to 111 subjects will be enrolled in the screening 
phase of the study.

Study Part 1 / dose escalation (all comer): 
The total number of subjects will depend on the number 
of cohorts necessary to identify the MTD.
Number of subjects
Relative bioavailability of the tablet formulation in 
comparison to the solution formulation will be 


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(continued)
performed in all subjects enrolled in one of the dose 
escalation cohorts; pharmacokinetic data are needed 
in a minimum of 3 subjects for relative 
bioavailability assessment. 
Study Part 1 / MTD expansion (all comer): …
Primary variables
Determination of MTD
The primary variable for MTD determination will be 
the incidence of DLTs during the first 21 days of 
treatment (Cycle 1). 
The primary study outcome is the MTD being defined 
as the maximum dose at which the incidence of DLTs 
during Cycle 1 is below 20%.
Pharmacokinetics: (BAY 1163877)
On Cycle 1 Day -3 (“tablet bridging cohort” only) 
and Cycle 1, Day 1: Cmax, AUC(0-12), AUC(0-tlast), 
AUC and corresponding dose adjusted parameters 
(Cmax/D, AUC(0-12)/D AUC(0-tlast)/D, AUC/D and 
AUC)
For Cycle 1, Day 15: Cmax,md, Cmax/Dmd, AUC(0-12)md, 
AUC(0-12)/Dmd, AUC(0-tlast)md, and AUC(0-tlast)/Dmd.
Plan for statistical analysis
…
The incidence of subjects with DLTs during Cycle 1 
will be summarized by cohort and, as possible, modeled 
as a function of BAY 1163877 dose using Bayesian 
logistic regression to guide the dose selection.
PK data will be summarized by descriptive statistics. 
To investigate dose proportionality an ANOVA will be 
performed on the log-transformed values of appropriate 
PK parameters and 90% confidence intervals will be 
derived.


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Section 2: Study objectives 
This section was changed as a result of Modification 1.
Old text:
Secondary objectives include:

To evaluate biomarker status, pharmacodynamic (PD) parameters, and tumor 
response.
New text:
Secondary objectives include:

To evaluate biomarker status, pharmacodynamic (PD) parameters, and tumor 
response.

To assess the relative bioavailability of the tablet formulation in comparison to the 
solution formulation of BAY 1163877.
Section 4: Study design 
This section was changed as a result of Modification 1.
Old text:
Design overview
…
Targeted / planned enrollment:

Study Part 1 / dose escalation (all comer): The total number of subjects will 
depend on the number of cohorts necessary to identify the MTD.

Study Part 1 / MTD expansion (all comer): Additional subjects will be enrolled to 
have 20 evaluable “all comer” subjects treated at MTD.

Study Part 2 / MTD expansion (sqNSCLC + BC): 40 additional subjects will be 
enrolled to have 20 evaluable subjects with sqNSCLC and 20 evaluable subjects with BC 
treated at MTD.
The minimum number of valid subjects completing study treatments, and PK is 3 per 
cohort. PK assessments will be performed in all subjects participating in study Part 1 / 
dose escalation and MTD expansion (all comer). Additionally, PK assessments are 
planned in at least 12 subjects participating in study Part 2 / MTD expansion (sqNSCLC + 
BC) such that valid PK data are available in 8 subjects. 
Study periods: 


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Figure 4-1: Schematic presentation of the treatment design
*Follow-up:  
- EOT (End of Treatment) visit within 7-14 days of last dose of BAY 1163877  
- FU (Follow-up) visit / contact at 30-35 days after last dose of BAY 1163877
In total, the “on study” period for all subjects comprises 3 phases (see Figure 4 1):

Screening (minimum 7 days, maximum 28 days)

Treatment 
-
Study Part 1 / dose escalation + MTD expansion (all comer): 
Individual number of 21-day Cycles with BAY 1163877 monotherapy until 
disease progression or as along as clinical benefit is assumed by the investigator or 
until unacceptable toxicity occurs. 
-
Study Part 2 / MTD expansion (sqNSCLC +BC): 
Individual number of 21-day Cycles with continuous BAY 1163877 monotherapy 
until disease progression or as along as clinical benefit is assumed by the 
investigator or until unacceptable toxicity occurs. 
Note: Treatment with BAY 1163877 at MTD in Part 1 (expansion cohort “all 
comer”) and Part 2 (expansion cohort “sqNSCLC + BC”) can run in parallel.

Follow-up (FU)….
…
Treatment: Subjects with PK assessment (all subjects of study Part 1 and at least 
12 subjects of study Part 2) will receive BAY 1163877 on a continuous schedule starting 
with single-dose administration on Cycle 1, Day 1, followed by a “drug-free day” (to 
enable single dose PK assessments). Treatment with BAY 1163877 will resume on Day 3 
of Cycle 1 if no protocol-defined dose-limiting toxicities (DLTs) are reported. Starting on 
Cycle 1, Day 3, the study drug will be self-administered twice daily for the remaining 
19 days of Cycle 1. For subsequent cycles, study drug will be administered twice daily for 
21 days until the maximum tolerated dose is determined.
Subjects without PK assessment in study Part 2 will receive BAY 1163877 twice daily 
from Cycle 1, Day 1 ongoing. 
On study
First study
visit
First dose
administration
on Cycle 1, Day 1
EOT visit
FU-visit / 
contact 
Screening
Treatment
Follow-up (FU)*
Last dose 
administration 
Cycle X


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At home, …
Pharmacokinetics (PK):  Single- and multiple-dose PK of BAY 1163877 will be 
evaluated in plasma on Cycle 1, Day 1 and Day 15, respectively, in all subjects 
participating in Part 1 (all comer) and in at least 12 subjects participating in Part 2 
(sqNSCLC + BC).  
Plasma concentration of BAY 1163877… 
Safety / tolerability:  
…
Women of childbearing potential must have a negative pregnancy test performed within 
7 days prior to first treatment with BAY 1163877 (i.e. 1 week before Cycle 1, Day 1). 
…
Electrocardiogram (ECG): 12-lead ECG readings in supine position will be performed 
at screening, on Cycle 1, Days 1, 2, and 15, thereafter on Day 1 of each subsequent Cycle. 
At screening and in Cycle 1, ECG readings should be done in triplicate. The triplicate 
ECGs will be recorded in close sequence and not more than 2 minutes apart. In all 
subsequent Cycles (Cycle ≥ 2), ECG readings will be performed as single readings. …
New text:
Design overview
...
Targeted / planned enrollment:

Study Part 1 / dose escalation (all comer): The total number of subjects will 
depend on the number of cohorts necessary to identify the MTD. Relative bioavailability 
of the tablet formulation in comparison to the solution formulation will be performed in all 
subjects enrolled in one of the dose escalation cohorts; pharmacokinetic data are needed in 
a minimum of 3 subjects for relative bioavailability assessment.

Study Part 1 / MTD expansion (all comer): Additional subjects will be enrolled to 
have 20 evaluable “all comer” subjects treated at MTD.

Study Part 2 / MTD expansion (sqNSCLC + BC): 40 additional subjects will be 
enrolled to have 20 evaluable subjects with sqNSCLC and 20 evaluable subjects with BC 
treated at MTD.
PK assessments will be performed in all subjects participating in study Part 1 / dose 
escalation and MTD expansion (all comer). Additionally, PK assessments are planned in 
at least 12 subjects participating in study Part 2 / MTD expansion (sqNSCLC + BC) such 
that valid PK data are available in 8 subjects. 
Study periods: 


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Figure 4-1: Schematic presentation of the treatment design
# The first dose will be administered on Cycle 1, Day 1, except for subjects participating in relative bioavailability 
assessment who will receive a single dose administered as tablet formulation on Cycle 1, Day -3.  
*Follow-up:  
- EOT (End of Treatment) visit within 7-14 days of last dose of BAY 1163877  
- FU (Follow-up) visit / contact at 30-35 days after last dose of BAY 1163877
In total, the “on study” period for all subjects comprises 3 phases (see Figure 4 1):

Screening (minimum 7 days, maximum 28 days)

Treatment 
-
Study Part 1 / dose escalation + MTD expansion (all comer):
Individual number of 21-day Cycles with BAY 1163877 monotherapy (tablet or 
solution) until disease progression or as along as clinical benefit is assumed by the 
investigator or until unacceptable toxicity occurs. 
-
Study Part 1 / “tablet bridging cohort” (all comer):
In one of the dose escalation cohorts, administration of a single dose of 
BAY 1163877 using the tablet formulation on Cycle 1, Day -3 followed by 
solution formulation starting Cycle 1 Day 1 as described above. 
-
Study Part 2 / MTD expansion (sqNSCLC + BC): 
Individual number of 21-day Cycles with continuous BAY 1163877 monotherapy 
(tablet or solution) until disease progression or as along as clinical benefit is 
assumed by the investigator or until unacceptable toxicity occurs. 
Note: Treatment with BAY 1163877 at MTD in Part 1 (expansion cohort “all 
comer”) and Part 2 (expansion cohort “sqNSCLC + BC”) can run in parallel.

Follow-up (FU)…
…
Treatment: Subjects with PK assessment (all subjects of study Part 1 and at least 
12 subjects of study Part 2) will receive BAY 1163877 (tablet or solution) on a continuous 
schedule starting with single-dose administration on Cycle 1, Day 1, followed by a “drug-
free day” (to enable single dose PK assessments). Treatment with BAY 1163877 will 
First study
visit
First dose
administration #
EOT visit
FU-visit / 
contact 
Screening
Treatment
Follow-up (FU)*
On study
Last dose 
administration 
Cycle X


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resume on Day 3 of Cycle 1 if no protocol-defined dose-limiting toxicities (DLTs) are 
reported. Starting on Cycle 1, Day 3, the study drug will be self-administered twice daily 
for the remaining 19 days of Cycle 1. For subsequent cycles, study drug will be 
administered twice daily for 21 days until the maximum tolerated dose is determined.
In one of the dose escalation cohorts in study Part 1 (“tablet bridging cohort”), relative 
bioavailability of the tablet formulation will be assessed by administration of a single dose 
of the tablet formulation on Cycle 1, Day -3. Starting with Cycle 1, Day 1, subjects 
enrolled in the “tablet bridging cohort” will continue with the solution formulation as 
described above.
Subjects without PK assessment in study Part 2 will receive BAY 1163877 (tablet or 
solution) twice daily from Cycle 1, Day 1 ongoing. 
At home, …
Pharmacokinetics (PK):  Single- and multiple-dose PK of BAY 1163877 will be 
evaluated in plasma samples collected on Cycle 1, Day -3 in the “tablet bridging cohort”, 
and on Cycle 1, Days 1 and 15 in all subjects participating in Part 1 (all comer) and in at 
least 12 subjects participating in Part 2 (sqNSCLC + BC).  
Plasma concentration of BAY 1163877 …
Safety / tolerability:  
…
Women of childbearing potential must have a negative pregnancy test performed within 
7 days prior to first treatment with BAY 1163877 (i.e. 1 week before Cycle 1, Day 1 or 
Cycle 1, Day -3, if applicable). 
…
Electrocardiogram (ECG): 12-lead ECG readings will be performed at screening, on 
Cycle 1, Day -3 (“tablet bridging cohort” only), on Cycle 1, Days 1, 2, and 15, thereafter 
on Day 1 of each subsequent Cycle, and at the EOT visit. At screening and in Cycle 1, 
ECG readings should be done in triplicate. The triplicate ECGs will be recorded in 
close sequence and not more than 2 minutes apart. In all subsequent Cycles (Cycle ≥ 2) 
and at the EOT visit, ECG readings will be performed as single readings. …
Section 4.1: Primary variable(s) 
This section was changed as a result of Modification 2.
Old text:
This is primarily a descriptive safety and tolerability Phase I study. The primary variable 
for MTD determination will be the incidence of DLTs during the first 21 days of treatment 
(Cycle 1). The primary study outcome is the MTD being defined as the maximum dose at 
which the incidence of DLTs during Cycle 1 is below 20%. 


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New text:
This is primarily a descriptive safety and tolerability Phase I study. The primary variable 
for MTD determination will be the incidence of DLTs during the first 21 days of treatment 
(Cycle 1). The primary study outcome is the MTD being defined as the maximum dose at 
which the incidence of DLTs during Cycle 1 is below 20%. 
Primary PK parameters are provided in Section 9.4.2.2. 
Section 6.1: Treatments to be administered 
This section was changed as a result of Modification 1.
Old text:
Investigational medicinal product (IMP) – test drug

BAY 1163877 drinking solution (test drug)
Non-investigational product(s) (NIMP)
Not applicable
In study Part 1 / dose escalation + MTD expansion (all comer), …
…. The dose decision will be guided by model-based dose-response analysis of the DLT 
rates (see Section 14.4 ). 
A solid (tablet) formulation is planned for later cohorts. The switch from liquid to solid 
formulation is planned after relative bioavailability assessment.
In study Part 2 / MTD expansion (sqNSCLC +BC), … 
New text:
Investigational medicinal product (IMP) – test drug

BAY 1163877 drinking solution (test drug)

BAY 1163877 tablet (test drug)
Non-investigational product(s) (NIMP)
Not applicable
In study Part 1 / dose escalation + MTD expansion (all comer), …
… The dose decision will be guided by model-based dose-response analysis of the DLT 
rates (see Section 16.4). 
In the “tablet bridging cohort”, relative bioavailability of the tablet formulation in 
comparison to the solution formulation will be assessed by administration of a single dose 


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of the tablet formulation on Cycle 1, Day -3 in at least 3 subjects.  Starting with Cycle 1, 
Day 1, subjects enrolled in this cohort will continue with the solution formulation as 
described above.     
In study Part 2 / MTD expansion (sqNSCLC +BC), … 
Section 6.2: Identity of study treatment 
This section was changed as a result of Modification 1.
Old text:
The details of BAY 1163877 are given in Table 6-1. 
Table 6-1:
Identity of test drug (IMP):  BAY 1163877 liquid formulation  
Generic name / brand name / INN
…
Substance code number(s)
…
Development no. / SH no.
BAY1163877 HCl H2O SOL 1% 11 mL ORAL
Galenical form / formulation / vehicle and 
reconstitution, if applicable
…
Composition
…
Strength (amount of drug per unit) or 
concentration
…
Type of packaging and content
…
Marketing Authorization Holder if applicable
…
Labeling:  …
New text:
The details of the two formulations of BAY 1163877 planned to be used in this study are 
given in Table 8-1(solution) and Table 8-2(tablet).


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Table 6-1:
Identity of test drug (IMP):  BAY 1163877 solution formulation  
Generic name / brand name / INN
…
Substance code number(s)
…
Material / formulation) number(s)
BAY1163877 HCl H2O SOL 1% 11 mL ORAL
Galenical form / formulation / vehicle and 
reconstitution, if applicable
…
Composition
…
Strength (amount of drug per unit) or 
concentration
…
Type of packaging and content
…
Marketing Authorization Holder if applicable
…
Table 6-2:
Identity of test drug (IMP):  BAY 1163877 tablet formulation  
Generic name / brand name / INN
Not applicable
Substance code number(s)
BAY 1163877 as BAY 1213802
Material / formulation) number(s)
81820457 for BAY 1163877 HCL TAB 50.0 mg 
363 COAT
81820449 for BAY 1163877 HCL TAB 200.0 mg 
364 COAT
Galenical form / formulation / vehicle and 
reconstitution, if applicable
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)*
* (contains hypromellose, macrogol, titanium
   dioxide,ferric oxide red)
Strength (amount of drug per unit) or 
concentration
50 mg BAY 1163877 per tablet
200 mg BAY 1163877 per tablet
Type of packaging and content
HDPE bottles with screw cap closure
Marketing Authorization Holder if applicable
Not applicable  
Labeling: ...


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Section 6.4.2.1: Dosing schedule 
This section was changed as a result of Modification 1.
Old text:
BAY 1163877 will be given in cycles. Each cycle lasts 21 days. There will be no break 
between treatment cycles. 
Study Part 1 / dose escalation + MTD expansion cohort (all comer):
Cycle 1:
Single-dose administration of BAY 1163877 on 
Cycle 1, Day 1 (in the morning)
No administration of BAY 1163877 on Cycle 1, 
Day 2 (“drug-free day”)
Twice daily administration of BAY 1163877 on 
Days 3-21
Cycle 2 and subsequent cycles:
Twice daily administration of BAY 1163877 on
Days 1-21. 
Study Part 2 / dose expansion (sqNSCLC + BC):…
…
New text:
BAY 1163877 will be given in cycles. Each cycle lasts 21 days. There will be no break 
between treatment cycles. 
Subjects will receive either the solution (IMP 1) or the tablet (IMP 2) formulation of 
BAY 1163877, except for subjects in the “tablet bridging cohort” who will receive both a 
single dose using the tablet formulation and multiple doses using the solution formulation. 
Study Part 1 / dose escalation + MTD expansion cohort (all comer):
Cycle 1 Day -3 (“tablet bridging cohort” only): 
Single-dose administration of
BAY 1163877 tablet formulation on Cycle 1, Day -3; 
thereafter continuation with solution formulation 
starting on Cycle 1, Day 1 (see dosing schedule 
below)
Cycle 1:
Single-dose administration of BAY 1163877 on 
Cycle 1, Day 1 (in the morning)
No administration of BAY 1163877 on Cycle 1, 
Day 2 (“drug-free day”)
Twice daily administration of BAY 1163877 on 
Days 3-21
Cycle 2 and subsequent cycles:
Twice daily administration of BAY 1163877 on
Days 1-21. 


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Study Part 2 / dose expansion (sqNSCLC + BC): …
…
Section 6.4.2.2: Mode of administration 
This section was changed as a result of Modification 1.
Old text:
BAY 1163877 will be administered per os (p.o.) at least 1 hour before or 2 hours after a 
meal or snack. 
Subjects should not take additional doses of BAY 1163877 to compensate for a missed 
dose.
New text:
BAY 1163877 will be administered per os (p.o.) at least 1 hour before or 2 hours after a 
meal or snack. 
The ready-to-use solution will be administered directly and undiluted via disposable 
syringe into the mouth of the subject. Immediately after administration, the subject has to 
drink a glass of water (approximately 200 mL / 7 ounces).
BAY 1163877 tablets should be taken with a glass of water (approximately 200 mL / 7 
ounces). Tablets should be swallowed intact and not chewed.
Subjects should not take additional doses of BAY 1163877 to compensate for a missed 
dose.
Section 6.4.2.3: Treatment duration 
This section was changed as a result of Modification 1.
Old text:
BAY 1163877 will be administered on a continuous schedule in at least one 21-day Cycle 
with no break between cycles until progression or as along as clinical benefit is assumed 
by the investigator or until unacceptable toxicity occurs.
Treatment starts on Cycle 1, Day 1. 
Further details on dosing schedule are provided in Section 6.4.2.1. 
New text:
BAY 1163877 will be administered on a continuous schedule in at least one 21-day Cycle 
with no break between cycles until progression or as along as clinical benefit is assumed 
by the investigator or until unacceptable toxicity occurs.
For subjects in the “tablet bridging cohort”, treatment starts on Cycle 1, Day -3.


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For all other subjects, treatment starts on Cycle 1, Day 1.  
Further details on dosing schedule are provided in Section 8.4.2.1. 
Section 6.4.3: Dose modification and delays
This section was changed as a result of Modification 3.
Old text:
Doses of study drug (BAY 1163877) may be delayed or reduced in case of clinically 
significant hematologic and other toxicities that are possibly, probably or definitely related 
to study drug therapy. Toxicities will be graded using the CTCAE v 4.03 (see 
Section 14.5). 
No intra-subject dose escalation will be permitted. However, the dose can be reduced or 
delayed for an individual subject based on toxicities that are related to study drug.
If a subject experiences a DLT during Cycle 1, the next dose of BAY 1163877 can be 
delayed for up to 21 days, but only in cases where Grade 3 events occur no longer than 
7 days.
All subjects who are re-treated following a DLT should undergo dose reduction (see Table 
6-3).
If the toxicity resolves to Grade 1, the next dose of BAY 1163877 can be considered. 
Re-treatment for this subject should be at 1 dose level below the initial dose (see Table 6-
3), provided that this dose level has been evaluated during the dose escalation part of the 
study. Detailed dose adjustments for hematological toxicities are described in Table 6-4. If 
the subject was dosed at the starting dose level, the subject should be removed from the 
study. If the toxicity fails to resolve to Grade 1within 21 days after the planned 
treatment date, the subject should be removed from the study. Subjects who experience a 
Grade 4 non-hematological toxicity should be removed from the study. 
Drug-related adverse events of Grade 3 
For Grade 3 adverse event regarded as related to study drug, the dose of BAY 1163877 
can be delayed for up to 21 days. If the toxicity fails to resolve to Grade 1 within 
21 days after the planned dosing date, the subject should be removed from the study. If the 
toxicity resolves to Grade 1, the next dose of BAY 1163877 can be considered.  
Re-treatment for this subject should be reduced by 1 dose level. Detailed dose adjustments 
for toxicities are described in Table 6-2.
If the re-treatment reproduces the same toxicity grade, the next dose of BAY 1163877 can 
be delayed for up to 21 days until the toxicity has resolved to Grade 1. Re-treatment is 
possible at 1 dose level below. 
Subjects who experience a Grade 4 non-hematological toxicity should be removed from 
the study. If more than 2 dose reductions are required, treatment will be discontinued. 


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Table 6-2:
Scheme for dose-level reduction of BAY 1163877 in subjects with solid 
tumors
Dose level
Action
-1
1 dose below level of DLT occurrencea
-2
2 doses below level of DLT occurencea
-3
Discontinue study drug permanently
a
alternatively, treatment can be continued at an interim dose level with at least 3 subjects 
evaluated
Table 6-3:
Hematological criteria for dose delay and dose modification
Gradea
ANC
(109/L)
Platelets
(109/L)
Dose delay
Dose modification
1 - 2
1.0
50
Treat on time
No change
3
<1.0 - 0.5
<50 - 25
Delayb until Grade 1
Decrease 1 dose levelc
4
<0.5
<25
Delayb until Grade 1
Decrease 1 dose levelc
a
Applies to all kinds of hematological toxicities; ANC and platelet count displayed as examples.
b
If no recovery after 21 days delay, treatment will be discontinued.
c
Dose will not be re-escalated to original dose level after reduction for toxicity. If more than 
2 dose reductions are required, treatment will be discontinued.
Table 6-4:
Non-hematological criteria for dose delay and dose modification
Gradea
Dose delay
Dose modification
1 – 2
Treat on time
No change
3
Delayb until Grade 1
Decrease 1 dose levelc
4
Discontinue study drug permanently
Discontinue study drug permanently
a
Excludes alopecia. A maximum duration of 48 hours of Grade 3 nausea or vomiting will be 
allowed and not be considered DLT. 
b
If no recovery after 21 days delay, treatment will be discontinued.
c
Dose will not be re-escalated after reduction for toxicity. If more than 2 dose reductions are 
required, treatment will be discontinued.
New text:
Doses of study drug (BAY 1163877) may be delayed or reduced in case of clinically 
significant hematologic and other toxicities that are possibly, probably or definitely related 
to study drug therapy. Toxicities will be graded using the CTCAE v 4.03 (see Section 
14.5). 
No intra-subject dose escalation will be permitted. However, the dose can be reduced or 
delayed for an individual subject based on toxicities that are related to study drug.


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If a subject experiences a DLT during Cycle 1, the next dose of BAY 1163877 can be 
delayed for up to 21 days, but only in cases Grade 3 non-hematological toxicities persist 
no longer than 7 days.
All subjects who are re-treated following a DLT should undergo dose reduction (see Table 
6-3).
If the toxicity resolves to Grade 1, the next dosing of BAY 1163877 at 1 dose level
below the current dose (see Table 6-3) can be considered, provided that this dose level has 
been evaluated during the dose escalation part of the study. Detailed dose adjustments for 
hematological toxicities are described in Table 6-4. If the subject was dosed at the starting 
dose level, the subject should be removed from the study. If the toxicity fails to resolve to 
Grade 1within 21 days after the planned treatment date, the subject will be removed 
from the study. Subjects who experience a Grade 4 non-hematological toxicity will be 
removed from the study. 
Drug-related adverse events of Grade 3 
For Grade 3 adverse event regarded as related to study drug, the next dosing of 
BAY 1163877 can be delayed for up to 21 days. If the toxicity fails to resolve to 
Grade 1 within 21 days after the scheduled dosing date, the subject will be removed 
from the study. If the toxicity resolves to Grade 1, the next dosing of BAY 1163877 at 1 
dose level below the current dose (see Table 6-3) can be considered, provided that this 
dose level has been evaluated during the dose escalation part of the study. Dose 
adjustments for toxicities are detailed in Table 6-3.
If the re-treatment reproduces the same toxicity grade, the next dosing of BAY 1163877 
can be delayed for up to 21 days until the toxicity has resolved to Grade 1. Re-treatment 
is possible at 1 dose level below the previous dose. 
Subjects who experience a Grade 4 non-hematological toxicity will be removed from the 
study. If more than 2 dose reductions are required, treatment will be permanently
discontinued. 
Table 6-3:
Scheme for dose-level reduction of BAY 1163877 in subjects with solid 
tumors
Dose level
Action
-1
1 dose below level of DLT occurrencea
-2
2 doses below level of DLT occurencea
-3
Discontinue study drug permanently
a
alternatively, treatment can be continued at an interim dose level with at least 3 subjects 
evaluated


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Table 6-4:
Hematological criteria for dose delay and dose modification
Gradea
ANC
(109/L)
Platelets
(109/L)
Dose delay
Dose modification
1 - 2
1.0
50
Treat as scheduled
No change
3
<1.0 - 0.5
<50 - 25
Delayb until Grade 1
Decrease 1 dose levelc
4
<0.5
<25
Delayb until Grade 1
Decrease 1 dose levelc
a
Applies to all kinds of hematological toxicities; ANC and platelet count displayed as examples.
b
If no recovery after 21 days delay, treatment will be permanently discontinued.
c
Dose will not be re-escalated to original dose level after reduction for toxicity. If more than 
2 dose reductions are required, treatment will be discontinued.
Table 6-5:
Non-hematological criteria for dose delay and dose modification
Gradea
Dose delay
Dose modification
1 – 2
Treat as scheduled
No change
3
Delayb until Grade 1
Decrease 1 dose levelc
4
Discontinue study drug permanently
Discontinue study drug permanently
a
Excludes alopecia. A maximum duration of 48 hours of Grade 3 nausea or vomiting will be 
allowed and not be considered DLT. 
b
If no recovery after 21 days delay, treatment will be permanently discontinued.
c
Dose will not be re-escalated after dose reduction for toxicity. If more than 2 dose reductions 
are required, treatment will be permanently discontinued.
Liver toxicity - amended
Dose modifications of BAY 1163877 for liver toxicity are presented in Table 6-6. Liver 
toxicity refers to ALT and / or AST and / or bilirubin increases and / or hepatic failure 
considered possibly related to BAY 1163877, and graded according to CTCAE v4.03. 


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Table 6-6:
Dose modifications of BAY 1163877 for liver toxicity
Toxicity
Modification schedule
Grade 1-2
No modifications. Treat as scheduled and check 
AST, ALT and bilirubin weekly for at least 4 weeks.
Grade 3 
Hold BAY 1163877 until recovery to ≤grade 2 or 
baseline, 
then reduce 1 dose level and check AST, ALT and 
bilirubin weekly for at least 4 weeks.a
- 1st reappearance
Hold BAY 1163877 until recovery to ≤grade 2 or 
baseline,
then reduce 1 additional dose level and check AST, 
ALT and bilirubin weekly for at least 4 weeksa.
- 2nd reappearance
Withdraw subject from the study treatment.b
Grade 3 with ALT or AST > 8x ULN 
and a concomitant rise in bilirubin 
(of any degree compared to previous 
bilirubin level) 
or hepatic failure (of any degree)
In case of a negative risk-benefit assessment, 
consider permanent discontinuation at the first 
occurrenceb,c
OR
Hold BAY 1163877 until recovery to ≤grade 2 or 
baseline,
then reduce 1 dose level and check AST, ALT and 
bilirubin weekly for at least 4 weeksa.
-1st reappearance
Withdraw subject from study treatment.b
Grade 4 b
Withdraw subject from study treatment.b
a
If all values remain stable for 2 cycles, dose re-escalation may be considered at the 
discretion of the investigator. After re-escalation, AST, ALT, and bilirubin should be 
checked weekly for at least 4 weeks.
b
In case of discontinuation, check AST, ALT, and bilirubin weekly until recovery to baseline 
or stabilization.
c
Subjects 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.
Tissue mineralization – amended
Dose modifications of BAY 1163877 for tissue mineralization are presented in Table 6-7. 
Tissue mineralization refers to Ca x PO4 ≥ 70 mg²/dL² considered possibly related to 
BAY 1163877.


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Table 6-7:
Dose modifications of BAY 1163877 for tissue mineralization
Toxicity
Modification schedule
Ca x PO4 (≥ 70 mg²/dL²)
Hold BAY 1163877, treat with phosphate
chelators until recovery, to Ca x PO4 < 70 mg²/dL². 
Resume same dose level, continue phosphate 
chelators and check weekly for at least 4 weeks.
- 1st reappearance
Hold BAY 1163877, treat with phosphate 
chelators until recovery to Ca x PO4 < 70 mg²/dL², 
then reduce 1 dose level, continue phosphate 
chelator and check weekly for at least 4 weeks.
- 2nd reappearance
Hold BAY 1163877 until recovery to
Ca x PO4 < 70 mg²/dL²,
then reduce 1 additional dose level, continue 
phosphate chelators and check weekly for at least 
4 weeks.
- 3rd reappearance
Withdraw subject from study treatment.
Section 7.1.2.3: Treatment
This section was changed as a result of Modification 1.
Old text:
The treatment phase comprises Cycle 1 (21 days) and a variable number of subsequent 
Cycles (each of 21 days duration) with no break between Cycles. 
There will be both visits and possible overnight stays at the study site. 
New text:
For subjects in the “tablet bridging cohort”, the treatment phase starts on Cycle 1, Day -3, 
followed by Cycle 1 (21 days) and a variable number of subsequent Cycles (each of 21 
days duration) with no break between Cycles.
For all other subjects, the treatment phase comprises Cycle 1 (21 days) and a variable 
number of subsequent Cycles (each of 21 days duration) with no break between Cycles. 
There will be both visits and possible overnight stays at the study site. 
Section 7.1.2.3.1: Cycle 1
This section was changed as a result of Modification 1.
Old text:
Days 1-3 (possible overnight stay)
Day 1


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
…

Triplicate 12-lead ECG readings (see Section 7.5.3.4) 

…
New text:
For “tablet bridging cohort” cohort only:
Day -3 to Day -1 (possible overnight stay)
Day -3

Update of concomitant therapy

Physical examination

Ask subject for changes in vision

Cardiovascular assessment (BP and HR) 

Measurement of body temperature and body weight

Triplicate 12-lead ECG readings (see Section 7.5.3.4).

ECOG performance status

Blood and urine collection for safety laboratory tests (repetitions for controls may 
be necessary), for details see Table 14-4

Calculation of eGFR (see Section 14.9)

Single oral administration of BAY 1163877 tablet formulation

PK sampling 

Toxicities / AE assessment and recording (if applicable)
Day -2 

No administration of BAY 1163877 (“drug-free day”)

Update of concomitant therapy

Physical examination

Ask subject for changes in vision

Cardiovascular assessment (BP and HR) 

Measurement of body temperature 

Triplicate ECG readings (see Section 7.5.3.4)

ECOG performance status

PK sampling  


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
Toxicities / AE assessment and recording (if applicable)
Day -1

No administration of BAY 1163877 (“drug-free day”)

Update of concomitant therapy

Physical examination

Ask subject for changes in vision

Cardiovascular assessment (BP and HR) 

Measurement of body temperature 

ECOG performance status

PK sampling  

Toxicities / AE assessment and recording (if applicable)
Days 1-3 (possible overnight stay)
Day 1

… 

Measurement of body temperature and body weight (measurement of weight not 
required for subjects in the “tablet bridging cohort”)

…
Section 7.4.1.1: Cardiovascular assessment
This section was changed as a result of Modification 1.
Old text:
...
BP and HR will be measured at the following time points:

Screening (one measurement within 7 days before start of treatment)

Cycle 1, Day 1 and Day 2
-
before and 0.5, 1, 2, 3, 4, 6, 8, 12 (Day 1), and 24 (Day 2) hour(s) after single dose 
administration 

Cycle 1, Day 3
before and 1, and 2 hour(s) after morning dose

Cycle 1, Day 15


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-
before and 0.5, 1, 2, 3, 4, 6, 8 and 12 hour(s) after morning dose [12-hour 
measurement before evening dose]
…
New text:
…
BP and HR will be measured at the following time points:

Screening (one measurement within 7 days before start of treatment)

Cycle 1, Day -3 to Day -1 (“tablet bridging cohort” only)
before and 0.5, 1, 2, 3, 4, 6, 8, 12 (Day -3), 24 (Day -2) and 48 (Day -1) hour(s) 
after single-dose administration 

Cycle 1, Day 1 and Day 2
before and 0.5, 1, 2, 3, 4, 6, 8, 12 (Day 1), and 24 (Day 2) hour(s) after single-dose 
administration 

Cycle 1, Day 3
before and 1, and 2 hour(s) after morning dose

Cycle 1, Day 8 (one measurement)

Cycle 1, Day 15
-
before and 0.5, 1, 2, 3, 4, 6, 8 and 12 hour(s) after morning dose [12-hour 
measurement before evening dose]
…
Section 7.4.2.1: Drug measurements
This section was changed as a result of Modification 1.
Old text:
Pharmacokinetics of BAY 1163877 will be evaluated on Cycle 1, Day 1 after single-dose 
administration and on Cycle 1, Day 15 after multiple-dose administration of 
BAY 1163877 at the respective dose level achieved during dose escalation.
…
Blood (plasma) samples for PK assessment of BAY 1163877 will be collected at the 
following time points:

Cycle 1, Day 1: single-dose PK 
…


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New text:
Pharmacokinetics of BAY 1163877 will be evaluated on Cycle 1, Day -3 (“tablet bridging 
cohort” only), Cycle 1, Day 1 after single-dose administration, and on Cycle 1, Day 15 
after multiple-dose administration of BAY 1163877 at the respective dose level achieved 
during dose escalation.
...
Blood (plasma) samples for PK assessment of BAY 1163877 will be collected at the 
following time points:

Cycle 1, Day -3 (“tablet bridging cohort” only): single-dose PK 
-
pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 and 48 hour(s) post-dose

Cycle 1, Day 1: single-dose PK 
…
Section 7.4.2.2: Pharmacokinetic evaluation
This section was changed as a result of Modification 1.
Old text:
…
Primary PK parameters (plasma): BAY 1163877

Cycle 1, Day 1 single dose: Cmax, Cmax/D, AUC(0-12), AUC(0-12)/D,
AUC(0-tlast), AUC(0-tlast)/D, AUC, and AUC/D
AUC may not be calculated if it is not possible to estimate half-life.

Cycle 1, Day 15 multiple dose: Cmax,md, Cmax/Dmd, AUC(0-12)md, AUC(0-12)/Dmd,
AUC(0-tlast)md, and AUC(0-tlast)/Dmd. 
Secondary PK parameters (plasma): BAY 1163877

tmax, tlast, t1/2 of Cycle 1, Day 1 and tmax,md and tlast,md of Cycle 1, Day 15.
Other PK parameters (plasma): BAY 1163877
...
New text:
…
Primary PK parameters (plasma): BAY 1163877

Cycle 1, Day -3 (“tablet bridging cohort” only) and Cycle 1, Day 1 single dose:
Cmax, Cmax/D, AUC(0-12), AUC(0-12)/D,
AUC(0-tlast), AUC(0-tlast)/D, AUC, and AUC/D
AUC may not be calculated if it is not possible to estimate half-life.


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
Cycle 1, Day 15 multiple dose: Cmax,md, Cmax/Dmd, AUC(0-12)md, AUC(0-12)/Dmd,
AUC(0-tlast)md, and AUC(0-tlast)/Dmd. 
Secondary PK parameters (plasma): BAY 1163877

tmax, tlast, t1/2 of Cycle 1, Day -3 (“tablet bridging cohort” only) and Cycle 1, Day 1 
and tmax,md and tlast,md of Cycle 1, Day 15.
Other PK parameters (plasma): BAY 1163877
…
Section 7.5.3.4: Electrocardiogram (ECG)
This section was changed as a result of Modification 1.
Old text:
...
12-lead ECG readings will be performed in the supine position at the following time 
points:

Screening (triplicate ECG readings)

Cycle 1, Day 1 and Day 2 (triplicate ECG readings)
-
before and 2, 3 (Day 1) and 24 (Day 2) hours after single-dose administration

Cycle 1, Day 15 (triplicate ECG readings) …
-
before morning dose, and 2 and 3 hours thereafter 

Cycle ≥ 2, Day 1 (single ECG readings)
-
after morning dose
…
New text:
…
12-lead ECG readings will be performed in the supine position at the following time 
points:

Screening (triplicate ECG readings)

Cycle 1, Day -3 and Day -2 (triplicate ECG readings) [“tablet bridging cohort” 
only]
before and 2, 3 (Day -3) and 24 (Day -2) hours after single-dose administration

Cycle 1, Day 1 and Day 2 (triplicate ECG readings)
-
before and 2, 3 (Day 1) and 24 (Day 2) hours after single-dose administration


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
Cycle 1, Day 15 (triplicate ECG readings)
before morning dose, and 2 and 3 hours thereafter 

Cycle ≥ 2, Day 1 (single ECG readings)
after morning dose

EOT visit (single ECG reading)
… 
Section 8.2: Analysis sets
This section was changed as a result of Modification 1.
Old text:
…
All subjects with valid pharmacokinetic data will be included in the evaluation of 
pharmacokinetic concentrations and parameters.
New text:
…
All subjects with valid pharmacokinetic data will be included in the evaluation of 
pharmacokinetic concentrations and parameters.
Subjects to be included in the relative bioavailability evaluation (“tablet bridging cohort”) 
should have evaluable pharmacokinetic data on both Cycle 1, Day -3 and Cycle 1, Day 1.
Section 8.4.5: Pharmacokinetic data
This section was changed as a result of Modification 1.
Old text:
…
To investigate dose proportionality, an explorative analysis of variance (ANOVA), 
including the factor cohort, will be performed on the log-transformed values of 
appropriate PK parameters calculated from single (where applicable) and multiple dose 
PK profiles.
New text:
…
To investigate dose proportionality, an explorative analysis of variance (ANOVA), 
including the factor cohort, will be performed on the log-transformed values of 


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appropriate PK parameters calculated from single (where applicable) and multiple dose 
PK profiles.
In order to evaluate the relative bioavailability of the tablet formulation, tablet Cmax/D, 
AUC(0-tlast)/D and AUC/D on Cycle 1, Day -3 will be compared to solution Cmax/D, 
AUC(0-tlast)/D, AUC/D on Cycle 1, Day 1 for all analytes. If needed, additional PK 
parameters may be used for relative bioavailability assessment. The logarithms of these 
PK parameters will be analyzed using analysis of variance (ANOVA) including subject 
and formulation effects. Based on these analyses, point estimates (LS-means) and 
exploratory 90% confidence intervals for the ratios (tablet/solution) of Cmax/D, AUC(0-
tlast)/D, AUC/D will be calculated by retransformation of the logarithmic data using the 
intra-individual standard deviation of the ANOVA.
Section 14.1: Study flow chart
A flow chart for Cycle 1 Day -3 to Day -1 was added for the “tablet bridging cohort” as a 
result of Modification 1.
Old text: 
Table 14-1 and Table 14-2 in the following provide flow charts presenting the time points 
for the study related measures / actions.
Table 14-1:
Study flow chart: Screening – Study Part 1 and Part 2
Screening
Measures / actions
Within 28 Days* 
Within 7 Days*
before first study drug administration
…
…
…


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Table 14–2: Study flow chart: Treatment and Follow-up – Study Part 1 and Part 2
Measures / actions
TREATMENT
FOLLOW-UP
Cycle 1 
(21 days)
Cycle≥2
(21 days)
EOT Visit
Within 
7-14 days after 
last dose
FU-Visit / 
Phone Call(A)
At 30-35 days 
after last dose
Day (D)
D1
D2
D3
D8 ±1
D15
D1
D8 ±1
D15 ±1
…
…
Obtain tumor biopsy for biomarker tests(H)
X
…
…
(C)
Cardiovascular assessment: Blood pressure (BP) and heart rate (HR) will be measured as follows (see Section 7.4.1.1):

Cycle 1, Day 1 and Day 2: 

before and 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 (Day 2) hour(s) after single-dose administration

Cycle 1, Day 3: 

before and 1 and 2 hour(s) after morning dose

Cycle 1, Day 15:

before and 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 (Day 2) hour(s) after single-dose administration
Cycle ≥ 2 and follow up…….
each visit (one measurement)…
Follow up …
(D)
In Cycle 1, all 12-lead ECGs should be performed in triplicate in close sequence and not more than 2 minutes apart. ECG readings will be 
performed at the following time points:
Cycle 1, Day 1 and Day 2 (triplicate ECG readings): before and 2, 3 (Day 1) and 24 (Day 2) hours after single-dose administration 
Cycle 1, Day 15 (triplicate ECG readings): before morning dose, and 2 and 3 hours thereafter 
Cycle ≥ 2, Day 1 (single ECG reading): after morning dose
…
(M) 
Subjects without PK assessment in study Part 2 will receive BAY 1163877 twice daily from Cycle 1, Day 1 ongoing.


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New text:
Table 14-1, Table 14-2 and Table 14-3 in the following provide flow charts presenting the 
time points for the study related measures / actions.
Table 14-1:
Study flow chart: Screening – Study Part 1 and Part 2
Screening
Measures / actions
Within 28 Days* 
Within 7 Days*
before first study drug administration
…
…
…


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Table 14 2: Study flow chart: Treatment (Cycle 1, Day -3 to Day -1 – Study Part 1
Measures / actions
TREATMENT 
(only for “tablet bridging cohort”)
Cycle 1
Day -3
Day -2
Day -1
Concomitant medication
X
X
X
Physical examination 
X
X
X
Ask subject for changes in vision(A)
X
X
X
Cardiovascular assessment(B)
XX
X
Body temperature
X
X
X
Body weight
X
12-lead ECG readings(C)
X
X
ECOG performance status
X
X
X
Blood / urine collection for safety lab tests(D)
X
Calculation of eGFR(E)
X
PK blood sampling(F)
XX
Administration of BAY 1163877 tablet (single dose)(G)
X
Toxicities / AE assessment
X
X
X
(A) 
If change in vision is reported by subject an ophthalmological examination must be performed 
(see Section 7.5.3.2)
(B)
Cardiovascular assessment: Blood pressure (BP) and heart rate (HR) will be measured as 
follows (see Section 7.4.1.1): before and 0.5, 1, 2, 3, 4, 6, 8, 12 (Day -3), 24 (Day -2) and
48 (Day -1) hour(s) after single-dose administration
If a reduction of systolic BP below 90 mmHg or an increase in HR to more than 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, subject’s 
blood pressure will be measured before collection of the PK sample.
(C) 
12-lead ECGs should be performed in triplicate in close sequence and not more than 
2 minutes apart. ECG readings will be performed at the following time points: 
before and 2, 3 (Day -3) and 24 (Day -2) hours after single-dose administration 
(D)
Safety laboratory tests, see Table 14–4 
(E)
For calculation of eGFR (estimated glomerular filtration rate), see Section 14.9
(F)
PK sampling will be done as follows (for details see Laboratory Manual):•

pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12 (Day -3), 24 (Day -2) and 48 (Day -1) hour(s) 
after single-dose administration[
(G)
Oral administration of BAY 1163877 tablet formulation on Cycle 1, Day -3 will be done by a
member of the site.


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Table 14-3: Study flow chart: Treatment (Cycle ≥1) and Follow-up – Study Part 1 and Part 2
Measures / actions
TREATMENT
FOLLOW-UP
Cycle 1 
(21 days)
Cycle≥2
(21 days)
EOT Visit
Within 
7-14 days after 
last dose
FU-Visit / 
Phone Call(A)
At 30-35 days 
after last dose
Day (D)
D1
D2
D3
D8 ±1
D15
D1
D8 ±1
D15 ±1
…
…
Obtain tumor biopsy for biomarker tests(H)
X
(Cycle 2 
only)
…
… 
(C)
Cardiovascular assessment: Blood pressure (BP) and heart rate (HR) will be measured as follows (see Section 7.4.1.1):

Cycle 1, Day 1 and Day 2: before and 0.5, 1, 2, 3, 4, 6, 8, 12 (Day 1), and 24 (Day 2) hour(s) after single-dose administration

Cycle 1, Day 3: before and 1 and 2 hour(s) after morning dose

Cycle 1, Day 8: (one measurement)

Cycle 1, Day 15: before and 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 (Day 2) hour(s) after single-dose administration

Cycle ≥ 2: each visit (one measurement)…
Follow up …
(D)
In Cycle 1, all 12-lead ECGs should be performed in triplicate in close sequence and not more than 2 minutes apart. ECG readings will be 
performed at the following time points:
Cycle 1, Day 1 and Day 2 (triplicate ECG readings): before and 2, 3 (Day 1) and 24 (Day 2) hours after single-dose administration 
Cycle 1, Day 15 (triplicate ECG readings): before morning dose, and 2 and 3 hours thereafter 
Cycle ≥ 2, Day 1 (single ECG reading): after morning dose
EOT visit (single ECG reading)
…
(L)
Subjects without PK assessment in study Part 2 will receive BAY 1163877 twice daily from Cycle 1, Day 1 ongoing.


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Section 14.2: Laboratory examinations
This section was changed as a result of Modifications 1 and 3. A missing link to Table 14-6 
was added. 
Old text:
Table 14-3, Table 14-4 and Table 14-6 provide the parameters and time points for the 
laboratory examinations (safety laboratory tests, biomarker investigations) to be performed 
during the study. Instructions for biomarker and PK sample collection, processing, storage 
and shipment will be described in a separate document (e.g. lab manual).


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Table 14-3:
Parameters and time points of laboratory examinations performed at 
local laboratory or study site (safety laboratory) – Study Part 1 and Part 2
Parameters
Screen
-ing
Treatment
Follow-up
Each Cycle
EOT
visit
FU 
visit
Day 1
Day 8
Day 15
BLOOD
Hematology: …
X
X
X
X
X
X
Coagulation: PT or PT-INR and PTT(A)
X
X
X
X
X
X
Biochemistry: Biochemistry: AST / GOT, ALT / 
GPT, gamma-GT, AP, LDH, amylase, lipase,
glucose, triglycerides, creatinine(B), BUN, uric 
acid, bilirubin (total & direct), total protein, 
albumin, sodium, potassium, chloride, CPK, 
X
X
X
X
X
X
Virology: …
X
URINE
Macroanalysis:
X
X
X
X
X
X
Urinalysis (dip stick): pH, erythrocytes or 
hemoglobin (blood, protein, glucose, bilirubin, 
urobilinogen, ketone, nitrite, leucocytes (or 
leucocyte esterase), specific gravity
X
X
X
X
X
X
Laboratory analysis(C): …
X
X
X
X
X
X
Microscopic urinalysis(D): …
X
X
X
X
X
X
Pregnancy test(F)
X
(A)
…
(B)
…
(C)
…
(D)
…
(F)
…
ALT / GPT
= alanine aminotransferase / glutamic pyruvic transaminase
anti-HCV
= hepatitis C virus antibodies
anti-HIV 1+2
= human immune deficiency virus 1 and 2 antibodies
AP
= alkaline phosphatase
AST / GOT
= aspartate aminotransferase / glutamic oxaloacetic transaminase
BUN
= blood urea nitrogen
CPK
= creatine phosphokinase
CRP
= C-reactive protein
gamma GT
= gamma glutamyl transferase
HBsAg
= hepatitis B virus surface antigen
MCH
= mean corpuscular hemoglobin
MCHC
= mean corpuscular hemoglobin concentration
MCV 
= mean corpuscular volume
PT-INR
= prothrombin time - international normalized ratio
PTT
= partial thromboplastin time
RBC
= red blood cell count
WBC
= white blood cell count 


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Table 14-4:
Parameters and time points for biomarker investigations
in study Part 1 / dose escalation (all comer)
Parameters
Screening
Treatment
Follow-up
EOT visit
TUMOR TISSUE: 
Cycle 2, Day 1
p-ERK1/2 levels, 
Tumor DNA
X(A)
X(B)
Blood (serum) samples *:
Cycle 1
Cycle ≥2
D1
D3
D8
D15
D1
D8
D15
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
Table 14-5:
Parameters and time points for biomarker investigations in study 
Part 1 / MTD expansion (all comer)
Parameters
Screening
Treatment
Follow-up
EOT visit
TUMOR TISSUE:
Cycle 2, Day 1
…
…
…
…
…
…
…
Blood (serum) samples *:
Cycle 1
Cycle ≥2
D1
D3
D8
D15
D1
D8
D15
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…


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Table 14-6: Parameters and time points for biomarker investigations 
in study Part 2 / MTD expansion (sqNSCLC + BC)
Parameters
Screening
Treatment
Follow-up
EOT visit
TUMOR TISSUE: 
Cycle 2, Day 1
…
…
…
…
…
…
…
Blood (serum) samples*:
Each Cycle
Day 1
Day 8
Day 15
…
…
…
…
…
…
…
…
…
…
…
…
…
New text:
Table 14-4, Table 14-5, Table 14-6 and Table 14-7 provide the parameters and time points for 
the laboratory examinations (safety laboratory tests, biomarker investigations) to be 
performed during the study. Instructions for biomarker and PK sample collection, processing, 
storage and shipment will be described in a separate document (e.g. lab manual).


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Table 14-4: Parameters and time points of laboratory examinations performed at 
local laboratory or study site (safety laboratory) – Study Part 1 and Part 2
Parameters
Screen-
ing
Treatment
Follow-up
Cycle 1
Day -3
Each Cycle
EOT
visit
FU 
visit
Day 1 Day 8
Day 15
BLOOD
Hematology: …
X
X
X
X
X
X
X
Coagulation: PT or PT-INR (obligatory at 
screening)  and PTT (aPTT)(A)
X
X
X
X
X
X
X
Biochemistry: Biochemistry: AST / GOT, 
ALT / GPT, gamma-GT, AP, LDH, amylase, 
lipase, glucose, triglycerides, creatinine(B), 
BUN, uric acid, bilirubin (total & direct), total 
protein, albumin, sodium, potassium, chloride, 
CPK, calcium, phosphate
X
X
X
X
X
X
X
Virology: …
X
URINE
Macroanalysis:
X
X
X
X
X
X
X
Urinalysis (dip stick): pH, blood, protein, 
glucose, bilirubin, urobilinogen, ketone, nitrite, 
leucocytes (or leucocyte esterase), specific 
gravity
X
X
X
X
X
X
X
Laboratory analysis(C): …
X
X
X
X
X
X
X
Microscopic urinalysis(D): … 
X
X
X
X
X
X
X
Pregnancy test(F)
X
(A)
…
(B)
…
(C)
…
(D)
…
(F)
…
ALT / GPT
= alanine aminotransferase / glutamic pyruvic transaminase
anti-HCV
= hepatitis C virus antibodies
anti-HIV 1+2
= human immune deficiency virus 1 and 2 antibodies
AP
= alkaline phosphatase
AST / GOT
= aspartate aminotransferase / glutamic oxaloacetic transaminase
BUN
= blood urea nitrogen
CPK
= creatine phosphokinase
CRP
= C-reactive protein
gamma GT
= gamma glutamyl transferase
HBsAg
= hepatitis B virus surface antigen
MCH
= mean corpuscular hemoglobin
MCHC
= mean corpuscular hemoglobin concentration
MCV 
= mean corpuscular volume
PT-INR
= prothrombin time - international normalized ratio
PTT / aPTT
= partial thromboplastin time / activated partial thromboplastin time
RBC
= red blood cell count
WBC
= white blood cell count 


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Table 14-5:
Parameters and time points for biomarker investigations
in study Part 1 / dose escalation (all comer)
Parameters
Screening
Treatment
Follow-up
EOT visit
TUMOR TISSUE: 
Cycle 2, Day 1
p-ERK1/2 levels 
X(A)
X(B)
Blood (serum) samples *:
Cycle 1
Cycle ≥2
D1
D3
D8
D15
D1
D8
D15
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
Table 14-6:
Parameters and time points for biomarker investigations in study 
Part 1 / MTD expansion (all comer)
Parameters
Screening
Treatment
Follow-up
EOT visit
TUMOR TISSUE:
Cycle 2, Day 1
…
…
…
…
…
…
…
Blood (serum) samples *:
Cycle 1
Cycle ≥2
D1
D3
D8
D15
D1
D8
D15
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…


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Table 14-7: Parameters and time points for biomarker investigations 
in study Part 2 / MTD expansion (sqNSCLC + BC)
Parameters
Screening
Treatment
Follow-up
EOT visit
TUMOR TISSUE: 
Cycle 2, Day 1
…
…
…
…
…
…
…
Blood (serum) samples*:
Each Cycle
Day 1
Day 8
Day 15
…
…
…
…
…
…
…
…
…
…
…
…
…
15.2 Amendment 2
Date of amendment: 19 Mar 2014
15.2.1 Overview of changes
Modification 1: Type of packaging for test drug was modified 
Rationale for introducing Modification 1 
The available stability data of the IMPD shelf life study for 50mg tablets show superiority 
of Alu/Alu blister against HDPE bottles. Therefore, as a precaution until real time data are 
available in HDPE bottles for 200 mg tablets, clinical supplies of 200mg tablets are 
packaged in Alu/Alu-blister. Stability studies for 200mg tablets in both packaging 
materials have been started.
15.2.2 Changes to the protocol
List of all CSP sections affected by Modification 1:
Section 6.2


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Old text:
Table 6-2:
Identity of test drug (IMP):  BAY 1163877 tablet formulation  
Generic name / brand name / INN
…
Substance code number(s)
…
Material / formulation) number(s)
…
Galenical form / formulation / vehicle and 
reconstitution, if applicable
…
Composition
…
Strength (amount of drug per unit) or 
concentration
…
Type of packaging and content
HDPE bottles with screw cap closure
Marketing Authorization Holder if applicable
…  
New text:
Table 6-2:
Identity of test drug (IMP):  BAY 1163877 tablet formulation  
Generic name / brand name / INN
…
Substance code number(s)
…
Material / formulation) number(s)
…
Galenical form / formulation / vehicle and 
reconstitution, if applicable
…
Composition
…
Strength (amount of drug per unit) or 
concentration
…
Type of packaging and content
HDPE bottles with screw cap closure or blisters 
of Foil 25/45/60 µm oPA/Al/PP (4320 / 0257)
sealed to Foil 20 µm Al sealable to PP (4345 / 
0202)
Marketing Authorization Holder if applicable
…  


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15.3 Amendment 3
Date of amendment: 19 Jun 2014
15.3.1 Overview of changes
Modification 1: Expansion of indications for study Part 2
Rationale for introducing Modification 1 
Preclinical data demonstrate a strong anti-tumor efficacy of BAY 1163877 not only in 
subjects with sqNSCLC and BC, but also in subjects with LAC or SCCHN. Protocol 
amendment 3 therefore expands the indications to evaluate biomarker status, PD 
parameters, and tumor response in Part 2 / MTD expansion from 2 specific populations 
(sqNSCLC + BC) to 4 specific populations (sqNSCLC + LAC + BC + SCCHN).
List of all CSP sections affected by Modification 1:
Due to the expansion from 2 to 4 indications in study Part 2, the term “sqNSCLC + BC” 
was replaced throughout the text by “sqNSCLC + LAC + BC + SCCHN”.
Modification 2: Introduction of a second SIS / ICF for subjects recruited for the 
MTD expansion cohort of study Part 1 and Part 2 
Rationale for introducing Modification 2 
In this study, the information on subjects’ FGFR expression level and the presence of 
activating mutations in FGFR encoding genes is a key prerequisite for subject 
stratification at screening. If subjects do not present the criteria required for stratification it 
is not necessary to perform all screening examinations and assessments. It was therefore 
decided to separate FGFR expression / FGFR mutation testing from screening procedures, 
and to introduce a separate SIS / ICF for FGFR expression / FGFR mutation testing which 
will only be used for subjects recruited for the MTD expansion cohort of Part 1 or Part 2. 
Due to this change, “FGFR expression / FGFR mutation testing” and “screening” have 
become two separate parts of the newly introduced generic term “pre-treatment” phase 
(see Section 7.1.2.1), and Section “Inclusion criteria” was divided in Section 5.1.1.1 
“Eligibility criteria for FGFR expression / FGFR mutation testing” and Section 5.1.1.2 
“Eligibility criteria for study treatment“. 
Additionally, it was clarified, that the evaluation of FGFR signaling pathway mutations 
(that may render a tumor drug-insensitive despite having high FGFR expression or an 
activating mutation) is planned retrospectively for subjects in the MTD expansion cohorts 
of both study parts, i.e. for subjects of Part 1 (all comer) and for subjects of Part 2 
(sqNSCLC + LAC + BC + SCCHN).
List of all CSP sections affected by Modification 2:
-
Synopsis
-
Section 4


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-
Section 5.1.1
-
Section 5.3
-
Section 6.3
-
Section 7.1.2
-
Section 7.4.4
-
Section 7.4.4.1
-
Section 7.5.4.2
-
Section 9.1
-
Section 11.2
-
Section 14.1
-
Section 14.2
Modification 3: Modification of inclusion and exclusion criteria
Rationale for introducing Modification 3 
Before, only subjects with amylase ≤ 1.5 x ULN and mild hepatic impairment (Child-Pugh 
score A) were eligible for the treatment period. The restriction was considered too strict 
for the target population (refractory, locally advanced or metastatic solid tumors). To 
improve subject recruitment, the criteria were changed to amylase ≤ 2.5 x ULN and not 
more than Child-Pugh score B7 to allow inclusion of subjects with more advanced 
pancreatic and hepatic impairment. 
Monoclonal antibodies with anticancer activity (e.g. bevacizumab or cetuximab etc.) were 
added to the list of not allowed previous chemotherapy within 6 weeks of pre-treatment 
biopsy for biomarker (p-ERK1/2) studies.
List of all CSP sections affected by Modification 3:
-
Synopsis
-
Section 5.1.1
-
Section 5.1.2
-
Section 7.4.4
-
Section 14.2


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Modification 4: Additional evaluation of food effect on the pharmacokinetics of 
BAY 1163877
Rationale for introducing Modification 4 
Food-effect bioavailability will be evaluated additionally to guide and select dosing 
regimen of BAY 1163877 in the further development. Evaluation of the effect of food on 
single-dose PK of BAY 1163877 is considered to impose only little extra burden on the 
study population. Approximately 8 subjects treated at MTD in Part 1 or Part 2 Part will be 
asked to participate in “Food effect assessment” with single-dose administration under fed 
and fasting conditions on Day -3 (after breakfast) respectively Day 1 (after an overnight 
fast) of Cycle 1.
List of all CSP sections affected by Modification 4:
-
Synopsis
-
Section 4
-
Section 6.1
-
Section 6.4.2.1
-
Section 6.4.2.2
-
Section 6.4.2.2.1 (new)
-
Section 6.4.2.3
-
Section 7.1.2.3
-
Section 7.1.2.3.1
-
Section 7.4.1.1
-
Section 7.4.2.1
-
Section 7.4.2.2
-
Section 7.5.3.4
-
Section 8.4.5
-
Section 14.1
Modification 5: Additional evaluation of urinary excretion of BAY 1163877 
Rationale for introducing Modification 5 
To evaluate the amount of drug evaluated via urine, 24-hour urine collection will be done 
in approximately 8 subjects enrolled in Part 1 or Part 2 MTD expansion cohorts on 
Cycle 1, Day 1.
List of all CSP sections affected by Modification 5:
-
Synopsis
-
Section 4
-
Section 7.1.2.3.1


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-
Section 7.4.2.1
-
Section 7.4.2.2
-
Section 8.4.5
-
Section 14.1
Modification 6: Additional PK assessments for population PK / PD modeling 
Rationale for introducing Modification 6 
To obtain longitudinal exposure data for PK / PD modeling (together with occurrences of 
selected adverse events and documented clinical responses), two blood samples (one pre-
dose and one post-dose) will be collected over 4 cycles (Cycles 2-5, Day 1) in all subjects 
participating in the MTD expansion cohorts of study Part 1 and Part 2
List of all CSP sections affected by Modification 6:
-
Synopsis
-
Section 4
-
Section 7.1.2
-
Section 7.4.2.1
-
Section 7.4.2.2
-
Section 8.6
-
Section 14.1
Modification 7: Replacement of subjects
Rationale for introducing Modification 7 
To ensure a sufficient number of subjects with paired biopsy samples for p-ERK1/2 
analysis, subjects with insufficient paired biopsy samples in Study Part 1 / MTD 
expansion (all comer) will be replaced.
List of all CSP sections affected by Modification 7:
Section 5.2.2
Modification 8: Change in visit schedule starting with Cycle 13
Rationale for introducing Modification 8
Starting with Cycle 13, the number of site visits per cycle will be reduced from 3 visits 
(Days 1, 8 and 15) to 2 visits (Days 1 and 11). The reduction in visits may provide greater 
convenience for patients and is sufficient to evaluate safety in subjects who are already 
stable on treatment for several months. 
List of all CSP sections affected by Modification 8:
-
Synopsis
-
Section 4


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-
Section 7.1.2
-
Section 7.4.4
-
Section 14.1
-
Section 14.2
Modification 9: Change in time window for EOT visit
Rationale for introducing Modification 9
The EOT visit can also be conducted on the same day or shortly after diagnosed tumor 
progression / other reasons for discontinuation. A time window of 7 days is not 
mandatory. Therefore, the time window for the EOT visit will be changed from 7-14 days 
to 0-14 days after last dose.
List of all CSP sections affected by Modification 9: 
-
Synopsis
-
Section 4
-
Section 7.1.2
-
Section 14.1
-
Section 14.2
Modification 10: Minor corrections
Rationale for introducing Modification 10 
Minor text modifications and corrections of omissions regarding virology testing, 
measurement of body weight and electronic data transfer, or terminology were done for 
clarification and to ensure correct and consistent wording. 
List of all CSP sections affected by Modification 10:
List of abbreviations
Section 6.4.2
Section 6.7
Section 6.9.1
Section 7.1.2
Section 7.5.1.3
Section 7.5.4.2
Section 7.6.1
Section 9.1
Section 12
Section 14.1


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Section 14.2
15.3.2 Changes to the protocol
In this section, all affected protocol sections are detailed; the sequence of the sections 
follows the structure of the original protocol. 
In the display of modifications, the “old text” refers to the protocol version preceding this 
amendment. Deletions are crossed out in the “old text”. Additions are underlined in the 
“new text”. 
The replacement of the term “sqNSCLC + BC” by “sqNSCLC + LAC + BC + SCCHN” 
throughout the protocol (see Section 15.1.1, Modification 1) and corrections of typing 
errors, omissions or terminology (minor corrections) are not highlighted in this 
amendment.


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Synopsis
This section was changed as a result of Modifications 1-6, 8 and 9.
Old text:
Title
…
Short title
…
Clinical study phase
…
Project number
…
Study objective(s)
…
Test drug(s) 
…
Name of active ingredient 
…
Formulation IMP 1
…
Formulation IMP 2
…
Dose(s)
…
Route of administration
…
Duration of treatment
…
Duration and dosing schedule of subjects enrolled for 
tablet relative bioavailability assessment (“tablet 
bridging cohort”) of study Part 1: 
…
Duration and dosing schedule for subjects of study 
Part 2 without PK assessment: 
…
Reference drug (s)
…
Indication
…


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Diagnosis and main criteria for 
inclusion
Inclusion criteria:

Signed informed consent (IC) obtained before any 
study specific procedure. Subjects must be able to 
understand and willing to sign the written IC.

Subjects with histologically or cytological 
confirmed, refractory, locally advanced or 
metastatic solid tumors who are not candidates for 
standard therapy.

Study Part 1 / dose escalation + MTD expansion 
cohort (all comer): Subjects with any type of 
solid tumor (all comer) will be eligible for dose 
escalation and dose expansion at MTD in Part 1;
Subjects enrolled for dose expansion (MTD 
expansion cohort “all comer”) will be 
stratified according to high fibroblast growth 
factor receptor (FGFR) expression levels and the 
presence or absence of additional genetic 
alterations in the FGFR signaling pathway using 
archival or fresh tumor biopsy material.

Study Part 2 / MTD expansion cohort (sqNSCLC 
+ BC): Subjects will be eligible for Part 2 only if 
they have histological or cytological confirmed 
squamous non-small cell lung cancer 
(sqNSCLC) or bladder cancer (BC). 
All subjects in Part 2 (MTD expansion cohort 
“sqNSCLC + BC”) will be stratified according 
to high FGFR expression levels and the presence 
or absence of additional genetic alterations in the 
FGFR signaling pathway using archival or fresh 
tumor biopsy specimen. 
BC subjects with low overall FGFR expression 
levels can be included if activating FGFR3
mutations are confirmed.

Subjects must have at least one measurable or 
evaluable lesion according to Response Evaluation 
Criteria in Solid Tumors (RECIST), version 1.1. A 
lesion in a previously irradiated area is eligible and 
to be considered as measurable disease as long as 
there is objective evidence of progression of the 
lesion prior to study enrollment.

Subjects with resected primary tumors who have 
documented metastases are eligible. Existence of an


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Diagnosis and main criteria for 
inclusion
(continued)
archival biopsy is mandatory for stratification of 
subjects included in the expansion cohorts at MTD 
in Part 1 (all comer) and Part 2 (sqNSCLC + BC). 
If no archival biopsy is available for a subject 
assigned to the MTD expansion cohort “all comer” 
(Part 1) respectively to the MTD expansion cohort 
“sqNSCLC + BC” (Part 2), fresh tumor biopsy 
material is required for stratification

A pre-treatment biopsy at screening and a second 
biopsy on Cycle 2, Day 1 will be obtained from all 
subjects who agreed on repeated biopsies.
The following rules apply to subjects participating 
in study Part 1 and study Part 2:

Study Part 1 / dose escalation (all comer):
Biopsies for biomarker studies are optional for 
subjects enrolled to the dose-escalation cohorts.

Study Part 1 / MTD expansion cohort (all comer):
Both a pre-treatment biopsy (screening) and a 
second biopsy (Cycle 2, Day 1) for biomarker 
studies are mandatory for all subjects in the MTD 
expansion cohort. Material from the mandatory pre-
treatment biopsy may be used for stratification of 
subjects if no archival biopsy is available at 
screening.

Study Part 2 / MTD expansion cohort (sqNSCLC + 
BC):
A pre-treatment biopsy for stratification is only 
mandatory for subjects for whom no archival biopsy 
is available.

Biopsies for biomarker studies are optional for all 
subjects with archival biopsies.
Note: Anticancer chemotherapy must have been 
stopped for at least 5 half-lives of the last applied 
therapy before the pre-treatment biopsy is taken. 
Mitomycin C or nitrosoureas should not be given 
within 6 weeks of pre-treatment biopsy.

Male or female subjects ≥ 18 years of age 

…


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Diagnosis and main criteria for 
inclusion 
(continued)

…

...

...

Adequate bone marrow, liver and renal function as 
assessed by the following laboratory requirements 
conducted within 7 days of starting the study 
treatment:
… 
…
Amylase and lipase ≤ 1.5 x ULN
Not more than mild hepatic impairment, Child-
Pugh score A
…
Study design
…
Methodology 
Eligible cancer subjects will be enrolled at multiple 
centers in Europe and Asia. In total, the “on study” 
period for the subjects comprises 3 phases:

Screening (minimum 7 days, maximum 28 days)

Treatment 
Study Part 1 / dose escalation + MTD expansion 
(all comer):
…
Study Part 1 /“tablet bridging cohort” 
(all comer)
…
Study Part 2 / MTD expansion (sqNSCLC + BC):
…
Note: Treatment with BAY 1163877 at MTD in 
Part 1 (expansion cohort “all comer”) and Part 2 
(expansion cohort “sqNSCLC + BC”) can run in 
parallel.

Follow-up (FU)
End of Treatment (EOT) visit 7-14 days 
after last dose of BAY 1163877
…


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Methodology 
(continued)
Determination of the MTD:
…
Pharmacokinetics (PK): Single- and multiple-dose PK 
of BAY 1163877 will be evaluated in plasma samples 
collected on Cycle 1, Day -3 (up to 48 hours after 
dosing) in the “tablet bridging cohort”, and on Cycle 1, 
Day 1 (up to 48 hours after dosing) and on Cycle 1, 
Day 15 (up to 12 hours after dosing), respectively, in all 
subjects participating in Study Part 1 (all comer) and in 
at least 12 subjects participating in Study Part 2 
(sqNSCLC + BC). Plasma concentration of 
BAY 1163877 will be measured using a validated 
method.
Exploratory monitoring of metabolites may also be 
performed in pooled plasma (most likely at the MTD or 
the therapeutic dose). Specifically, if performed at the 
MTD, this will be done initially in 2 subjects (highest 
and lowest BAY 1163877 area under the curve (AUC)).
Safety / tolerability:  
…
Cardiovascular assessment: 
…
Electrocardiogram (ECG): 12-lead ECG readings will 
be performed at screening, on Cycle 1, Days -3 and -2 
(“tablet bridging cohort” only), on Cycle 1, Days 1, 2, 
and 15, thereafter on Day 1 of each subsequent Cycle, 
and at the EOT visit.
At screening...
Pharmacodynamic (PD) biomarkers:
…
Biomarker analysis in serum
Blood Blood (serum) samples for quantification of 
fibroblast growth factor 23 (FGF23), phosphate and 
calcium levels will be collected at screening, on Days 
1*, 8* and 15* of each Cycle, and at EOT visit. In …
* Blood collection before administration of morning dose


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Methodology 
(continued)
Biomarker analysis in serum
Blood Blood (serum) samples for quantification of 
fibroblast growth factor 23 (FGF23), phosphate and 
calcium levels will be collected at screening, on Days 
1*, 8* and 15* of each Cycle, and at EOT visit. In …
* Blood collection before administration of morning dose
Biomarker analysis in tumor tissue
Biomarker analysis will be done at screening for subject 
stratification in the MTD expansion cohorts (Part 1: all 
comer; Part 2: sqNSCLC + BC) according to FGFR 
expression levels / pathway mutations using either an 
archival or fresh tumor biopsy material (see inclusion 
criteria).
Analysis of …
Tumor response evaluation:
... 
Recommended Phase II dose (RP2D):
...
Type of control
…
Number of subjects
...

Study Part 1 / dose escalation (all comer): 
…. 

Study Part 1 / MTD expansion (all comer): 
...

Study Part 2 / MTD expansion (sqNSCLC + BC):
40 additional subjects will be enrolled to have 
20 evaluable subjects with sqNSCLC and 
20 evaluable subjects with BC treated at MTD.
Primary variables
Determination of MTD
…


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Primary variables
(continued)
Pharmacokinetics: (BAY 1163877)
On Cycle 1 Day -3 (“tablet bridging cohort” only) 
and Cycle 1, Day 1: Cmax, AUC(0-12), AUC(0-tlast), 
AUC and corresponding dose adjusted parameters 
(Cmax/D, AUC(0-12)/D AUC(0-tlast)/D, AUC/D and 
AUC).
For Cycle 1, Day 15: Cmax,md, Cmax/Dmd, AUC(0-12)md, 
AUC(0-12)/Dmd, AUC(0-tlast)md, and AUC(0-tlast)/Dmd
Plan for statistical analysis
… 
To investigate dose proportionality an ANOVA will be 
performed on the log-transformed values of appropriate 
PK parameters and 90% confidence intervals will be 
derived.
New text:
Title
…
Short title
…
Clinical study phase
…
Project number
…
Study objective(s)
…
Test drug(s) 
…
Name of active ingredient 
…
Formulation IMP 1
…
Formulation IMP 2
…
Dose(s)
…
Route of administration
…


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Duration of treatment
…
Duration and dosing schedule of subjects enrolled for 
tablet relative bioavailability assessment (“tablet 
bridging cohort”) of study Part 1: 
…
Duration and dosing schedule of subjects enrolled for 
food effect assessment in the MTD expansion cohorts 
of study Part 1 and Part 2:
Approximately 8 subjects will receive single doses of 
BAY 1163877 on Cycle 1, Day -3 (after consumption 
of a high-fat, high-calorie breakfast) and on Cycle 1, 
Day 1 (after an overnight fast of at least 8 hours)
followed by treatment according to the schedule 
described above starting on Cycle 1, Day 3.
Duration and dosing schedule for subjects of study 
Part 2 without PK assessment: 
…
Reference drug (s)
…
Indication
…
Diagnosis and main criteria for 
inclusion
Inclusion criteria:
Eligibility criteria for FGFR expression / FGFR 
mutation testing (only for MTD expansion cohorts of 
study Part 1 and Part 2)

Ability to understand and willingness to sign the 
written subjects information sheet / informed 
consent form (SIS / ICF) for FGFR expression / 
FGFR mutation testing. Signed informed consent 
(IC) has to be obtained before any study specific 
procedure. 

Subjects with histologically or cytological 
confirmed, refractory, locally advanced or 
metastatic solid tumors (all comer for study Part1; 
sqNSCLC, LAC, BC or SCCHN for Part 2) who are 
not candidates for standard therapy.  

Male or female subjects ≥18 years of age


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Diagnosis and main criteria for 
inclusion
(continued)

Eastern Cooperative Oncology Group (ECOG) 
Performance Status of 0, 1 or 2

Life expectancy of at least 3 months

Existence of archival or fresh tumor biopsy 
specimen for FGFR expression / FGFR mutation 
testing
Besides these basic criteria, any criterion as outlined 
below already known to prohibit the patient’s 
participation in the study should be considered.
Eligibility criteria for study treatment

Ability to understand and willingness to sign the 
written SIS / ICF for study treatment eligibility. 
Signed IC obtained before any study specific 
procedure.

Subjects with histologically or cytological 
confirmed, refractory, locally advanced or 
metastatic solid tumors who are not candidates for 
standard therapy.
Subjects with any type of solid tumors (all comer) 
will be eligible for dose escalation and dose 
expansion at MTD in Part 1.

Subjects enrolled in the MTD expansion cohorts of 
Study Part 1 and Part 2 must present high FGFR 
expression levels based on archival or fresh tumor 
biopsy specimen analysis.
Bladder cancer subjects with low overall FGFR 
expression levels can be included if activating 
FGFR3 mutations are confirmed. 
(only for MTD expansion cohorts of study Part 1 
(all comer) and Part 2 (sqNSCLC + LAC +BC + 
SCCHN))

Subjects must have at least one measurable or 
evaluable lesion according to Response Evaluation 
Criteria in Solid Tumors (RECIST), version 1.1. A 
lesion in a previously irradiated area is eligible and 
to be considered as measurable disease as long as 
there is objective evidence of progression of the 
lesion prior to study enrollment.

Subjects with resected primary tumors who have 
documented metastases are eligible. 


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Diagnosis and main criteria for 
inclusion
(continued)

Subjects consent to undergo a paired biopsy at 
screening and on Cycle 2, Day 1
(only for MTD expansion cohorts of study Part 1 
(all comer)
Note: Anticancer chemotherapy must have been 
stopped for at least 5 half-lives of the last applied 
therapy before the pre-treatment biopsy is taken. 
Mitomycin C, nitrosoureas or monoclonal 
antibodies with anticancer activity (e.g. 
bevacizumab or cetuximab etc.) should not be given 
within 6 weeks of pre-treatment biopsy for 
biomarker (p-ERK1/2) studies.

Male or female subjects ≥ 18 years of age 

…
Diagnosis and main criteria for 
inclusion 
(continued)

…

...

...

Adequate bone marrow, liver and renal function as 
assessed by the following laboratory requirements 
conducted within 7 days of starting the study 
treatment:
… 
…
Amylase and lipase ≤ 2.5 x ULN
Not more than Child-Pugh score B7 hepatic 
impairment
… 
Study design
…


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Methodology 
Eligible cancer subjects will be enrolled at multiple 
centers in Europe and Asia. In total, the “on study” 
period for the subjects comprises 3 phases:
Pre-treatment
FGFR expression / FGFR mutation testing
Screening
Treatment 
Study Part 1 / dose escalation + MTD expansion 
(all comer):
…
Study Part 1 /“tablet bridging cohort” 
(all comer)
…
Study Part 2 / MTD expansion (sqNSCLC + LAC 
+ BC + SCCHN):
…
MTD expansion cohorts (study Part 1 and 
Part 2) / “food effect assessment”:
Approximately 8 subjects will receive single 
doses of BAY 1163877 on Cycle 1, Day -3 
(after consumption of a high-fat, high-calorie 
breakfast) and on Cycle 1, Day 1 (after an 
overnight fast of at least 8 hours) followed by 
treatment according to the schedule described 
above starting on Cycle 1, Day 3.
Note: Treatment with BAY 1163877 at MTD in 
Part 1 (expansion cohort “all comer”) and Part 2 
(expansion cohort “sqNSCLC + LAC + BC + 
SCCHN”) can run in parallel.

Follow-up (FU)
End of Treatment (EOT) visit 0-14 days 
after last dose of BAY 1163877
…
Determination of the MTD:
…


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Methodology 
(continued)
Pharmacokinetics (PK): Single- and multiple-dose PK 
of BAY 1163877 will be evaluated in plasma samples 
collected on Cycle 1, Day -3 (up to 48 hours after 
dosing) in the “tablet bridging cohort”, and on Cycle 1, 
Day 1 (up to 48 hours after dosing) and on Cycle 1, 
Day 15 (up to 12 hours after dosing), respectively, in all 
subjects participating in Study Part 1 (all comer) and in 
at least 12 subjects participating in Study Part 2 
(sqNSCLC + LAC + BC + SCCHN). In approximately 
8 subjects enrolled in MTD expansion cohorts (study 
Part 1 and Part 2), single dose PK of BAY 1163877 will 
be evaluated in plasma samples collected on Cycle 1, 
Day -3 (up to 48 hours after dosing) and on Cycle 1, 
Day 1 (up to 48 hours after dosing) for food effect 
assessment.
Plasma concentration of BAY 1163877 will be 
measured using a validated method.
In approximately 8 subjects enrolled in MTD expansion 
cohorts (study Part 1 and Part 2), urine will be collected 
for 24 hours after dosing on Cycle 1, Day 1 
(concurrently with plasma PK samples) and analyzed 
using validated method.
Exploratory monitoring of metabolites may also be 
performed in pooled plasma (most likely at the MTD or 
the therapeutic dose) and urine samples.
Safety / tolerability:  
…
Cardiovascular assessment: 
…
Electrocardiogram (ECG): 12-lead ECG readings will 
be performed at screening, on Cycle 1, Days -3 and -2 
(“tablet bridging cohort” and “food effect assessment”
only), on Cycle 1, Days 1, 2, and 15, thereafter on 
Day 1 of each subsequent Cycle, and at the EOT visit.
At screening...
Pharmacodynamic (PD) biomarkers:
...


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Methodology 
(continued)
Biomarker analysis in serum
Blood serum) samples for quantification of fibroblast 
growth factor 23 (FGF23), phosphate and calcium 
levels will be collected at screening, on Days 1*, 8* and 
15* of Cycles 1-12, on Days 1 and 11 of Cycles ≥13, 
and at EOT visit. In …
* Blood collection before administration of morning dose only for Cycle 1 
of Part 1 and Part 2.
Biomarker analysis in tumor tissue
Biomarker analysis will be done at screening for subject 
stratification in the MTD expansion cohorts (Part 1: all 
comer; Part 2: sqNSCLC + LAC + BC + SCCHN) 
according to FGFR expression levels / FGFR mutation 
using either an archival or fresh tumor biopsy material 
(see inclusion criteria).
Analysis of …
Tumor response evaluation:
... 
Recommended Phase II dose (RP2D):
...
Type of control
…
Number of subjects
...

Study Part 1 / dose escalation (all comer): 
…. 

Study Part 1 / MTD expansion (all comer): 
...

Study Part 2 / MTD expansion (sqNSCLC + LAC + 
BC + SCCHN): 
40 additional subjects will be enrolled to have 
20 evaluable subjects with sqNSCLC or LAC and a 
cohort of 20 evaluable subjects with BC or SCCHN
treated at MTD (at least 8 subjects per indication).


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Primary variables
Determination of MTD
…
Pharmacokinetics: (BAY 1163877)
On Cycle 1 Day -3 (“tablet bridging cohort” and 
“food effect assessment” only) and Cycle 1, Day 1:
Cmax, AUC(0-12), AUC(0-tlast), AUC and corresponding 
dose adjusted parameters (Cmax/D, AUC(0-12)/D 
AUC(0-tlast)/D, AUC/D and AUC)
Amount of BAY 1163877 excreted renally during 0 to 
12 h (AE,ur(0-12)), 12 to 24 h (AE,ur(12-24)) and 0 to 
24 h (AE,ur(0-24)) post-dose will be calculated at the 
MTD and also expressed as percent of dose 
administered.
For Cycle 1, Day 15: Cmax,md, Cmax/Dmd, AUC(0-12)md, 
AUC(0-12)/Dmd, AUC(0-tlast)md, and AUC(0-tlast)/Dmd. 
Plan for statistical analysis
… 
To investigate dose proportionality, bioavailability and 
food effect an ANOVA will be performed on the log-
transformed values of appropriate PK parameters and 
90% confidence intervals will be derived.


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Section 1: Introduction
This section was changed as a result of Modification 1.
Old text:
Background information 
…
FGFRs are commonly altered in various human tumor diseases, including FGFR1 
amplification in squamous non-small cell lung cancer (sqNSCLC (3)(4)), or activating 
mutations of FGFR3 in bladder cancers (5)(6)(7). 
…
Rationale of the study 
The target indications for BAY 1163877 in the expansion phase of this study are 
sqNSCLC and bladder cancer (BC). Preclinical data demonstrate a strong anti-tumor 
efficacy of BAY 1163877 in both tumor types as a single agent. In human sqNSCLC, 
amplification of FGFR1 has been demonstrated in up to 21% of cases (8)(9)(10)(11), 
which is usually detected by FISH-based analysis of gene copy number alterations.
…
New text:
Background information 
…
FGFRs are commonly altered in various human tumor diseases, including FGFR1 
amplification in non-small cell lung cancer (e.g. sqNSCLC (3)(4)), squamous cell 
carcinoma of the head and neck (SCCHN (38)), or activating mutations of FGFR3 in 
bladder cancers (BC(5)(6)(7)). 
…
Rationale of the study 
The target indications for BAY 1163877 in the expansion phase of this study are 
sqNSCLC, lung adenocarcinoma (LAC), BC and SCCHN. Preclinical data demonstrate a 
strong anti-tumor efficacy of BAY 1163877 in both tumor types as a single agent. In 
human sqNSCLC, amplification of FGFR1 has been demonstrated in up to 21% of 
cases(8)(9)(10)(11), and FGFR1 amplification was found in 15 % of SCCHN cases (38) 
which is usually detected by FISH-based analysis of gene copy number alterations.
…


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Section 4: Study design - amended
This section was changed as a result of Modification 1, 2, 4, 5, 6, 8 and 9.
Old text:
Design overview
…
Targeted / planned enrollment:

Study Part 1 / dose escalation (all comer): ...

Study Part 1 / MTD expansion (all comer): ...

Study Part 2 / MTD expansion (sqNSCLC + BC): 40 additional subjects will be 
enrolled to have 20 evaluable subjects with sqNSCLC and 20 evaluable subjects with BC 
treated at MTD.
PK assessments will be performed in all subjects participating in study Part 1 / dose 
escalation and MTD expansion (all comer). Additionally, PK assessments are planned in 
at least 12 subjects participating in study Part 2 / MTD expansion (sqNSCLC + BC) such 
that valid PK data are available in 8 subjects. 
…
Study periods: 
Figure 4-1:
Schematic presentation of the treatment design
# The first dose will be administered on Cycle 1, Day 1, except for subjects participating in relative 
bioavailability assessment who will receive a single dose administered as tablet formulation on 
Cycle 1, Day -3.  
*Follow-up:  
- EOT (End of Treatment) visit within 7-14 days of last dose of BAY 1163877  
- FU (Follow-up) visit / contact at 30-35 days after last dose of BAY 1163877
In total, the “on study” period for all subjects comprises 3 phases (see Figure 4-1):

Screening (minimum 7 days, maximum 28 days) 
First study
Visit
First dose
administration #
EOT visit
FU-visit / 
contact 
Screening
Treatment
Follow-up (FU)*
On study
Last dose 
administration 
Cycle X


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
Treatment 
Study Part 1 / dose escalation + MTD expansion (all comer): 
… 
Study Part 1 / “tablet bridging cohort” (all comer):
... 
Study Part 2 / MTD expansion (sqNSCLC + BC): 
   
Note: Treatment with BAY 1163877 at MTD in Part 1 (expansion cohort “all comer”) and 
Part 2 (expansion cohort “sqNSCLC + LAC + BC + SCCHN”) can run in parallel.

Follow-up (FU)
End of Treatment (EOT) visit 7-14 days after last dose of BAY 1163877
…
The first screening visit is scheduled within 28 days before administration of the first dose 
of BAY 1163877. The informed consent form will be signed by the subject before or at 
the first screening visit. The screening period ends just before start of treatment.
The treatment period starts on the day of the first administration of study treatment on 
Cycle 1, Day 1 and ends with the last day when the study medication is administered in 
Cycle X. The length of treatment period …
…
An End of Treatment (EOT) visit will be performed for all subjects within 7-14 days after 
administration of the last dose of BAY 1163877. …
Treatment: …
…
In one of the dose escalation cohorts in study Part 1 (“tablet bridging cohort”), relative 
bioavailability of the tablet formulation will be assessed by administration of a single dose 
of the tablet formulation on Cycle 1, Day -3. Starting with Cycle 1, Day 1, subjects 
enrolled in the “tablet bridging cohort” will continue with the solution formulation as 
described above.
Subjects without PK assessment ...
...
Determination of the maximum tolerated dose (MTD)
...
Pharmacokinetics (PK):  Single- and multiple-dose PK of BAY 1163877 will be 
evaluated in plasma samples collected on Cycle 1, Day -3 in the “tablet bridging cohort”, 
and on Cycle 1, Days 1 and 15 in all subjects participating in Part 1 (all comer) and in at 
least 12 subjects participating in Part 2 (sqNSCLC + BC).
Plasma concentration of BAY 1163877 will be measured using a validated method. 


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Exploratory monitoring of metabolites may also be performed in pooled plasma samples 
(most likely at the MTD or the therapeutic dose). Specifically, if performed at the MTD, 
this will be done initially in 2 subjects (highest and lowest BAY 1163877 area under the 
curve (AUC)).
The time points for PK sampling and further details are provided in Section 7.4.2.1.
Safety / tolerability:
... 
Cardiovascular assessment:
... 
Electrocardiogram (ECG): 12-lead ECG readings will be performed at screening, on 
Cycle 1, Days -3 and -2 (“tablet bridging cohort” and “food effect assessment”, only), on 
Cycle 1, Days 1, 2, and 15, thereafter on Day 1 of each subsequent Cycle, and at the EOT 
visit. …
…
Pharmacodynamic (PD) biomarkers: … 
… 
Biomarker analysis in serum: Blood (serum) samples for quantification of fibroblast 
growth factor 23 (FGF23), phosphate and calcium levels will be collected at screening, on 
Days 1, 8 and 15 of each Cycle, and at EOT visit. …
Biomarker analysis in tumor tissue: Biomarker analysis will be done screening for subject 
stratification in the MTD expansion cohorts (Part 1: all comer; Part 2: sqNSCLC + BC) 
according to FGFR expression levels / pathway mutations using either an archival tumor 
tissue specimen or fresh tumor biopsy material (see Section 5.1.1, inclusion criteria).
Analysis of phospho-extracellular signal-regulated kinase 1/2 levels, (p-ERK1/2) will be 
done at screening and on Cycle 2, Day 1 for all subjects who are willing to undergo a 
biopsy both at screening and on Cycle 2, Day 1. Both biopsies are mandatory for “all 
comer” subjects included in the MTD expansion cohort of Part 1.
Tumor response evaluation: …
…
Recommended Phase II dose (RP2D):
…


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New text:
Design overview
…
Targeted / planned enrollment:

Study Part 1 / dose escalation (all comer): ...

Study Part 1 / MTD expansion (all comer): ...

Study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN): 40 additional 
subjects will be enrolled to have 20 evaluable subjects with sqNSCLC or LAC and 20 
evaluable subjects with BC or SCCHN (at least 8 subjects per indication) treated at MTD.
PK assessments will be performed in all subjects participating in study Part 1 / dose 
escalation and MTD expansion (all comer). Additionally, PK assessments are planned in 
at least 12 subjects participating in study Part 2 / MTD expansion (sqNSCLC + LAC + BC 
+ SCCHN) such that valid PK data are available in 8 subjects. Food effect PK assessment 
is planned in approximately 8 subjects enrolled in the MTD expansion cohorts (study 
Part 1 and Part 2). Subjects participating in “food effect assessment” in study Part 2 may 
be included in the total sample size of 12 if all protocol requirements are met.
All subjects participating in either of the 2 MTD expansion cohorts (Part 1 and Part 2) will 
have 2 PK samples drawn for the purpose of exposure-response modelling on Day 1 of 
Cycles 2, 3, 4, and 5 (1 blood sample just before the morning dose of BAY 1163877 and 
1 blood sample between 0.5 and 1.5 hours post-dose). The dose needs to be taken under 
supervision and the time recorded.


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Study periods: 
Figure 4-1:
Schematic presentation of the treatment design
§ The first study (screening) visit is scheduled within 7 days / within 28 days before administration of 
the first dose of BAY 1163877 (written informed consent for study treatment eligibility). 
Subjects recruited for Part 1 or Part 2 MTD expansion cohorts have their first study visit before 
study (screening) visit to perform a biomarker analysis for subject stratification (mandatory written 
informed consent for FGFR expression / FGFR mutation testing). Those subjects who are eligible 
for participation in the MTD expansion cohort must additionally sign the informed consent for study 
treatment eligibility at the screening visit.
# The first dose will be administered on Cycle 1, Day 1, except for subjects participating in relative 
bioavailability assessment (“tablet bridging cohort”) and “food effect assessment” who will receive 
the first dose on Cycle 1, Day -3.  
*Follow-up:  
- EOT (End of Treatment) visit within 0-14 days of last dose of BAY 1163877  
- FU (Follow-up) visit / contact at 30-35 days after last dose of BAY 1163877
In total, the “on study” period for all subjects comprises 3 phases (see Figure 4-1):

Pre-treatment 
-
Testing for FGFR and FGFR mutation (only for subjects recruited for Part 1 or 
Part 2 MTD expansion cohorts)
-
Screening 

Treatment 
Study Part 1 / dose escalation + MTD expansion (all comer): 
… 
Study Part 1 / “tablet bridging cohort” (all comer):
... 
Study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN): 
   
Study Part 1 (MTD expansion cohort) and Study Part 2 (sqNSCLC + LAC + BC + 
SCCHN) / “Food Effect Assessment”: 
Approximately 8 subjects will receive single doses of BAY 1163877 on Cycle 1, Day -3 
(after consumption of a high-fat, high-calorie breakfast) and on Cycle 1, Day 1 (after an 
First study
Visit§
First dose
administration #
EOT visit
FU-visit / 
contact 
Pre-treatment
Treatment
Follow-up (FU)*
On study
Last dose 
administration 
Cycle X


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overnight fast of at least 8 hours) followed by treatment according to the schedule 
described above starting on Cycle 1, Day 3.
Note: Treatment with BAY 1163877 at MTD in Part 1 (expansion cohort “all comer”) and 
Part 2 (expansion cohort “sqNSCLC + LAC + BC + SCCHN”) can run in parallel.

Follow-up (FU)
… End of Treatment (EOT) visit 0-14 days after last dose of BAY 1163877
…
The first screening visit is scheduled within 7 days / within 28 days before administration 
of the first dose of BAY 1163877. The informed consent form will be signed by the 
subject before or at the first screening visit (please refer to Section 11.2). The screening 
period ends just before start of treatment.
The treatment period starts on the day of the first administration of study treatment either
on Cycle 1, Day 1 or on Cycle 1, Day -3 (“tablet bridging cohort” and “food effect 
assessment”) and ends with the last day when the study medication is administered in 
Cycle X. The length of treatment period …
…
An End of Treatment (EOT) visit will be performed for all subjects within 0-14 days after 
administration of the last dose of BAY 1163877. …
Treatment: …
…
In one of the dose escalation cohorts in study Part 1 (“tablet bridging cohort”), relative 
bioavailability of the tablet formulation will be assessed by administration of a single dose 
of the tablet formulation on Cycle 1, Day -3. Starting with Cycle 1, Day 1, subjects 
enrolled in the “tablet bridging cohort” will continue with the solution formulation as 
described above. Depending on the results from the relative bioavailability assessment, 
subjects who initially start with solution formulation may be switched to tablet 
formulation in later cycles.
Approximately 8 subjects enrolled in the MTD expansion cohorts (study Part 1 and Part 2) 
will receive single doses of BAY 1163877 on Cycle 1, Day -3, after consumption of a 
high-fat, high-calorie breakfast and on Cycle 1, Day 1, after an overnight fast of at least 
8 hours followed by treatment according to the schedule described above starting on 
Cycle 1, Day 3.
Subjects without PK assessment ...
...
Determination of the maximum tolerated dose (MTD)
...
Pharmacokinetics (PK):  Single- and multiple-dose PK of BAY 1163877 will be 
evaluated in plasma samples collected on Cycle 1, Day -3 in the “tablet bridging cohort”, 


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and on Cycle 1, Days 1 and 15 in all subjects participating in Part 1 (all comer) and in at 
least 12 subjects participating in Part 2 (sqNSCLC + LAC + BC + SCCHN). In 
approximately 8 subjects enrolled in the MTD expansion cohorts (study Part 1 and Part 2), 
the effect of food on the PK of BAY 1163877 will be determined by comparing exposures 
on Cycle 1 Day -3 (administration after consumption of a high-fat, high-calorie breakfast) 
and Cycle 1 Day 1 (administration after an overnight fast of at least 8 hours), see 
Section 6.1.
Plasma concentration of BAY 1163877 will be measured using a validated method. 
In approximately 8 subjects enrolled in MTD expansion cohorts (study Part 1 and Part 2), 
urine will be collected for 24 hours after dosing on Cycle 1, Day 1 (concurrently with 
plasma PK samples) and analyzed using validated method.
Exploratory monitoring of metabolites may also be performed in pooled plasma samples 
(most likely at the MTD or the therapeutic dose) and urine samples.
The time points for PK sampling and further details are provided in Section 7.4.2.1.
Safety / tolerability:
...
Cardiovascular assessment:
... 
Electrocardiogram (ECG): 12-lead ECG readings will be performed at screening, on 
Cycle 1, Days -3 and -2 (“tablet bridging cohort” and “food effect assessment”, only), on 
Cycle 1, Days 1, 2, and 15, thereafter on Day 1 of each subsequent Cycle, and at the EOT 
visit. …
…
Pharmacodynamic (PD) biomarkers: … 
… 
Biomarker analysis in serum: Blood (serum) samples for quantification of fibroblast 
growth factor 23 (FGF23), phosphate and calcium levels will be collected at screening, on 
Days 1, 8 and 15 of Cycles 1-12, on Days 1 and 11 of Cycles ≥13, and at EOT visit.
Biomarker analysis in tumor tissue: Biomarker analysis will be done screening for subject 
stratification in the MTD expansion cohorts (Part 1: all comer; Part 2: sqNSCLC + LAC + 
BC + SCCHN) according to FGFR expression levels / FGFR mutation using either an 
archival tumor tissue specimen or fresh tumor biopsy material (see Section 5.1.1, inclusion 
criteria).
Analysis of phospho-extracellular signal-regulated kinase 1/2 levels, (p-ERK1/2) will be 
done at screening and on Cycle 2, Day 1 for all subjects who are willing to undergo a 
biopsy both at screening and on Cycle 2, Day 1. Both biopsies are mandatory for “all 
comer” subjects included in the MTD expansion cohort of Part 1 (please refer to 
Section 5.1.1 for details).


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Tumor response evaluation: …
…
Recommended Phase II dose (RP2D):
…
Section 5.1.1: Inclusion criteria
This section was changed as a result of Modifications 1 and 2.
Old text:
Screening must be performed within 28 days prior to the first dose of study drug. Subjects 
must fulfill all of the following criteria before being included in the treatment phase (i.e, 
before receiving any dose of BAY 1163877):

Signed informed consent (IC) obtained before any study specific procedure. 
Subjects must be able to understand and willing to sign the written IC. 

Subjects with histologically or cytological confirmed, refractory, locally advanced 
or metastatic solid tumors who are not candidates for standard therapy.
-
Study Part 1 / dose escalation + MTD expansion cohort (all comer): Subjects with 
any type of solid tumors (all comer) will be eligible for dose escalation and dose 
expansion at MTD in Part 1; Subjects enrolled for dose expansion (MTD 
expansion cohort “all comer”) will be stratified according to high fibroblast 
growth factor receptor (FGFR) expression levels and the presence or absence of 
additional genetic alterations in the FGFR signaling pathway using archival or 
fresh tumor biopsy material.
-
Study Part 2 / MTD expansion cohort (sqNSCLC + BC): Subjects will be eligible 
for Part 2 only if they have histological or cytological confirmed squamous non-
small cell lung cancer (sqNSCLC) or bladder cancer (BC). 
All subjects in Part 2 (MTD expansion cohort “sqNSCLC + BC”) will be 
stratified according to high FGFR expression levels and the presence or absence 
of additional genetic alterations in the FGFR signaling pathway using archival or 
fresh tumor biopsy specimen. 
BC subjects with low overall FGFR expression levels can be included if activating 
FGFR3 mutations are confirmed. 

Subjects must have at least one measurable or evaluable lesion according to 
Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. A lesion in a 
previously irradiated area is eligible and to be considered as measurable disease as long as 
there is objective evidence of progression of the lesion prior to study enrollment. 

Subjects with resected primary tumors who have documented metastases are 
eligible.

Existence of an archival biopsy is mandatory for stratification of subjects included 
in the expansion cohorts at MTD in Part 1 (all comer) and Part 2 (sqNSCLC + BC). If no 


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archival biopsy is available for a subject assigned to the MTD expansion cohort “all 
comer” (Part 1) respectively to the MTD expansion cohort “sqNSCLC + BC” (Part 2), 
fresh tumor biopsy material is required for stratification. 

A pre-treatment biopsy at screening and a second biopsy on Cycle 2, Day 1 will be
obtained from all subjects who agreed on repeated biopsies.
The following rules apply to subjects participating in study Part 1and study Part 2:
Study Part 1 / dose escalation (all comer):
-
Biopsies for biomarker studies are optional for subjects enrolled to the dose-
escalation cohorts.
Study Part 1 / MTD expansion cohort (all comer):
-
Both a pre-treatment biopsy (screening) and a second biopsy (Cycle 2, Day 1) for 
biomarker studies are mandatory for all subjects in the MTD expansion cohort. 
Material from the mandatory pre-treatment biopsy may be used for stratification of 
subjects if no archival biopsy is available at screening.
Study Part 2 / MTD expansion cohort (sqNSCLC + BC):
-
A pre-treatment biopsy for stratification is only mandatory for subjects for whom 
no archival biopsy is available.
-
Biopsies for biomarker studies are optional for all subjects with archival biopsies.
Note: Anticancer chemotherapy must have been stopped for at least 5 half-lives of 
the last applied therapy before the pre-treatment biopsy is taken. Mitomycin C or 
nitrosoureas should not be given within 6 weeks of pre-treatment biopsy.
…

Adequate bone marrow, liver and renal function as assessed by the following 
laboratory requirements conducted within 7 days of starting the study treatment:
…
-
Amylase and lipase ≤ 1.5 x ULN
-
Not more than mild hepatic impairment, Child-Pugh score A
-
…
New text:
5.1.1.1
Eligibility criteria for FGFR expression / FGFR mutation testing (only for 
MTD expansion cohorts of study Part 1 and Part 2)

Ability to understand and willingness to sign the written subject information sheet / 
informed consent form (SIS / ICF) for FGFR expression / FGFR mutation testing (see 
Section 11.2). Signed informed consent (IC) has to be obtained before any study specific 
procedure. 


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
Subjects with histologically or cytological confirmed, refractory, locally advanced 
or metastatic solid tumors (all comer for study Part1; sqNSCLC, LAC, BC or SCCHN for 
Part 2) who are not candidates for standard therapy. 

Male or female subjects ≥18 years of age

Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or 2

Life expectancy of at least 3 months

Existence of archival or fresh tumor biopsy specimen for FGFR expression / FGFR 
mutation testing

Besides these basic criteria, any criterion as outlined below under inclusion and exclusion 
criteria (Sections 5.1.1.2 and 5.1.2) already known to prohibit the patient’s participation in 
the study should be considered.  
5.1.1.2 Eligibility criteria for study treatment
Screening for study treatment eligibility must be performed within 7 days / within 28 days 
prior to the first dose of study drug. Subjects must fulfill all of the following criteria 
before being included in the treatment phase (i.e, before receiving any dose of BAY 
1163877):

Ability to understand and willingness to sign the written SIS / ICF for study 
treatment eligibility. Signed IC obtained before any further study specific procedure. 

Subjects with histologically or cytological confirmed, refractory, locally advanced 
or metastatic solid tumors who are not candidates for standard therapy. 
Subjects with any type of solid tumors (all comer) will be eligible for dose escalation and 
dose expansion at MTD in Part 1.

Subjects enrolled in the MTD expansion cohorts of Study Part 1 and Part 2 must 
present high FGFR expression levels based on archival or fresh tumor biopsy specimen 
analysis.
Bladder cancer subjects with low overall FGFR expression levels can be included if 
activating FGFR3 mutations are confirmed. 
(only for MTD expansion cohorts of study Part 1 (all comer) and Part 2 (sqNSCLC + 
LAC +BC + SCCHN))

Subjects must have at least one measurable or evaluable lesion according to 
Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. A lesion in a 
previously irradiated area is eligible and to be considered as measurable disease as long as 
there is objective evidence of progression of the lesion prior to study enrollment. 

Subjects with resected primary tumors who have documented metastases are 
eligible.

Subjects consent to undergo a paired biopsy at screening and on Cycle 2, Day 1
(only for MTD expansion cohorts of study Part 1(all comer))


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Note: Anticancer chemotherapy must have been stopped for at least 5 half-lives of 
the last applied therapy before the pre-treatment biopsy is taken. Mitomycin C, 
nitrosoureas or monoclonal antibodies with anticancer activity (e.g. bevacizumab or 
cetuximab etc.) should not be given within 6 weeks of pre-treatment biopsy for 
biomarker (p-ERK1/2) studies.
…

Adequate bone marrow, liver and renal function as assessed by the following 
laboratory requirements conducted within 7 days of starting the study treatment:
…
Amylase and lipase ≤ 2.5 x ULN
Not more than Child-Pugh score B7 hepatic impairment
…
Section 5.1.2: Exclusion criteria
This section was changed as a result of Modification 1 and 3.
Old text:
Subjects are to be excluded from the study if they display any of the following criteria:
Medical and surgical history

For “all comer” subjects to be enrolled in study Part 1 / MTD expansion: 
-
No consent to mandatory biopsies at screening and on Cycle 2, Day 1. 
-
Low FGFR expression levels quantified by RNA in situ-hybridization (RNAscope 
score ≤ 3). 

For subjects with sqNSCLCto be enrolled in study Part 2 / MTD expansion:
-
No archival biopsy available and no consent to pre-treatment biopsy.
-
Low FGFR expression levels quantified by RNA in situ-hybridization (RNAscope 
score ≤ 3).

For subjects with BC to be enrolled in study Part 2 / MTD expansion:
No archival biopsy available and no consent to pre-treatment biopsy.
Low FGFR expression levels quantified by RNA in situ-hybridization (RNAscope 
score ≤ 3) and having no activating mutation in FGFR3 gene.

Previous or concurrent cancer …
…

Moderate and severe hepatic impairment, Child-Pugh B or C
…


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Medication, drug use and special behavioral patterns
…

Anticancer chemotherapy or immunotherapy during the study or within 5-half-
lives prior to start of study treatment. Mitomycin C or nitrosoureas should not be given 
within 6 weeks of start of study treatment. Acute toxic effects …
…
New text:
Subjects are to be excluded from the study if they display any of the following criteria:
5.1.2.1
Exclusion criteria for FGFR expression / FGFR mutation testing (only for 
MTD expansion cohorts of study Part 1)

No archival biopsy available and no consent to obtain tumor biopsy. 

Subject still on anticancer treatment or in the washout period of a previous 
anticancer treatment (defined as 5 half-lives of the anticancer agent [or 6 weeks for 
monoclonal antibodies]) at the time the fresh biopsy would be obtained if no archival 
biopsy is available.
5.1.2.2
Exclusion criteria for FGFR expression / FGFR mutation testing (only for 
MTD expansion cohorts of study Part 2)

No archival biopsy available and no consent to obtain tumor biopsy.
5.1.2.3
Exclusion criteria

FGFR testing shows low FGFR expression levels
(only for MTD expansion cohorts of study Part 1 (all comer) and Part 2 (sqNSCLC + LAC 
+ SCCHN))

No consent for mandatory paired biopsies for biomarker
(only for MTD expansion cohorts of study Part 1 (all comer))

FGFR expression / FGFR mutation testing shows low FGFR expression levels and 
absence of activating mutation in FGFR3 gene
(only for Part 2 (BC))
Medical and surgical history

Previous or concurrent cancer …
…
Medication, drug use and special behavioral patterns
…

Anticancer chemotherapy or immunotherapy during the study or within 5-half-
lives prior to start of study treatment. Mitomycin C, nitrosoureas or monoclonal antibodies 
with anticancer activity (e.g. bevacizumab or cetuximab etc.) should not be given within 6 
weeks of pre-treatment biopsy for biomarker (p-ERK1/2) studies. Acute toxic effects …


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…
Section 5.2.2: Replacement 
This section was changed as a result of Modification 7.
Old text:
Subjects who discontinue due to a DLT will NOT be replaced.
Subjects who discontinue during the first cycle of therapy (Cycle 1) due to any reason 
other than a DLT and / or related toxicity, and subjects who took less than 80% of the 
required study drug (BAY 1163877) in Cycle 1 (see Section 6.7) will be replaced to
ensure 3 evaluable subjects per cohort for the determination of MTD and PK of 
BAY 1163877. Subjects who discontinue after the first cycle (Cycle 1) will not be 
replaced. 
New text:
Subjects who discontinue due to a DLT will NOT be replaced.
Subjects who discontinue during the first cycle of therapy (Cycle 1) due to any reason 
other than a DLT and / or related toxicity, and subjects who took less than 80% of the 
required study drug (BAY 1163877) in Cycle 1 (see Section 6.7) will be replaced to 
ensure 3 evaluable subjects per cohort for the determination of MTD and PK of 
BAY 1163877. Subjects who discontinue after the first cycle (Cycle 1) will not be 
replaced.
Subjects enrolled in Study Part 1 / MTD expansion (all comer) with insufficient paired 
biopsy samples will be replaced to ensure at least 10 subjects with paired biopsy samples 
for p-ERK1/2 analysis. 
Section 5.3: Subject identification 
This section was changed as a result of Modification 2.
Old text:
Each subject who signs a consent form for the study and undergoes any screening 
procedure(s) will be assigned a unique 9-digit screening number (SNR) in ascending order 
of recruitment into the study at that center. The first 2 digits will refer to the country, the 
subsequent 3 digits to the site number, and the following 4 digits will be subject 
identifiers. 
…
New text:


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Each subject who signs a consent form for the study will be assigned a unique 9-digit 
screening number (SNR) in ascending order of recruitment into the study at that center. 
The first 2 digits will refer to the country, the subsequent 3 digits to the site number, and 
the following 4 digits will be subject identifiers. 
…
Section 6.1: Treatments to be administered - amended
This section was changed as a result of Modifications 1 and 4.
Old text:
In study Part 1 / dose escalation + MTD expansion (all comer), …
… 
In study Part 2 / MTD expansion (sqNSCLC + BC), …
… 
New text:
In study Part 1 / dose escalation + MTD expansion (all comer), …
… 
In study Part 1 / MTD expansion (all comer), subjects will receive the MTD of 
BAY 1163877 determined at the end of dose escalation.
For the “food effect assessment”, subjects will receive one single dose of BAY 1163877 
on Cycle 1, Day -3 after consumption of a high-fat, high-calorie breakfast, and a second 
single dose BAY 1163877 on Cycle 1, Day 1 after an overnight fast of at least 8 hours. 
Further details are provided in Section 6.4.2.2.1. 
In study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN), …
… 
Section 6.3: Treatment assignment
This section was changed as a result of Modification 2.
Old text:
After completion of the screening examinations, subjects who meet the entry criteria will 
be placed in the current cohort at the specified dose level. A random list is not necessary 
because this is a non-randomized open label clinical trial. All subjects will be assigned a 
unique screening number (SNR), whether or not they are treated after the first signed 
informed consent. For subject identification, see Section 5.3.


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New text:
After completion of the screening examinations, subjects who meet the entry criteria will 
be placed in the current cohort at the specified dose level. A random list is not necessary 
because this is a non-randomized open label clinical trial. All subjects will be assigned a 
unique screening number (SNR), whether or not they are treated after the first signed 
informed consent. For subject identification, see Section 5.3.
Section 6.4.2: Selection and timing of dose for each subject - amended
This section was changed as a result of Modifications 1 and 10.
Old text:
…. Dose escalation for subsequent cohorts will only be considered after full evaluation of 
at least the first Cycle of all subjects from the previous cohort.
Extent and duration of drug exposure of the individual subject in study Part 2 / dose 
expansion (sqNSCLC + BC) are given in Section 4.
New text:
…. Dose escalation for subsequent cohorts will only be considered after all subjects from 
the previous cohort have completed the first cycle or early discontinued.
Extent and duration of drug exposure of the individual subject in study Part 2 / dose 
expansion (sqNSCLC + LAC + BC + SCCHN) are given in Section 4.
Section 6.4.2.1: Dosing schedule - amended
This section was changed as a result of Modification 1 and 4.
Old text:
Study Part 2 / dose expansion (sqNSCLC + BC):

…

…
Evidence of tumor progression, …
New text:
Study Part 2 / dose expansion (sqNSCLC + LAC + BC + SCCHN):

…

…


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Study Part 1 (MTD expansion cohort) or Study Part 2 / “Food Effect Assessment”: 
Approximately 8 subjects will receive single doses of BAY 1163877 on Cycle 1, Day -3 
(after consumption of a high-fat, high-calorie breakfast) and on Cycle 1, Day 1 (after an 
overnight fast of at least 8 hours). BAY 1163877 will not be administered on Cycle 1, 
Day -2 and Day -1, in the evening of Cycle 1, Day 1 and on Cycle 1, Day 2. 
Evidence of tumor progression, …
Section 6.4.2.2: Mode of administration - amended
This section was changed as a result of Modification 4.
Old text:
BAY 1163877 will be administered per os (p.o.) at least 1 hour before or 2 hours after a 
meal or snack. 
The ready-to-use solution …
New text:
BAY 1163877 will be administered per os (p.o.) at least 1 hour before or 2 hours after a 
meal or snack. Subjects participating in “food effect assessment” will receive a single dose 
after consumption of high-fat, high-calorie meal (Cycle 1, Day -3) and a single dose after 
an overnight fast of at least 8 hours (Cycle 1, Day 1) see Section 6.4.2.2.1.
The ready-to-use solution …
Section 6.4.2.2.1: Food effect assessment 
This section was changed as a result of Modification 4.
Old text:
Not applicable (new section).
New text:
To assess the effect of food on the PK of BAY 1163877, a single dose of BAY 1163877 
will be administered immediately (within 5 minutes) after consumption of a high-fat, high-
calorie breakfast on Cycle 1, Day -3 followed by PK profiling in subjects participating in 
the MTD expansion cohorts of study Part 1 and Part 2.  
Examples of high-fat, high-calorie breakfast: 
50 grams of smoked cooked ham, 30 grams of chicken liver sausage, 50 grams of 
rye bread, 7 ounces (210 mL) whole milk, 40 grams of butter, 30 grams of butter cheese 
and 17 Crispbread Wasa Mjölk
2 eggs (fried), 2 strips of bacon, 2 slices of bread toast, 8 ounces (240 mL) whole 
milk and 3 teaspoons of butter (for frying and for toast) 


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High-fat, high-calorie breakfast may be adapted depending on the country while 
maintaining similar fat and calorie content (approximately 50 % fat and 800 to 1000 
calories). Breakfast should be consumed within 25 minutes. No snack is permitted for 
4 hours after study drug administration.  
BAY 1163877 will not be administered on Cycle 1, Day -2 and Day -1.
A single dose of BAY 1163877 will be administered on Cycle 1, Day 1 after an overnight 
fast of at least 8 hours (water is allowed ad libitum) followed by PK profiling. No food or 
snack is permitted for 4 hours after drug administration, but water is allowed 1 hour after 
dosing.  
Study drug will not be administered in the evening of Cycle 1, Day 1 and on Cycle 1, 
Day 2 (“drug-free day”). 
Starting with Cycle 1, Day 3, BAY 1163877 will be taken twice daily (at least 1 hour 
before or 2 hours after a meal).
Section 6.4.2.3: Treatment duration - amended
This section was changed as a result of Modification 4.
Old text:
…
For subjects in the “tablet bridging cohort” treatment starts on Cycle 1, Day -3.
…
New text:
…
For subjects in the “tablet bridging cohort” and “food effect assessment”, treatment starts 
on Cycle 1, Day -3.
…
Section 7.1.2: Timing of assessment
This section was changed as a result of Modifications 1, 2, 4, 5, 6, 8, 9 and 10.
Old text:
If not stated otherwise…
7.1.2.1
Screening 
Pre-study examinations will be performed within 28 days before first administration of 
BAY 1163877 (i.e. before Cycle 1, Day 1) ... 


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…
Study specific required screening examinations will only be performed after having 
received the subject’s written informed consent.
The following examinations will be performed prior to the first study drug administration:
Within 28 Days Prior to First Dose of BAY 1163877  

Signed informed consent (within 28 days or earlier)

Inclusion / exclusion criteria

Demographic data

Documentation of the primary diagnosis (refractory, locally advanced or metastatic 
solid tumor) using the complete pathological report 

Complete medical / oncological history, TNM classification (see Section 7.2.3) 

…

ECOG performance status assessment 

…

CT scans of the chest, abdomen and pelvis; CT scans of other metastatic lesions as 
applicable or MRI and documentation of lesion(s) according to RECIST, v1.1. CT/MRI 
scans prior screening can be used for documentation according to RECIST, v1.1, if scans 
were done the latest 28 days prior to first dose of BAY 1163877 (see Section 7.3.1)

Obtain pre-treatment biopsy: mandatory for all subjects in the MTD expansion 
cohort of Part 1 (all comer), mandatory for all subjects in the MTD expansion cohort of 
Part 2 (sqNSCLC +BC) for whom no archival biopsy is available, voluntary for all other 
study subjects) depending on necessity of wash-out period of potential previous anti-
cancer therapy and send to laboratory for biomarker evaluation, see Table 14–5, Table 14–
6 and Table 14–7.

Stratification of subjects to be enrolled in MTD expansion cohorts of Part 1 (all 
comer) and Part 2 (sqNSCLC +BC): Obtain archival tissue samples for subject 
stratification according to biomarker assessment. If no archival biopsy is available, 
material from a pre-treatment biopsy is required for stratification, see Table 14–6 and 
Table 14–7.
Within 7 Days Prior to First Dose of BAY 1163877 

…
7.1.2.2
Randomization
…
7.1.2.3
Treatment – amended
…
7.1.2.3.1
Cycle 1 - amended


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For “tablet bridging cohort” cohort only:
Day -3 to Day -1 (possible overnight stay)
Day -3

…

Single oral administration of BAY 1163877 tablet formulation 

… 
Days 1-3 (possible overnight stay)
Day 1

…

Measurement of body temperature and body weight (measurement of weight not 
required for subjects in the “tablet bridging cohort”)

…

PK sampling (all subjects of study Part 1 and at least 12 subjects of study Part 2)

Dispense of study medication (BAY 1163877) and diary
Oral administration of BAY 1163877 (single dosing for subjects with PK
     assessment, twice daily dosing for subjects without PK assessment)

Toxicities / AE assessment and recording (if applicable)
Day 2  

No administration of BAY 1163877 (“drug-free day”) for subjects with PK 
assessment (all subjects of study Part 1 and at least 12 subjects with PK assessment in 
study Part 2)

…
7.1.2.3.2
Subsequent Cycles
Day 1 (Visit)

...

Blood (serum) samples collection for biomarker tests, see Table 14–5 - Table 14–7

Obtain second biopsy: mandatory for all subjects in the MTD expansion cohort of 
Part 1 (all comer), voluntary for all other subjects, and send to laboratory, see Table 14–5, 
Table 14–6 and Table 14–7.

…
End of Every Second Cycle 


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
…
End of Cycle 2, then after every 3rd cycle

…
7.1.2.3.3
Follow up
An End of Treatment (EOT) visit will be performed within 7-14 days after the last study 
drug administration. 
…
Within 7-14 Days of Last Study Drug Administration (EOT Visit)

…
New text:
7.1.2
Timing of assessment
If not stated otherwise …
…
7.1.2.1
Pre-treatment - amended
7.1.2.1.1
FGFR expression / FGFR mutation testing (MTD expansion cohorts 
only)
A separate subject information sheet / informed consent form (SIS / ICF) for FGFR 
expression / FGFR mutation testing must be signed by all subjects recruited for study Part 
1 or Part 2 MTD expansion cohort (see Section 11.2). 
The following activities / examinations will be performed prior to FGFR expression / 
FGFR mutation testing:

Signed informed consent for FGFR expression / FGFR mutation testing  

Inclusion criteria limited to FGFR expression / FGFR mutation testing (see 
Section 5.1.1.1) 

ECOG performance status assessment

Demographic data 

Documentation of the primary diagnosis (refractory, locally advanced or metastatic 
solid tumor) using the complete pathological report

Complete medical /oncological history, TNM classification (see Section 7.2.3)

Obtain archival tumor tissue sample for FGFR expression / FGFR mutation testing
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 


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
Toxicity / AE assessment and recording 
All subjects enrolled into the study will be listed on a subject enrollment log provided by 
the sponsor’s representatives.
7.1.2.1.2
Screening 
Pre-study examinations will be performed within 7 days / within 28 days before first 
administration of BAY 1163877 (i.e. before Cycle 1, Day 1) ... 
… 
Study specific required screening examinations will only be performed after having 
received the subject’s written IC for study treatment eligibility. The subject 
information sheet / informed consent form (SIS / ICF) for study treatment eligibility must 
be signed by all subjects including those subjects presenting FGFR expression / FGFR 
mutation who have signed the SIS / ICF for FGFR expression / FGFR mutation testing 
before (see Section 7.1.2.1.1).
The following examinations will be performed prior to the first study drug administration:
Within 28 Days Prior to First Dose of BAY 1163877  

Signed informed consent for study treatment eligibility (within 28 days or earlier), 
see Section 11.2.

Inclusion / exclusion criteria

Demographic data (already collected for subjects of Part 1 or Part 2 MTD 
expansion cohorts, see Section 7.1.2.1.1)

Documentation of the primary diagnosis (refractory, locally advanced or metastatic 
solid tumor) using the complete pathological report (already done for subjects of Part 1 or 
Part 2 MTD expansion cohorts, see Section 7.1.2.1.1)

Complete medical / oncological history, TNM classification (see Section 7.2.3) 
(already done for subjects of Part 1 or Part 2 MTD expansion cohorts, see Section 
7.1.2.1.1)

…

ECOG performance status assessment (also for subjects of Part 1 or Part 2 MTD 
expansion cohorts, see Section 7.1.2.1.1)

…

CT scans of the chest, abdomen and pelvis; CT scans of other metastatic lesions as 
applicable or MRI and documentation of lesion(s) according to RECIST, v1.1. CT/MRI 
scans prior screening can be used for documentation according to RECIST, v1.1, if scans 
were done the latest 28 days prior to first dose of BAY 1163877 (see Section 7.3.1)

Virology tests, for details see Table 14–4

Obtain pre-treatment biopsy: 


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-
optional for subjects in the dose escalation cohorts of study Part 1 (all comer)
-
mandatory for all subjects in the MTD expansion cohort of Part 1 (all comer).
-
optional for subjects in the MTD expansion cohort of Part 2 (sqNSCLC + LAC + 
BC + SCCHN)
-
Note 1: A biopsy is mandatory for all subjects in the MTD expansion cohort of 
Part 1 and Part 2 for whom no archival biopsy is available for FGFR expression / 
FGFR mutation testing. Additional biopsy is not requested if a biopsy was already 
obtained for FGFR expression / FGFR mutation testing prior to the screening visit 
(see Section 7.1.2.1.1). 
Note 2: Anticancer chemotherapy must have been stopped for at least 5 half-lives of 
the last applied therapy before the pre-treatment biopsy is taken. Mitomycin C, 
nitrosoureas or monoclonal antibodies with anticancer activity (e.g. bevacizumab or 
cetuximab etc.) should not be given within 6 weeks of pre-treatment biopsy for 
biomarker (p-ERK1/2) studies.
Within 7 Days Prior to First Dose of BAY 1163877 

…
7.1.2.2
Randomization
…
7.1.2.3
Treatment – amended
…
7.1.2.3.1
Cycle 1 - amended
For “tablet bridging cohort” or “food effect assessment” only:
Day -3 to Day -1 (possible overnight stay)
Day -3

…

Single oral administration of BAY 1163877 tablet formulation (“tablet bridging 
cohort” only)

Single oral administration of BAY 1163877 immediately after consumption of 
high-fat, high-calorie meal as specified in Section 6.4.2.2.1 (“food effect assessment” 
only)

… 
Days 1-3 (possible overnight stay)
Day 1

…


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
Measurement of body temperature and body weight (measurement of weight not 
required for subjects in the “tablet bridging cohort” and for subjects with “food effect 
assessment”)

…

PK sampling (all subjects of study Part 1 and at least 12 subjects of study Part 2)

Urine collection for PK analysis (to be performed in approximately 8 subjects in 
Part 1 or Part 2 MTD expansion cohorts, see Section 7.4.2.1)

Dispense of study medication (BAY 1163877) and diary
Oral administration of BAY 1163877 (single dosing for subjects with PK
     assessment, twice daily dosing for subjects without PK assessment)
Oral administration of a single dose of BAY 1163877 after at least 8 hours of 
     overnight fast as specified in Section 6.4.2.2.1 (“food effect assessment” only)

Toxicities / AE assessment and recording (if applicable)
Day 2  

No administration of BAY 1163877 (“drug-free day”) for subjects with PK 
assessment (all subjects of study Part 1 and at least 12 subjects with PK assessment in 
study Part 2 [including “food effect assessment”])

…
7.1.2.3.2
Subsequent Cycles (Cycles 2-12)
Day 1 (Visit)

Measurement of body temperature and body weight 

...

Blood (serum) samples collection for biomarker tests, see Table 14–5 - Table 14–7

Only on Day 1 of Cycles 2, 3, 4 and 5: Blood (plasma) sample collection for 
exposure-response modelling at pre-dose and between 0.5 and 1.5 hours post-dose in all 
subjects participating in the MTD expansion cohorts of study Part 1 and part 2, see Table 
14–3. The dose needs to be taken under supervision and the time recorded. 

Only on Day 1 of Cycle 2: Obtain second biopsy: mandatory for all subjects in the 
MTD expansion cohort of Part 1 (all comer), voluntary for all other subjects, and send to 
laboratory, see Table 14–5, Table 14–6 and Table 14–7.

…
End of Cycle 2 and every 2nd subsequent Cycle (i.e., end of Cycles 2, 4, 6, 8, 10, 12)

…
End of Cycle 2 and every 3rd subsequent Cycle (i.e., end of Cycles 2, 5, 8, 11)

…


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7.1.2.3.3
Subsequent Cycles (Cycles ≥13)
Day 1 (Visit)

Update of concomitant therapy

Physical examination

Ask subject for changes in vision

Cardiovascular assessment (BP and HR) 

Measurement of body temperature and body weight 

12-lead ECG, single reading (see Section 7.5.3.4)  

ECOG performance status

Blood and urine collection for safety laboratory tests (repetitions for controls may 
be necessary), for details see Table 14-4

Calculation of eGFR (see Section 14.9)

Blood (serum) samples collection for biomarker tests, see Table 14-5 - Table 14-7

Oral administration of BAY 1163877 

Toxicities / AE assessment and recording (if applicable)
Day 11 (Visit)

Update of concomitant therapy

Physical examination

Ask subject for changes in vision

Cardiovascular assessment (BP and HR) 

ECOG performance status

Blood and urine collection for safety laboratory tests (repetitions for controls may 
be necessary), for details see Table 14-4

Calculation of eGFR (see Section 14.9)

Blood (serum) samples collection for biomarker tests, see see Table 14-5 - Table 
14-7

Oral administration of BAY 1163877 

Toxicities / AE assessment and recording (if applicable)
End of Cycle 14 and every 2nd subsequent Cycle (i.e., end of Cycles 14, 16, 18, …)

Send subject to consultant ophthalmologist for ophthalmological examination and 
review certificate


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End of Cycle 14 and every 3rd subsequent Cycle (i.e., end of Cycles 14, 17, 21, …)

CT scans of the chest, abdomen and pelvis; CT scans of other metastatic lesions as 
applicable or MRI and documentation of response according to RECIST, v1.1 (see 
Section 7.3.1)
7.1.2.3.4
Follow up
An End of Treatment (EOT) visit will be performed within 0-14 days after the last study 
drug administration. 
…
Within 0-14 Days of Last Study Drug Administration (EOT Visit)

…
Section 7.4.1.1: Cardiovascular assessment - amended
This section was changed as a result of Modification 4.
Old text:
…
BP and HR will be measured at the following time points:

Screening (one measurement within 7 days before start of treatment)

Cycle 1, Day -3 to Day -1 (“tablet bridging cohort” only)
New text:
…
BP and HR will be measured at the following time points:

Screening (one measurement within 7 days before start of treatment)

Cycle 1, Day -3 to Day -1 (“tablet bridging cohort” and “food effect assessment” 
only)


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Section 7.4.2.1: Drug measurements - amended
This section was changed as a result of Modifications 1, 4, 5 and 6.
Old text:
Pharmacokinetics of BAY 1163877 will be evaluated on Cycle 1, Day -3 (“tablet bridging 
cohort”, only), Cycle 1, Day 1 after single-dose administration, and on Cycle 1, Day 15 
after multiple-dose administration of BAY 1163877 at the respective dose level achieved 
during dose escalation.
Pharmacokinetic assessments will be performed in all subjects enrolled in Part 1 (dose 
escalation and MTD expansion (all comer) cohorts). The plan is to perform 
pharmacokinetic assessments in at least 12 subjects in Part 2 MTD expansion cohort 
(sqNSCLC + BC) such that valid PK data are available in 8 subjects. 
Blood (plasma) samples for PK assessment of BAY 1163877 will be collected at the 
following time points:

Cycle 1, Day -3 (“tablet bridging cohort” only): single-dose PK
-
… 

Cycle 1, Day 1: single-dose PK
… 

Cycle 1, Day 15: multiple-dose PK
…
…
When blood pressure measurement and PK sample collection are scheduled at the same 
time point, subject’s blood pressure will be measured before collection of the PK sample
Plasma concentrations of BAY 1163877 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 
(most likely at the MTD or the therapeutic dose). Specifically, if performed at the MTD, 
this will be done initially in 2 subjects (highest and lowest BAY 1163877 area under the 
curve (AUC)).
New text
Pharmacokinetics of BAY 1163877 will be evaluated on Cycle 1, Day -3 (“tablet bridging 
cohort” and “food effect assessment”, only), on Cycle 1, Day 1 after single-dose 
administration, and on Cycle 1, Day 15 after multiple-dose administration of 
BAY 1163877 at the respective dose level achieved during dose escalation.
Pharmacokinetic assessments will be performed in all subjects enrolled in Part 1 (dose 
escalation and MTD expansion (all comer) cohorts). The plan is to perform 


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pharmacokinetic assessments in at least 12 subjects in Part 2 MTD expansion cohort 
(sqNSCLC + LAC + BC + SCCHN) such that valid PK data are available in 8 subjects.
“Food effect assessment” will be performed in approximately 8 subjects enrolled in the 
MTD expansion cohorts (study Part 1 and Part 2).
Blood (plasma) samples for PK assessment of BAY 1163877 will be collected at the 
following time points:

Cycle 1, Day -3 (“tablet bridging cohort” and “food effect assessment” only): 
single-dose PK
… 

Cycle 1, Day 1: single-dose PK
-
… 

Cycle 1, Day 15: multiple-dose PK
… 

Cycles 2-5, Day 1: exposure-response modelling
-
pre-dose (before supervised dose administration), and 1 (0.5) hour post-dose
…
When blood pressure measurement and PK sample collection are scheduled at the same 
time point, subject’s blood pressure will be measured before collection of the PK sample
24-hour urine collection: In approximately 8 subjects of the MTD expansion cohorts 
(study Part 1 and Part 2), on Cycle 1 Day 1, complete urine output will be collected over 
24 hours post administration in 0 to 12 hour and 12 to 24 hour intervals concurrently with 
plasma PK samples. For each subject, within each collection interval, the collected urine 
will be combined and the total volume of the combined urine will be determined. 
A representative aliquot of the pooled urine will be used to determine the concentration of 
BAY 1163877.
Plasma and urine concentrations of BAY 1163877 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 
(most likely at the MTD or the therapeutic dose) and in urine. 
Section 7.4.2.2: Pharmacokinetic evaluation - amended
This section was changed as a result of Modification 1, 4, 5 and 6.
Old text:
Primary PK parameters (plasma): BAY 1163877

Cycle 1, Day -3 (“tablet bridging cohort”) and Cycle 1, Day 1 single dose:


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Cmax, Cmax/D, AUC(0-12), AUC(0-12)/D,
AUC(0-tlast), AUC(0-tlast)/D, AUC, and AUC/D
AUC may not be calculated if it is not possible to estimate half-life
…
Pre-dose plasma concentrations (if additionally collected) will be used for monitoring 
purpose only.
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.
New text:
Primary PK parameters (plasma): BAY 1163877

Cycle 1, Day -3 (“tablet bridging cohort” and “food effect assessment” only) 
and Cycle 1, Day 1 single dose: Cmax, Cmax/D, AUC(0-12), AUC(0-12)/D,
AUC(0-tlast), AUC(0-tlast)/D, AUC, and AUC/D
AUC may not be calculated if it is not possible to estimate half-life
…
Pre-dose plasma concentrations (if additionally collected) will be used for monitoring 
purpose only.
Amount of BAY 1163877 excreted renally during 0 to 12 h (AE,ur(0-12)), 12 to 24 h 
(AE,ur(12-24)) and 0 to 24 h (AE,ur(0-24)) post-dose will be calculated at the MTD and 
also expressed as percent of dose administered.
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.
These samples collected on Day 1 of Cycles 2 through 5 at pre-dose and between 0.5 and 
1.5 hours post-dose will document a longitudinal exposure under steady state condition. 
No detailed dosing history is required before the pre-dose sample, but the dose that 
separates the pre- and post-dose sample needs to be taken under supervision and the time 
recorded. The longitudinal exposure data will be used in exposure-response modelling of 
adverse events and clinical responses.
Section 7.4.4: Biomarker investigations - amended
This section was changed as a result of Modifications 1, 2, 3, and 8.
Old text:


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…
Biomarker analysis in blood (serum) samples 
Blood (serum) samples for the quantification of fibroblast growth factor 23 (FGF23), 
phosphate and calcium levels will be collected as follows:

Study Part 1 / dose escalation + MTD expansion (all comer)
-
…
-
… 
-
Cycle ≥2:  Days 1*, 8*, 15*
-
EOT visit

Study Part 2 / MTD expansion (sqNSCLC + BC)
-
…
-
…
-
…
-
*Blood collection before administration of morning dose.
Biomarker analysis in TUMOR TISSUE
Biomarker analysis will be done at screening for subject stratification in the MTD 
expansion cohorts (Part 1: all comer; Part 2: sqNSCLC + BC) according to FGFR 
expression levels / pathway mutations using either an archival tumor tissue specimen or 
fresh tumor biopsy material (see Section 5.1.1: Inclusion criteria, and Section 7.4.4.1: 
Predictive marker investigation). … 

Study Part 1 / dose escalation (all comer):
-
…
-
…

Study Part 1 / MTD expansion (all comer):
-
… 
-
…

Study Part 2 / MTD expansion (sqNSCLC + BC):
… 
…
*Optional biopsy: Only for subjects who agreed on biopsy both at screening and on Cycle 2, Day 1.
Anticancer chemotherapy must have been stopped for at least 5 half-lives of the last 
applied therapy before the pre-treatment biopsy is taken. Mitomycin C or nitrosoureas 
should not be given within 6 weeks of pre-treatment biopsy.


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Tumor response evaluation …
…
New text:
…
Biomarker analysis in blood (serum) samples 
Blood (serum) samples for the quantification of fibroblast growth factor 23 (FGF23), 
phosphate and calcium levels will be collected as follows:

Study Part 1 / dose escalation + MTD expansion (all comer)
…
… 
Cycle 2-12:  Days 1, 8, 15
Cycles ≥13 Days 1 and 11
EOT visit

Study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN)
-
…
-
…
-
…
-
*Blood collection before administration of morning dose only for Cycle 1 of Part 1 
and Part 2.
Biomarker analysis in TUMOR TISSUE
Biomarker analysis will be done at pre-screening for subject stratification in the MTD 
expansion cohorts (Part 1: all comer; Part 2: sqNSCLC + LAC + BC + SCCHN) 
according to FGFR expression levels / FGFR mutation using either an archival tumor 
tissue specimen or fresh tumor biopsy material (see Section 5.1.1: Inclusion criteria, and 
Section 7.4.4.1: Predictive marker investigation). … 

Study Part 1 / dose escalation (all comer):
-
…
-
…

Study Part 1 / MTD expansion (all comer):
… 
…


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
Study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN):
-
… 
-
…
*Optional biopsy: Only for subjects who agreed on biopsy both at screening and on Cycle 2, Day 1.
Anticancer chemotherapy must have been stopped for at least 5 half-lives of the last 
applied therapy before the pre-treatment biopsy is taken. Mitomycin C, nitrosoureas or 
monoclonal antibodies with anticancer activity (e.g. bevacizumab or cetuximab etc.) 
should not be given within 6 weeks of pre-treatment biopsy for biomarker (p-ERK1/2) 
studies.
The evaluation of FGFR pathway mutations is planned retrospectively for subject in the 
MTD expansion cohorts.
Tumor response evaluation …
…
Section 7.4.4.1: Predictive marker investigations 
This section was changed as a result of Modifications 1 and 2.
Old text:
Prediction Biomarker:
For subjects to be enrolled in study Part 1 / MTD expansion (all comer) and subjects to be 
enrolled in Study Part 2 / MTD expansion (sqNSCLC + BC) biomarker analysis will be 
done prior study start (subject stratification) on either a fresh or archival tumor biopsy 
sample to confirm high fibroblast growth factor receptor (FGFR) expression levels and the 
presence or absence of additional genetic alterations in the FGFR signaling pathway (see 
Section 5.1.1: Inclusion criteria).
Rationale for the quantification of tumor FGFR-1 -2- and -3 levels by RNA in situ 
hybridization
Amplification of the FGFR1 8p12 gene locus has been observed in up to 20 % of 
sqNSCLC subjects (8)(9)(11). FGFR1 gene amplification is so far the one of the most 
frequently observed molecular alteration in sqNSCLC (30). Mutations in FGFR-encoding 
genes are rare in sqNSCLC subjects (< 2 %), whereas in bladder cancer, up to 70 % of all 
cases reveal mutations within FGFR3 gene (31). …
…
… In house data revealed that the best correlation with anti-tumor efficacy upon 
BAY1163877-treatment in preclinical cancer models was observed for total-FGFR mRNA 
tumor expression levels - including lung and bladder cancer models. …
... We therefore consider to stratify sqNSCLC and bladder cancer subjects to be enrolled 
in study Part 2 / MTD expansion by the quantification of total FGFR mRNA expression 


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levels in archival tissue samples using RNA in situ hybridization to exclude subjects that 
are unlikely to benefit from BAY1163877 therapy due to low overall FGFR target 
expression levels.
Rationale for the detection of genetic alterations in FGFR encoding genes and in 
FGFR pathway downstream signaling molecules
In subjects included in study Part 2 / MTD expansion (sqNSCLC + BC), genetic testing of 
tumor tissue may be necessary if a subject lacks a treatment response to BAY1163877 
despite FGFR overexpression in tumor -as revealed by RNA in situ hybridization.
…
Existence of such FGFR downstream pathway activating mutations in the case of lack of 
response to BAY1163877 treatment - despite high total FGFR mRNA tumor expression 
levels - should be evaluated retrospectively in subjects to be enrolled in study Part 2 / 
MTD expansion (sqNSCLC + BC).
…
We therefore consider genetic testing for FGFR3-activating mutations in bladder cancer 
subjects prior to treatment start - in case they lack high FGFR mRNA expression levels in 
tumor as revealed by RNA in situ hybdridization. 
For both investigations, DNA can be isolated from either tumor biopsy samples of 
archival tissue samples derived thereof.
New text:
Prediction Biomarker:
For subjects to be enrolled in study Part 1 / MTD expansion (all comer) and subjects to be 
enrolled in Study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN) biomarker 
analysis will be done prior study start (subject stratification) on either a fresh or archival 
tumor biopsy sample to confirm high fibroblast growth factor receptor (FGFR) expression 
levels / FGFR mutation (see Section 5.1.1: Inclusion criteria).
Rationale for the quantification of tumor FGFR-1 -2- and -3 levels 
Amplification of the FGFR1 8p12 gene locus has been observed in up to 20 % of 
sqNSCLC subjects (8)(9)(11). FGFR1 gene amplification is so far one of the most 
frequently observed molecular alteration in sqNSCLC (30). In SCCHN, the FGFR1 gene 
was amplified in about 15 % of all cases (38). In vitro experiments with BAY 1163877 
and published data with competitor compounds revealed equal sensitivity to proliferation 
inhibition by either adenocarcinoma or squamous subtype-derived lung cancer cell lines. 
In- house quantification of FGFR1-3 mRNA expression levels in patient-derived lung 
cancer tumors revealed a high FGFR1, 2 or 3 mRNA expression levels also in cases of 
lung adenocarinomas. In line with this, a recent publication confirmed a strong expression 
of FGFR1 mRNA also in adenocarcinoma biopsy samples in the absence of FGFR1 
amplification (39). Therefore, we suggest to include lung adenocarcinoma patients into 
Part 2 of the study. Mutations in FGFR-encoding genes are rare in sqNSCLC subjects (< 2 


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%), whereas in bladder cancer, up to 70 % of all cases reveal mutations within FGFR3 
gene (31). …
…
… In house data revealed that the best correlation with anti-tumor efficacy upon 
BAY1163877-treatment in preclinical cancer models was observed for total-FGFR mRNA 
tumor expression levels - including lung and bladder cancer models, and head and neck 
squamous cell cancer models. …
... We therefore consider to stratify sqNSCLC, LAC, BC and SCCHN subjects to be 
enrolled in study Part 2 / MTD expansion by the quantification of total FGFR mRNA 
expression levels in archival tissue samples in order to exclude subjects that are unlikely to 
benefit from BAY1163877 therapy due to low overall FGFR target expression levels.
Rationale for the detection of genetic alterations in FGFR encoding genes and in 
FGFR pathway downstream signaling molecules
In subjects included in study Part 1 / MTD expansion (all comer) and Part 2 / MTD 
expansion (sqNSCLC + LAC + BC + SCCHN), genetic testing of tumor tissue may be 
necessary if a subject lacks a treatment response to BAY1163877 despite FGFR 
overexpression in tumor.
…
Existence of such FGFR downstream pathway activating mutations in the case of lack of 
response to BAY1163877 treatment - despite high total FGFR mRNA tumor expression 
levels - should be evaluated retrospectively in subjects enrolled in study Part 1 / MTD 
expansion (all comer) and Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN).
…
We therefore consider genetic testing for FGFR3-activating mutations in bladder cancer 
subjects prior to treatment start - in case they lack high FGFR mRNA expression levels in 
tumor.


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Section 7.5.1.3: Assessments and documentation of adverse events
This section was changed as a result of Modifications 2 and 10.
Old text:
AEs observed, mentioned upon open questioning by a member of the investigator team or 
spontaneously reported by the subject, will be documented in the subject’s eCRF. AEs 
will be documented event based (using the CTCAE v4.03 guidelines). The observation 
phase for AEs will start with signing the Informed Consent and will end in general with 
the last visit of follow-up. Adverse events should be collected past 30 days after the study 
treatment stop for all AEs that were ongoing at the end of treatment as well as new SAEs 
(information may be obtained via phone call). The investigator is responsible for the 
grading of each category mentioned in Section 7.5.1.2.
…
If any subject dies within 30 days of last dose of study drug, the investigator will inform 
the sponsor and record the cause of death in detail within 24 hours on a SAE form.
…
New text:
AEs observed, mentioned upon open questioning by a member of the investigator team or 
spontaneously reported by the subject, will be documented (see Section 9.1 for details).
AEs will be documented event based (using the CTCAE v4.03 guidelines). The 
observation phase for AEs will start with signing the first Informed Consent and will end 
in general with the last visit of follow-up. Adverse events should be collected past 30-35
days after the study treatment stop for all AEs that were ongoing at the end of treatment as 
well as new SAEs (information may be obtained via phone call). The investigator is 
responsible for the grading of each category mentioned in Section 7.5.1.2.
…
If any subject dies within 30-35 days of last dose of study drug, the investigator will 
inform the sponsor and record the cause of death in detail within 24 hours on a SAE form.
…


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Section 7.5.3.4: Electrocardiogram (ECG) - amended
This section was changed as a result of Modification 4.
Old text:
…
12-lead ECG readings will be performed in the supine position at the following time 
points:

…

Cycle 1, Day -3 and Day -2 (triplicate ECG readings) [“tablet bridging cohort” 
only]

…
New text:
…
12-lead ECG readings will be performed in the supine position at the following time 
points:

…

Cycle 1, Day -3 and Day -2 (triplicate ECG readings) [“tablet bridging cohort” and
“food effect assessment” only]
…


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Section 7.5.4.2: Laboratory examinations
This section was changed as a result of Modification 2.
Old text:
…
Detailed information about the handling and labeling of the samples will be provided 
separately in the Laboratory Manual.
…
Tumor biopsies: 
-
Quantification of tumor p-ERK levels pre- and post-treatment by 
immunohistochemistry
In this clinical trial, tumor biopsies will be examined using immunohistochemistry 
in order to examine the relationship between tumor p-ERK and response to 
BAY 1163877 therapy. Paired tumor biopsies should be obtained prior to study 
entry (screening) and on Cycle 2, Day 1 (at the end of Cycle 1) for analysis of p-
ERK in tumor tissue. 
-
Quantification of tumor FGFR1,2 and 3 levels by RNA in situ hybridization
In this clinical trial tumor biopsies will be examined for FGFR1, FGFR2 and 
FGFR3 mRNA levels using RNA in situ hybridization from biopsy samples/ 
archival biopsy samples.
-
Evaluation of mutations in either FGFR encoding genes or in FGFR downstream 
pathway genes by PCR using Qiagen FGFR pathway mutation kit and genomic 
DNA from biopsy samples / archival tissue samples.
…
New text:
…
Detailed information about the handling and labeling of the samples will be provided in a 
separate document (e.g. Laboratory Manual).
…
Tumor biopsies: 
-
Quantification of tumor p-ERK levels pre- and post-treatment by 
immunohistochemistry
In this clinical trial, tumor biopsies will be examined using immunohistochemistry 
in order to examine the relationship between tumor p-ERK and response to 
BAY 1163877 therapy. Paired tumor biopsies should be obtained prior to study 
treatment and on Cycle 2, Day 1 (at the end of Cycle 1) for analysis of p-ERK in 


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tumor tissue. 
-
Quantification of tumor FGFR1,2 and 3 mRNA levels 
In this clinical trial tumor biopsies will be examined for FGFR1, FGFR2 and 
FGFR3 mRNA levels from biopsy samples/ archival biopsy samples.
-
Retrospective evaluation of mutations in either FGFR encoding genes or in FGFR 
downstream pathway genes from biopsy samples / archival tissue samples.
…
Section 7.6.1: Diary
This section was changed as a result of Modification 10.
Old text:
…
The daily records of study drug intake will be transferred to the database.
…
New text:
…
The daily records of study drug intake will be transferred to the database in accordance 
with the data entry guidelines.
…


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Section 8.4.5: Pharmacokinetic data - amended
This section was changed as a result of Modifications 4 and 5.
Old text:
…
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 by treatment using both linear and semilogarithmic scale.
Pharmacokinetic characteristics (tmax and 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.
…
… Based on these analyses, point estimates (LS-means) and exploratory 90% confidence 
intervals for the ratios (tablet/solution) of Cmax/D, 
AUC(0-tlast)/D, AUC/D will be calculated by retransformation of the logarithmic data 
using the intra-individual standard deviation of the ANOVA.
New text:
…
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 by treatment using both linear and semilogarithmic scale. The amount and 
percent of drug excreted into urine will be graphically illustrated for the sampling interval 
as well as for the whole sampling period (bar-charts for the individual data and the 
arithmetic mean including standard deviation).
Pharmacokinetic characteristics (tmax and 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. Amount and percent of drug excreted in urine 
will be described by arithmetic statistics, minimum, maximum and median.
…
…Based on these analyses, point estimates (LS-means) and exploratory 90% confidence 
intervals for the ratios (tablet/solution) of Cmax/D, 
AUC(0-tlast)/D, AUC/D will be calculated by retransformation of the logarithmic data 
using the intra-individual standard deviation of the ANOVA.
In order to evaluate the food effect, BAY 1163877 Cmax and AUC(0-tlast) on Cycle 1, 
Day -3 and Cmax and AUC(0-tlast) on Cycle 1, Day 1 will be compared. The logarithms of 
Cmax and AUC(0- tlast) will be analyzed using ANOVA including subject and food effects. 
Based on these analyses, point estimates (LS-means) and exploratory 90% confidence 
intervals for the ratios (high-fat, high-calorie meal / fasting) of Cmax and AUC(0- tlast) will 


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be calculated by retransformation of the logarithmic data using the intra-individual 
standard deviation of the ANOVA.
Section 8.6: Further analysis described and reported under separate cover
This section was changed as a result of Modification 6.
Old text:
Not applicable (new section).
New text:
In order to evaluate the exposure-response during 4 cycles, two blood samples will be 
collected on Day 1 of Cycles 2-5, one before and one after a supervised dose. The 
resulting longitudinal exposure data will be modelled together with occurrences of 
selected adverse events and documented clinical responses. Also longitudinally measured 
PD biomarkers will be modelled with this exposure data. Exposure-response models and 
simulations after alternative dosing schedules will be reported in a separate document.
Section 9.1: Data recording
This section was changed as a result of Modifications 2 and 10.
Old text:
Entries made in the eCRF must be either verifiable against source documents, or have 
been directly entered into the eCRF, in which case the entry in the eCRF will be 
considered as the source data.
A Source Document Checklist will be used at site to identify the source data for all points 
collected.
…

Results from pharmacokinetic analyses
The results of drug concentration measurements will be provided as electronic data files 
and transferred to Data Management, where the information necessary for evaluation will 
be added (e.g. administration and sampling time points, demographic data). This data set 
will be evaluated by the responsible pharmacokineticist. The complete pharmacokinetic 
evaluation will then be retransferred to Data Management.

Data recorded from “only screened subjects (screening failures)”
For screening failures, …
New text:


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It is the expectation of the sponsor that all data entered into the eCRF has source 
documentation available at the study site. Entries into the eCRF should be made as soon as 
possible.
A Source Document Checklist will be used at site to identify the source data for all points 
collected.
…

Results from pharmacokinetic analyses
The results of drug concentration measurements will be provided as electronic data files 
and transferred to Data Management, where the information necessary for evaluation will 
be added (e.g. administration and sampling time points, demographic data). This data set 
will be evaluated by the responsible pharmacokineticist. The complete pharmacokinetic 
evaluation will then be retransferred to Data Management.
Results from biomarker analyses
The results of biomarker analyses will be provided by the laboratories as electronic data 
files and transferred to Data Management, where the data is mapped into the database.
Results from ECG measurement
A part of the ECG analyses will be performed by Nabios. Nabios will send the electronic 
data files to Data Management, where the data is mapped into the database.

Data recorded during the FGFR expression / FGFR mutation testing period (MTD 
expansion cohorts only)
Limited data will be recorded for all subjects in the FGFR expression / FGFR 
mutation testing period as described below: 
-
Subject number
-
Demographic data
-
Cancer classification including primary diagnosis (all comer for study Part 1; 
sqNSCLC, LAC, BC or SCCHN for Part 2), complete medical / oncological 
history data and TNM classification
-
Life expectancy
-
ECOG Performance Status
-
Information on existence of an archival tumor biopsy specimen
-
Details on collection of fresh tumor material (if applicable)
-
Adverse events(s)

Data recorded from “only screened subjects (screening failures)” including pre-
screening
For screening failures, …


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Section 11.2: Subject information and consent
This section was changed as a result of Modifications 1 and 2.
Old text:
All relevant information on the study will be summarized in an integrated subject 
information sheet and informed consent form provided by the sponsor or the study center. 
A sample form is provided as a document separate to this protocol.
Based on this subject information sheet, the investigator or designee will explain all 
relevant aspects of the study to each subject prior to his / her entry into the study 
…
Only if the subject voluntarily agrees to sign the informed consent form and has done so, 
may he / she enter the study. Additionally, the investigator and other information provider 
(if any) will personally sign and date the form. The subject will receive a copy of the 
signed and dated form.
The signed informed consent statement is to remain in the ISF or, if locally required, in 
the subject’s note / file of the medical institution.
...
The informed consent form and any other written information provided to subjects will be 
revised whenever important new information becomes available that may be relevant to 
the subject’s consent, or there is an amendment to the protocol that necessitates a change 
to the content of the subject information and / or the written informed consent form. The 
investigator will inform the subject of changes in a timely manner and will ask the subject 
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
New text:
All relevant information on the study will be summarized in 2 separate integrated subject 
information sheet and informed consent forms (SIS / ICFs) provided by the sponsor or the 
study center. 
SIS / ICF for FGFR expression / FGFR mutation testing
For subject stratification in the MTD expansion cohorts (Part 1: all comer; Part 2: 
sqNSCLC + LAC + BC + SCCHN), a separate SIS / ICF  will be provided to subjects for 
FGFR expression / FGFR mutation testing. This separate SIS / ICF gives brief information 
on the study conduct, details on the tissue sample required to be taken to perform the tests 
along with information on possible risks. 
SIS / ICF for study treatment eligibility
All subjects who have interest to participate in this study (including those who are 
confirmed presenting the appropriate FGF receptor level, or - for bladder cancer subjects -


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who are confirmed carrying the FGFR mutation) will be provided the SIS / ICF for 
screening of study treatment eligibility no longer than 28 days prior to start of study 
treatment. 
Samples of the 2 SIS /ICFs are provided as a document separate to this protocol.
Based on the subject information sheet(s), the investigator or designee will explain all 
relevant aspects of the study to each subject prior to his / her entry into the study 
…
Only if the subject voluntarily agrees to sign the informed consent form(s) and has done 
so, may he / she enter the study. Additionally, the investigator and other information 
provider (if any) will personally sign and date the form(s). The subject will receive a copy 
of the signed and dated form(s).
The signed informed consent statement(s) is (are) to remain in the ISF or, if locally 
required, in the subject’s note / file of the medical institution.
...
The informed consent form(s) and any other written information provided to subjects will 
be revised whenever important new information becomes available that may be relevant to 
the subject’s consent, or there is an amendment to the protocol that necessitates a change 
to the content of the subject information and / or the written informed consent form(s). 
The investigator will inform the subject of changes in a timely manner and will ask the 
subject to confirm his / her participation in the study by signing the revised informed 
consent form(s). Any revised written informed consent form and written information must 
receive the IEC / IRB’s approval / favorable opinion in advance of use.
Section 12: Reference list
This section was changed as a result of Modifications 1 and 10.
Old text:
…
(36)
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, 
Carbone PP. (1982) Toxicity and Response Criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5: 649-55
(37)
Tibaldi F, Beck B, Bedding A (2008). Implementation of a Phase 1 Adaptive 
Clinical Trial in a Treatment of Type 2 Diabetes. Drug Information Journal: 42(05)
New text:
…
(36)
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, 
Carbone PP. Toxicity and Response Criteria of the Eastern Cooperative Oncology 


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Group. Am J Clin Oncol. 1982; 5: 649-55
(37)
Tibaldi F, Beck B, Bedding A. Implementation of a Phase 1 Adaptive Clinical 
Trial in a Treatment of Type 2 Diabetes. Drug Information Journal. 2008; 
42(05):455-465
(38)
von Mässenhausen A, Franzen A, Heasley LE, Perner S. FGFR1 as a novel 
prognostic and predictive biomarker in squamous cell cancers of the lung and the 
head and neck area. Ann Transl Med. 2013;1(3). doi: 10.3978/j.issn.2305-
5839.2013.06.08
(38)
Wynes MW, Hinz TK, Gao D, Martini M, Marek LA, Ware KE, Edwards MG, 
Böhm D, Perner S, Helfrich BA, Dziadziuszko R, Jassem J, Wojtylak S, Sejda A, 
Gozgit JM, Bunn PA Jr, Camidge DR, Tan AC, Hirsch FR, Heasley LE. FGFR1 
mRNA and protein expression, not gene copy number, predict FGFR TKI 
sensitivity acroll all lung cancer histologies. Clin Cancer Res, 2014 April 25 [Epup 
ahead of print] doi: 10.1158/1078-0432.CCR-13-3060


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Section 14.1: Study flow chart - amended
This section was changed as a result of Modifications 1, 2, 4-6, 8, 9 and 10.
Old text:
Table 14-1:
Study flow chart: Screening – Study Part 1 and Part 2
Screening
Measures / actions
Within 28 Days*
Within 7 Days*
before first study drug administration
Signed informed consent(A)
X
Inclusion / exclusion criteria
X
X
Demographic data
X
Documentation of the primary diagnosis (refractory, 
locally advanced or metastatic solid tumor) using the 
complete pathological report
X
Complete medical / oncological history
X
TNM classification
X
Concomitant diseases, NYHA grading
X
Review of baseline toxicities 
X
X
Baseline characteristics (smoking habits / history, 
alcohol consumption)
X
Previous therapy
X
Concomitant therapy
X
X
Physical examination 
X
Body height
X
Body weight / calculation of BMI(B)
X
Vital signs(C)
X
ECOG performance status
X
12-lead ECG(D)
X
Echocardiography or MUGA scan
X
Obtain pre-treatment biopsy(E)  
X
Stratification of subjects to be enrolled in MTD 
expansion cohorts (Part 1 and Part 2)(F)  
X
Blood / urine collection for safety lab tests(G)
X
Blood (serum) samples collection for biomarker 
investigations(H)
X
Only females: Urine pregnancy test
X
Calculation of eGFR(I)
X
Ophthalmological examination at consultant
X
CT / MRI scans 
X


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Table 14-1:
Study flow chart: Screening – Study Part 1 and Part 2
Documentation of lesion(s) according to 
RECIST v1.1
X
Adverse events(J)
X
*Pre-study examinations may require hospitalization for 1- 2 days.
(A)
Informed consent can be signed before 28-day screening phase.
(B)
…
(C)
... 
(D)
...
(E) 
A pre-treatment biopsy at screening will be obtained from all subjects who agreed on this. 
The biopsy sample will be sent to laboratory for biomarker evaluation, see Table 14–5, Table 
14–6 and Table 14–7.
A pre-treatment biopsy is optional … 
…for subjects in study Part 1 / dose-escalation (all comer).
…for subjects in study Part 2 / MTD expansion (sqNSCLC + BC) for whom an archival biopsy
    is available.
A pre-treatment biopsy is mandatory … 
…for subjects in study Part 1 / MTD expansion (all comer).
…for subjects in study Part 2 / MTD expansion (sqNSCLC + BC) who have no archival 
    biopsy. 
Anticancer chemotherapy must have been stopped for at least 5 half-lives of the last applied 
therapy before the pre-treatment biopsy is taken. Mitomycin C or nitrosoureas should not be 
given within 6 weeks of pre-treatment biopsy.
(F) 
Obtain archival tissue samples for stratification of subjects participating in the MTD expansion 
cohorts of study Part 1 (all comer) and study Part 2 (sqNSCLC + BC), see Table 14–6 and 
Table 14–7. If no archival material is available, fresh tumor biopsy material is required for 
stratification (see E: mandatory biopsy).
(G) 
Safety lab tests: see Table 14–4
(H)
...
(I)
...
(J)
...


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Table 13–3:
Study flow chart: Treatment (Cycle 1, Day -3 to Day -1) – Study Part 1 
and Part 2 
Measures / actions
TREATMENT 
(only for “tablet bridging cohort”)
Cycle 1
Day -3
Day -2
Day -1
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
PK blood sampling(F)
…
Administration of BAY 1163877 tablet (single dose)(G)
…
…
…
…
…
(A) 
…
(B)
…
(C) 
…
(D)
…
(E)
…
(F)
PK sampling will be done as follows (for details see Laboratory Manual):

…
(G)
Oral administration of BAY 1163877 tablet formulation on Cycle 1, Day -3 will be done by a 
member of the site.


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Table 14-3:
Study flow chart: Treatment (Cycle ≥ 1) and Follow-up – Study Part 1 and Part 2 
Measures / actions
TREATMENT
FOLLOW-UP
Cycle 1 
(21 days)
Cycle≥2
(21 days)
EOT Visit
Within 
7-14 days after 
last dose
FU-Visit / 
Phone Call(A)
At 30-35 days 
after last dose
Day (D)
D1
D2
D3
D8 ±1
D15
D1
D8 ±1
D15 ±1
Concomitant medication
…
…
…
…
…
…
…
…
…
…
Physical examination 
…
…
…
…
…
…
…
…
…
…
Ask subject for changes in vision(B)
…
…
…
…
…
…
…
…
…
…
Cardiovascular assessment(C)
…
…
…
…
…
…
…
…
…
Body temperature
…
…
…
…
…
…
…
Body weight
…
…
12-lead ECG readings(D)
…
…
…
…
…
ECOG performance status
…
…
…
…
…
…
…
…
…
Blood / urine collection for safety lab tests(E)
…
…
…
…
…
…
…
Calculation of eGFR(F)
…
…
…
…
…
…
…
Blood (serum) samples collection for 
biomarker investigations(G)
…
…
…
…
…
…
…
…
Obtain tumor biopsy for biomarker tests(H)
…
PK blood sampling(I)
…
…
Ophthalmological examination
…
…
CT / MRI scans and documentation of 
response according to RECIST v1.1
…
Dispense / return of BAY 1163877 and diary(J)
…
…
…
…
…
…
…
…
Continued
Table 14–3:
Study flow chart: Treatment (Cycle ≥ 1) and Follow-up – Study Part 1 and Part 2 (Continued)
Measures / actions
TREATMENT
FOLLOW-UP
Cycle 1 
(21 days)
Cycle≥2
(21 days)
EOT Visit
Within 
FU-Visit / 
Phone Call(A)


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Table 14–3:
Study flow chart: Treatment (Cycle ≥ 1) and Follow-up – Study Part 1 and Part 2 (Continued)
7-14 days after 
last dose
At 30-35 days 
after last dose
Day (D)
D1
D2
D3
D8 ±1
D15
D1
D8 ±1
D15 ±1
Administration of BAY 1163877
if PK assessment (K)
…
…
Administration of BAY 1163877
if no PK assessment(L)
…
Toxicities / AE assessment
…
…
…
…
…
…
…
…
…
…
... 
(A)
... 
(B)
…
(C)
…
(D)
…
(E)
…
(F)
…
(G)
... 
(H)
... 
A biopsy on Cycle 2, Day 1 is optional …
….
…for subjects in study Part 2 / MTD expansion (sqNSCLC + BC).
….
Continued


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Table 14–3:
Study flow chart: Treatment (Cycle ≥ 1) and Follow-up – Study Part 1 and Part 2 (Continued)
(I)
…
(J)
First oral administration of BAY 1163877 on Cycle 1 Day 1 will be done …
(K)
Subjects with PK assessment (all subjects of study Part 1 and at least 12 subjects of study Part 2) will receive a single-dose of BAY 1163877 
on Cycle 1, Day 1 (morning), followed by a “drug-free day” (to enable single dose PK assessments).Treatment with BAY 1163877 will 
resume ...
(L)
Subjects without PK assessment in study Part 2 …


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New text
Table 14-1:
Study flow chart: Pre-Treatment – Study Part 1 and Part 2 - amended
FGFR expression / 
FGFR mutation 
testing 
Screening
Measures / actions
Only for subjects 
recruited for MTD 
expansion cohorts 
(Part 1 and Part 2)  
Within 28 Days* 
Within 7 Days*
before first study drug 
administration
Signed informed consent
X(A1)
X(A2)
Limited inclusion criteria 
X
Inclusion / exclusion criteria
X
X
Demographic data
X(K)
X(K)
Documentation of the primary 
diagnosis (refractory, locally 
advanced or metastatic solid 
tumor) using the complete 
pathological report
X(K)
X(K)
Complete medical / oncological 
history
X(K)
X(K)
TNM classification
X(K)
X(K)
Concomitant diseases, NYHA 
grading
X
Review of baseline toxicities 
X
X
X
Baseline characteristics (smoking 
habits / history, alcohol 
consumption)
X
Previous therapy
X
Concomitant therapy
X
X
Physical examination 
X
Body height
X
Body weight / calculation of BMI(B)
X
Vital signs(C)
X
ECOG performance status
X
X
12-lead ECG(D)
X
Echocardiography or MUGA scan
X
Obtain pre-treatment biopsy(E)  
X
Obtain archival tissue sample or 
fresh tumor material for FGFR 
expression / FGFR mutation testing
X
Continued


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Table 14-1: Study flow chart: Pre-Treatment – Study Part 1 and Part 2 - amended
(Continued)
FGFR expression / 
FGFR mutation 
testing 
Screening
Measures / actions
Only for subjects 
recruited for MTD 
expansion cohorts 
(Part 1 and Part 2)  
Within 28 Days* 
Within 7 Days*
before first study drug 
administration
Stratification of subjects to be 
enrolled in MTD expansion cohorts 
(Part 1 and Part 2)(F)  
X
Blood / urine collection for safety 
lab tests(G)
X
X
Blood (serum) samples collection 
for biomarker investigations(H)
X
Only females: Urine pregnancy 
test
X
Calculation of eGFR(I)
X
Ophthalmological examination at 
consultant
X
CT / MRI scans 
X
Documentation of lesion(s) 
according to RECIST v1.1
X
Adverse events(J)
X
X
X
*Pre-study examinations may require hospitalization for 1- 2 days.
(A1)
Informed consent for FGFR expression / FGFR mutation testing
(A2)
Informed consent for study treatment eligibility can be signed before 28-day screening phase.
(B)
…
(C)
... 
(D)
...
(E) 
A pre-treatment biopsy at screening will be obtained from all subjects who agreed on this. 
The biopsy sample will be sent to laboratory for biomarker evaluation, see Table 14–5, 
Table  14–6 and Table 14–7.
(F) 
For details, see Table 14–6 and Table 14–7. 
(G) 
Safety lab tests: Virology tests within 28 days before first study drug administration, all other 
blood and urine tests within 7 days before first study drug administration, for details 
see Table 14–4. 
(H)
…
(I)
…
Continued


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Table 14–1: Study flow chart: Pre-Treatment – Study Part 1 and Part 2 - amended 
(Continued)
(J)
…
(K)
Documentation has not to be provided twice for subjects enrolled in the MTD expansion 
cohorts.


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Table 14–2: Study flow chart: Treatment (Cycle 1, Day -3 to Day -1) – Study Part 1 
and Part 2 - amended
Measures / actions
TREATMENT 
(only for “tablet bridging cohort”
(Part 1) and for “food effect 
assessment” (Part 1 and Part 2))
Cycle 1
Day -3
Day -2
Day -1
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
PK blood sampling(F)
…
Administration of BAY 1163877 (single dose) after a 
high-fat, high-calorie breakfast(G)
X
Administration of BAY 1163877 tablet (single dose)(H)
…
…
…
…
…
(A) 
…
(B)
…
(C) 
…
(D)
…
(E)
…
(F)
PK sampling will be done as follows (for details see separate document e.g. Laboratory 
Manual):

…
(G)
Only for subjects with “food effect assessment” in Part 1 and Part 2:  Oral administration of a 
single dose of BAY 1163877 immediately (within 5 minutes) after consumption of a high-fat, 
high-calorie breakfast (supervised by a member of the site), see Section 6.4.2.2.1.
(H)
Only for subjects included in the “tablet bridging cohort” of Part 1 / dose escalation:
Oral administration of BAY 1163877 tablet formulation on Cycle 1, Day -3 will be done by a 
member of the site.
Continued


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Table 14–3:
Study flow chart: Treatment (Cycle ≥ 1) and Follow-up – Study Part 1 and Part 2 - amended
Measures / actions
TREATMENT
FOLLOW-UP
Cycle 1 
(21 days)
Cycles 2-12
(21 days)
Cycles ≥13
(21 days)
EOT Visit
Within 
0-14 days after 
last dose
FU-Visit / 
Phone Call(A)
At 30-35 days 
after last dose
Day (D)
D1
D2
D3
D8 ±1
D15
D1
D8 ±1
D15 ±1
D1
D11
Concomitant medication
…
…
…
…
…
…
…
…
X
X
…
Physical examination 
…
…
…
…
…
…
…
…
X
X
…
…
Ask subject for changes in vision(B)
…
…
…
…
…
…
…
…
X
X
…
…
Cardiovascular assessment(C)
…
…
…
…
…
…
…
X
X
…
…
Body temperature
…
…
…
…
…
…
X
…
Body weight
…
X
X
…
12-lead ECG readings(D)
…
…
…
…
X
…
ECOG performance status
…
…
…
…
…
…
…
…
X
X
…
Blood / urine collection for safety lab tests(E)
…
…
…
…
…
…
X
X
…
Calculation of eGFR(F)
…
…
…
…
…
…
X
X
…
Blood (serum) samples collection for 
biomarker investigations(G)
…
…
…
…
…
…
…
X
X
…
24-hour urine collection(N)
X
…
…
Obtain tumor biopsy for biomarker tests(H)
X
(Cycle 2 
only)
PK blood sampling(I)
…
…
PK blood sampling for PK / PD modeling(J)
X
Ophthalmological examination
Every 2nd cycle
…
CT / MRI scans and documentation of 
response according to RECIST v1.1
End of Cycle 2, then after every 3rd
cycle
Dispense / return of BAY 1163877 and 
diary(K)
…
…
…
…
…
…
…
X
X
…
Continued


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Table 14–3:
Study flow chart: Treatment (Cycle ≥ 1) and Follow-up – Study Part 1 and Part 2 – amended (Continued)
Measures / actions
TREATMENT
FOLLOW-UP
Cycle 1 
(21 days)
Cycles 2-12
(21 days)
Cycles ≥13
(21 days)
EOT Visit
Within 
0-14 days after 
last dose
FU-Visit / 
Phone Call(A)
At 30-35 days 
after last dose
Day (D)
D1
D2
D3
D8 ±1
D15
D1
D8 ±1
D15 ±1
D1
D11
Administration of BAY 1163877
if PK assessment(L)
…
Continuous, twice-daily administration 
Administration of BAY 1163877
if no PK assessment(M)
   Continuous, twice-daily administration
Toxicities / AE assessment
…
…
…
…
…
…
…
…
X
X
…
…
…... 
(A)
... 
(B)
…
(C)
…
(D)
…
(E)
…
(F)
…
(G)
... 
(H)
... 
A biopsy on Cycle 2, Day 1 is optional …
….
…for subjects in study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN).
(I)
... (J)
All subjects participating in the MTD expansion cohorts (Part 1 or Part 2) will have 2 PK samples drawn for the purpose of exposure-response 
modelling on Day 1 of Cycles 2, 3, 4, and 5 (1 blood sample just before the morning dose of BAY 1163877 and 1 blood sample between 0.5 and 1.5 hours 


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Table 14–3:
Study flow chart: Treatment (Cycle ≥ 1) and Follow-up – Study Part 1 and Part 2 – amended (Continued)
post-dose). The dose needs to be taken under supervision and the time recorded.
(K)
First oral administration of BAY 1163877 on Cycle 1 Day 1 will be done …
(L)
Subjects with PK assessment (all subjects of study Part 1 and at least 12 subjects of study Part 2) will receive a single-dose of BAY 1163877 on Cycle 1, 
Day 1 (morning), followed by a “drug-free day” (to enable single dose PK assessments). Subjects with “food effect assessment” in Part 1 and Part 2 take 
the morning dose after an overnight fast of at least 8 hours (see Section 6.4.2.2.1). 
Treatment with BAY 1163877 will resume ...
(M)
Subjects without PK assessment in study Part 2 …
(N)
In approximately 8 subjects enrolled in MTD expansion cohorts (study Part 1 and Part 2), urine will be collected for 24 hours after dosing.


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Section 14.2: Laboratory examinations - amended
This section was changed as a result of Modifications 1-3, 8 and 10.
Old text:
Table14-4:
Parameters and time points of laboratory examinations performed at local 
laboratory or study site (safety laboratory) – Study Part 1 and Part 2 - amended
Parameters
Screen-
ing
Treatment
Follow-up
Cycle 1
Day -3
Each Cycle
EOT
visit
FU 
visit
Day 1 Day 8
Day 15
BLOOD
Hematology: …
…
…
…
…
…
…
…
Coagulation: …
…
…
…
…
…
…
…
Biochemistry: …
…
…
…
…
…
…
…
Virology: …
…
URINE
Macroanalysis: …
…
…
…
…
…
…
…
Urinalysis (dip stick): …
…
…
…
…
…
…
…
Laboratory analysis(C): …
…
…
…
…
…
…
…
Microscopic urinalysis(D): …
…
…
…
…
…
…
…
Pregnancy test(F)
…
…


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Table14-5:
Parameters and time points for biomarker investigations 
in study Part 1 / dose escalation (all comer) 
Parameters
Screening
Treatment
Follow-up
EOT visit
TUMOR TISSUE: 
Cycle 2, Day 1
…
…
…
Blood (serum) samples*:
Cycle 1
Cycle ≥2
D1
D3
D8
D15
D1
D8
D15
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
D  = day
…
…
* Blood (serum) samples to be collected before administration of the morning dose of BAY 1163877.
(A)
… Mitomycin C, or nitrosoureas should not be given within 6 weeks of pre-treatment biopsy.
(B)
…
…


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Table 14–6:
Parameters and time points for biomarker investigations in study 
Part 1 / MTD expansion (all comer)
Parameters
Screening
Treatment
Follow-up
EOT visit
TUMOR TISSUE:
Cycle 2, Day 1
…
…
…
FGFR1/2/3 expression
X(C)
FGFR and FGFR 
pathway mutations
X(C)
Blood (serum) samples*:
Cycle 1
Cycle ≥2
D1
D3
D8
D15
D1
D8
D15
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
D  = day
…
…
* Blood (serum) samples to be collected before administration of the morning dose of BAY 1163877.
(A)
A pre-treatment biopsy (e.g. endoscopic or ultrasound-guided biopsy) must be obtained at 
screening (mandatory biopsy within 28 days prior to start of treatment).
Anticancer chemotherapy must have been stopped for at least 5 half-lives of the last applied 
therapy before the pre-treatment biopsy is taken. Mitomycin C or nitrosoureas should not be 
given within 6 weeks of pre-treatment biopsy.
(B)
...
(C) 
An archival tumor tissue specimen will be used for the quantification of fibroblast FGFR 
expression levels and evaluation of FGFR mutations necessary for subject stratification (see 
Section 5.1.1: Inclusion criteria). If no archival biopsy sample is available the biopsy sample 
from the mandatory pre-treatment biopsy at screening may be used for subject stratification. 
Additionally isolated tumor DNA, if available, can be requested for genetic testing.


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Table 14–7: Parameters and time points for biomarker investigations 
in study Part 2 / MTD expansion (sqNSCLC + BC) 
Parameters
Screening
Treatment
Follow-up
EOT visit
TUMOR TISSUE:
Cycle 2, Day 1
…
…
…
FGFR1/2/3 expression
X(C)
FGFR and FGFR 
pathway mutations
X(C)
Blood (serum) samples*:
Each Cycle
Day 1
Day 8
Day 15
…
…
…
…
…
…
…
…
…
…
…
…
…
…
…
* Blood (serum) samples to be collected before administration of the morning dose of BAY 1163877.
(A)
A pre-treatment biopsy (e.g. endoscopic or ultrasound-guided biopsy) will be obtained at 
screening if the subject agreed on this. The pre-treatment biopsy is optional for subjects for 
whom an archival biopsy is available. If no archival biopsy is available, the pre-treatment 
biopsy is mandatory, see C
Anticancer chemotherapy must have been stopped for at least 5 half-lives of the last applied 
therapy before the pre-treatment biopsy is taken. Mitomycin C or nitrosoureas should not be 
given within 6 weeks of pre-treatment biopsy.
(B)
…
(C)
An archival tumor tissue specimen will be used for the quantification of fibroblast FGFR 
expression levels and evaluation of FGFR mutations necessary for subject stratification (see 
Section 5.1.1: Inclusion criteria). If no archival biopsy is available generation of a pre-treatment 
biopsy at screening is mandatory for subject stratification, see (A). Additionally isolated tumor 
DNA, if available, can be requested for genetic testing.
…


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New text:
Table 14-4: Parameters and time points of laboratory examinations performed at local laboratory or study site (safety laboratory) – Study Part 1 and 
Part 2 – amended 
Parameters
PRE-TREATMENT
TREATMENT
FOLLOW-UP
FGFR ex-
pression / FGFR 
mutation testing
Screen-
ing
Cycle 1
Cycles 2-12
Cycle ≥13
EOT
visit
FU 
visit
Day -3
Day 1
Day 8
Day 15 Day 1
Day 11
BLOOD
Hematology: …
…
…
…
…
…
X
X
…
…
Coagulation: …
…
…
…
…
…
X
X
…
…
Biochemistry: …
…
…
…
…
…
X
X
…
…
Virology: …
…
URINE
Macroanalysis: …
…
…
…
…
…
X
X
…
…
Urinalysis (dip stick): …
…
…
…
…
…
X
X
…
…
Laboratory analysis(C): …
…
…
…
…
…
X
X
…
…
Microscopic urinalysis(D): …
…
…
…
…
…
X
X
…
…
Pregnancy test(F)
…
…


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Table 14–5:
Parameters and time points for biomarker investigations in study Part 1 / dose escalation (all comer) - amended
Parameters
PRE-TREATMENT
TREATMENT
FOLLOW-UP
FGFR expression 
/ FGFR mutation 
testing
Screening
Cycle 1
Cycles 2-12
Cycles ≥13
EOT visit
Day 1
Day 3
Day 8
Day 15
Day 1
Day 8
Day 15
Day 1
Day 11
Tumor tissue:
p-ERK1/2 levels 
…
X(B)
only Cycle 2
Blood (serum) samples*:
FGF23
…
…
…
…
…
…
…
…
X
X
…
Phosphate, Calcium
…
…
…
…
…
…
…
…
X
X
…
…
* Blood (serum) samples to be collected before administration of the morning dose of BAY 1163877 only for Cycle 1.
(A)
… Mitomycin C, nitrosoureas or monoclonal antibodies with anticancer activity (e.g. bevacizumab or cetuximab etc.) should not be given within 6 weeks of 
pre-treatment biopsy for biomarker (p-ERK1/2) studies.
(B)
…
…


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Table 14-6:
Parameters and time points for biomarker investigations in study Part 1 / MTD expansion (all comer) - amended
Parameters
PRE-TREATMENT 
TREATMENT
FOLLOW-UP
FGFR expression / 
FGFR mutation 
testing 
Screening
Cycle 1
Cycles 2-12
Cycles ≥13
EOT visit
Day 1
Day 3
Day 8
Day 15
Day 1
Day 8
Day 15
Day 1
Day 11
Tumor tissue:
p-ERK1/2 levels
X(A)
X(B)
only Cycle 2
FGFR1/2/3 expression
X(C)
FGFR and FGFR 
pathway mutations
X(C)
Blood (serum) samples*:
FGF23
…
…
…
…
…
…
…
…
X
X
…
Phosphate, Calcium
…
…
…
…
…
…
…
…
X
X
…
…
FGFR 1/2/3
= fibroblast growth factor receptor 1, 2 and 3
…
* Blood (serum) samples to be collected before administration of the morning dose of BAY 1163877 only for Cycle 1.
(A)
An additional biopsy is not requested if a biopsy was already obtained for FGFR expression / FGFR mutation testing prior to the screening visit. Anticancer 
chemotherapy must have been stopped for at least 5 half-lives of the last applied therapy before the pre-treatment biopsy is taken. Mitomycin C, 
nitrosoureas or monoclonal antibodies with anticancer activity (e.g. bevacizumab or cetuximab etc.) should not be given within 6 weeks of pre-treatment 
biopsy for biomarker (p-ERK1/2) studies.
(B)
…
(C)
An archival or fresh tumor tissue specimen will be used for the quantification of fibroblast FGFR expression levels, necessary for subject stratification (see 
Section 5.1.1: Inclusion criteria). If no archival biopsy sample is available which has been handled and processed as described in the lab manual, collection 
of fresh tumor biopsy material is mandatory for stratification.
The evaluation of FGFR pathway mutations is planned retrospectively for all subjects.


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Table 14-7:
Parameters and time points for biomarker investigations in study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN) - amended
Parameters
PRE-TREATMENT
TREATMENT
FOLLOW-UP
FGFR expression / 
FGFR mutation testing
Screening
Cycles 2-12
Cycles ≥13
EOT visit
Day 1
Day 8
Day 15
Day 1
Day 11
Tumor tissue:
p-ERK1/2 levels
X(A)
X(B)
only Cycle 2
FGFR1/2/3 expression
X(C)
FGFR and FGFR pathway 
mutations
X(C)
Blood (serum) samples*:
FGF23
…
…
…
…
X
X
…
Phosphate, calcium
…
…
…
…
X
X
…
…
* Blood (serum) samples to be collected before administration of the morning dose of BAY 1163877 only for Cycle 1.
(A)
A pre-treatment biopsy (e.g. endoscopic or ultrasound-guided biopsy) will be obtained at screening if the subject agreed on this. The pre-treatment biopsy 
is optional for subjects for whom an archival biopsy is available. An additional biopsy is not requested if a biopsy was already obtained for FGFR expression 
/ FGFR mutation testing prior to the screening visit.
Anticancer chemotherapy must have been stopped for at least 5 half-lives of the last applied therapy before the pre-treatment biopsy is taken. Mitomycin C, 
nitrosoureas or monoclonal antibodies with anticancer activity (e.g. bevacizumab or cetuximab etc.) should not be given within 6 weeks of pre-treatment 
biopsy for biomarker (p-ERK1/2) studies.
(B)
…
(C)
An archival tumor tissue specimen will be used for the quantification of fibroblast FGFR expression levels necessary for subject stratification (see 
Section 5.1.1: Inclusion criteria). If no archival biopsy is available which has been handled and processed as described in the lab manual, collection of fresh 
tumor biopsy material is mandatory for stratification. 
Samples of BC subjects will also be tested on activating FGFR3 mutation status for stratification. 
The evaluation of FGFR pathway mutations is planned retrospectively for all subjects.
p-ERK1/2 levels will only be analyzed if a subject is willing to undergo both a pre-treatment biopsy at screening and a second biopsy on Cycle 2, Day 1.


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15.4 Amendment 4
Date of amendment: 31 Oct 2014
15.4.1 Overview of changes
Modification 1: Modification of the total number of subjects
Rationale for introducing Modification 1 
Available data of the conducted study have revealed, that the total number of screening 
failures is larger than anticipated. Therefore an adaptation of the total number of subjects 
is necessary.
List of all CSP sections affected by Modification 1:
-
Synopsis
-
Section 4
Modification 2: Definition of the MTD
Rationale for introducing Modification 2
Preliminary data of the conducted study have revealed, that dose escalations without 
major toxicities could be carried out beyond the planned maximum dosage of 1100 
mg/day. Therefore the decision to define the RP2D should be determined by PK and/or 
PD results.
List of all CSP sections affected by Modification 2:
-
Synopsis
-
Section 4
Modification 3: Minor corrections/inconsistencies
Rationale for introducing Modification 3
Minor text modifications and corrections of omissions or terminology were done for 
clarification and to ensure correct and consistent wording. 
List of all CSP sections affected by Modification 3:
-
Section 5.1.2.3
-
Section 6.9.2
-
Section 7.3.1
-
Section 9.1
Modification 4: Assessment and recording of toxicity and AE in the FGFR 


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expression / FGFR mutation testing group (MTD expansion cohorts only)
Rationale for introducing Modification 4
Subjects without invasive procedure to obtain tumor material for testing of the FGFR 
expression pattern are no subject of toxicity / AE assessment and recording.
List of all CSP sections affected by Modification 4:
Section 7.1.2.1.1
Section 7.5.1.1
Section 7.5.1.3
Section 9.1
Table 14-1
Modification 5: Laboratory examinations for coagulation parameters, safety 
laboratory FU visit
Rationale for introducing Modification 5
Coagulation parameters will be determined for all subjects once per cycle. The FU visit 
will not cover safety laboratory parameter as described in section 7.1.2.3.4.
List of all CSP sections affected by Modification 5:
-
Section 7.5.4.2
-
Table 14-4
Modification 6: Biomarker investigations
Rationale for introducing Modification 6
Standardization of biomarker sampling in all MTD subjects.
List of all CSP sections affected by Modification 6:
-
Section 7.1.2.3.1
-
Section 7.4.4
-
Table 14-6
-
Table 14-7
15.4.2 Changes of protocol
In this section, all affected protocol sections are detailed; the sequence of the sections 
follows the structure of the original protocol. In the display of modifications, the “old 


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text” refers to the protocol version preceding this amendment. Deletions are crossed out in 
the “old text”. Additions are underlined in the “new text”. Corrections of typing errors, 
omissions or terminology (minor corrections) are not highlighted in this amendment.
Synopsis
This section was changed as a result of Modifications 1 and 2.
Old text:
Title
…
Short title
…
Clinical study phase
…
Project number
…
Study objective(s)
…
Test drug(s) 
…
Name of active ingredient 
…
Formulation IMP 1
…
Formulation IMP 2
…
Dose(s)
…
Route of administration
…
Duration of treatment
…
Reference drug (s)
…
Indication
…
Diagnosis and main criteria for 
inclusion
…
Study design
…
Methodology
… 
Type of control
…


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Number of subjects
Up to 111 subjects will be enrolled in the screning
phase of the study.

Study Part 1 / dose escalation (all comer): 
The total number of subjects will depend on the number 
of cohorts necessary to identify the MTD. Relative 
bioavailability of the tablet formulation in comparison 
to the solution formulation will be performed in all 
subjects enrolled in one of the dose escalation cohorts; 
pharmacokinetic data are needed in a minimum of 
3 subjects for relative bioavailability assessment. 
…
Primary variables
…
New text:
Title
…
Short title
…
Clinical study phase
…
Project number
…
Study objective(s)
…
Test drug(s) 
…
Name of active ingredient 
…
Formulation IMP 1
…
Formulation IMP 2
…
Dose(s)
…
Route of administration
…
Duration of treatment
…
Reference drug (s)
…
Indication
…


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Diagnosis and main criteria for 
inclusion
…
Study design
…
Methodology 
…
Determination of the MTD: An adaptive dose 
escalation design will be used to determine the MTD in 
study Part 1 (all comer). The MTD is defined as the 
highest dose that can be given such that not more than 
20% of subjects experience a DLT during Cycle 1. The 
dose escalation will be performed as follows:

Initially 3 subjects per dose level will be enrolled. In 
case 2 or more sites are conducting the dose 
escalation part, the initial enrolment of 4 subjects 
per dose level is optional.

The starting dose of BAY 1163877 is 50 mg given 
as a single dose on Cycle 1, Day 1, and twice daily 
(b.i.d.) from Cycle 1, Day 3 (100 mg /day)

The maximum dose escalation will be 2-fold.

Possible daily doses of BAY 1163877 starting from 
100 mg in increments of 100 mg.
If at least 1 subject out of 3 or 1 out of 4 in a cohort has 
DLTs or if at least 2 subjects report drug-related AEs 
(CTCAE v4.03) of Grade ≥ 2, any further dose 
escalation, de-escalation or cohort expansion will be 
decided in consultation between all investigator(s), and 
the sponsor (within the drug safety monitoring team = 
DSMT) after consideration of all available safety data 
of the previous cohorts. Any subsequent dose will be 
selected in order to determine the MTD. 
Model-based dose-response analysis of the DLT rates 
will be performed during these interim reviews in order 
to guide the dose decision (see details in Section 16.4). 


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Methodology 
(continued)
The model-based dose selection procedure is 
considering data at all dose levels (not just at the last 
cohort). The dose predicted to yield 20% DLT rates will 
be reported from that model as a best candidate for the 
next cohort. 
The final decision about the next dose will be made by 
the sponsor in consultation with all investigators 
(DSMT). If the selected dose is larger than the last dose 
tested, then escalation will be pursued. If it is lower, a 
de-escalation step will occur. 
Without the occurrence of toxicities, dose escalation 
could be stopped and RP2D may be determined based 
on PK and/or PD results. The decision to continue 
treatment for an individual patient will be made by the 
investigator according to the criteria specified in the 
protocol (Section 8.4).
Cohort expansion will occur when a previously tested 
dose is selected again for the next cohort of 3 subjects. 
Expansions at any given dose up to a total of 9 subjects 
are allowed. In principle, the selection of a next dose 
level where the predicted DLT rate is close to 20% 
should insure that the next dose tested will remain safe. 
Nevertheless, the following constraint will be added in 
order to protect subject safety during the adaptive dose 
selection decisions:
… 
Type of control
…


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Number of subjects
Approximately 200 subjects will be enrolled in the pre-
treatment phase of the study.

Study Part 1 / dose escalation (all comer): 
The total number of subjects will depend on the number 
of cohorts necessary to identify the MTD. Relative 
bioavailability of the tablet formulation in comparison 
to the solution formulation will be performed in all 
subjects enrolled in one of the dose escalation cohorts; 
pharmacokinetic data are needed in a minimum of 
3 subjects for relative bioavailability assessment. 

Study Part 1 / MTD expansion (all comer): 
Additional subjects will be enrolled to have 20 
evaluable “all comer” subjects treated at MTD.

Study Part 2 / MTD expansion (sqNSCLC + 
LAC + BC + SCCHN): 
40 additional subjects will be enrolled to have 
20 evaluable subjects with sqNSCLC or LAC and a 
cohort of 20 evaluable subjects with BC or SCCHN 
treated at MTD (at least 8 subjects per indication).
Primary variables
…
Plan for statistical analysis
…
Section 4: Study design
This section was changed as a result of Modification 1.
Old text:
…
Planned sample size:
It is expected that up to 111 subjects will be enrolled in the screening phase of the study 
and approximately 92 subjects will be enrolled in the treatment phase.
…
New text:
…
Planned sample size:


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It is expected that approximately 200 subjects will be enrolled in the pre-treatment phase 
of the study and approximately 92 subjects will be enrolled in the treatment phase.
…
Section 4: Study design
This section was changed as a result of Modification 2.
Old text:
...
Determination of the maximum tolerated dose (MTD)
An adaptive dose escalation design will be used to determine the MTD in study Part 1 (all 
comer). The MTD is defined as the highest dose that can be given such that not more than 
20% of subjects experience a DLT during Cycle 1.
Each cohort will be evaluated after all subjects have completed the first 21 days of 
treatment (which will subsequently referred to as “Cycle 1”) or early discontinued.
...
New text:
…
Determination of the maximum tolerated dose (MTD)
An adaptive dose escalation design will be used to determine the MTD in study Part 1 (all 
comer). The MTD is defined as the highest dose that can be given such that not more than 
20% of subjects experience a DLT during Cycle 1.
Without the occurrence of toxicities, dose escalation could be stopped and RP2D may be 
determined based on PK and/or PD results. The decision to continue treatment for an 
individual subjects will be made by the investigator according to the criteria specified in 
the protocol (Section 8.4).
Each cohort will be evaluated after all subjects have completed the first 21 days of 
treatment (which will subsequently referred to as “Cycle 1”) or early discontinued.
...
Section 5.1.2.3: Exclusion criteria
This section was modified as a result of Modification 3.
Old text:
Medical and surgical history


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
...

Unresolved toxicity higher than CTCAE v 4.03 Grade 1 (excluding alopecia and
anemia) attributed to any prior therapy / procedure 

...
New text:
Medical and surgical history

...

Unresolved toxicity higher than CTCAE v 4.03 Grade 1 (excluding alopecia, 
anemia and / or hypothyroidism) attributed to any prior therapy / procedure 

...
Section 6.9.2: Prohibited concomitant therapy
This section was modified as a result of Modification 3.
Old text:
Concomitant therapy with the following medication is NOT allowed:

Systemic anticancer therapy including cytotoxic therapy, signal transduction 
inhibitors, hormonal therapy and experimental or approved therapies during this trial or 
within 30 days before starting to receive study medication

Bone marrow transplant or stem cell rescue.

...
New text:
Section 6.9.2: Prohibited concomitant therapy

Anticancer chemotherapy or immunotherapy during the study or within 5-half-
lives prior to start of study treatment. Acute toxic effects of previous anticancer 
chemotherapy or immunotherapy have to be normalized completely (excluding alopecia, 
anemia and / or hypothyroidism). Anticancer therapy is defined as any agent or 
combination of agents with clinically proven anti-tumor activity administered by any route 
with the purpose of affecting the malignancy, either directly or indirectly, including 
palliative and therapeutic endpoints.

Mitomycin C, nitrosoureas or monoclonal antibodies with anticancer activity (e.g. 
bevacizumab or cetuximab etc.) should not be given within 6 weeks before starting to 
receive study treatment or within 6 weeks of pre-treatment biopsy for biomarker (p-
ERK1/2) studies in case of performed biopsy procedure


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
Bone marrow transplant or stem cell rescue.

...
Section 7.1.2.1.1: FGFR expression / FGFR mutation testing (MTD expansion 
cohorts only)
This section was changed as a result of Modification 4.
Old text:
FGFR expression / FGFR mutation testing (MTD expansion cohorts 
only)
A separate subject information sheet / informed consent form (SIS / ICF) for FGFR 
expression / FGFR mutation testing must be signed by all subjects recruited for study Part 
1 or Part 2 MTD expansion cohort (see Section 13.2). 
The following activities / examinations will be performed prior to FGFR expression / 
FGFR mutation testing:

...

Toxicity / AE assessment and recording 
All subjects enrolled into the study will be listed on a subject enrollment log provided by 
the sponsor’s representatives.
New text:
FGFR expression / FGFR mutation testing (MTD expansion cohorts 
only)
A separate subject information sheet / informed consent form (SIS / ICF) for FGFR 
expression / FGFR mutation testing must be signed by all subjects recruited for study Part 
1 or Part 2 MTD expansion cohort (see Section 13.2). 
The following activities / examinations will be performed prior to FGFR expression / 
FGFR mutation testing:

...

Toxicity / AE assessment and recording only in case an invasive procedure will be 
performed to obtain tumor material after subjects´ informed consent
All subjects enrolled into the study will be listed on a subject enrollment log provided by 
the sponsor’s representatives.
Section 7.1.2.3.1: Cycle 1


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This section was changed as a result of Modification 6.
Old text:
Day 3 

Update of concomitant therapy

Physical examination

Ask subject for changes in vision

Cardiovascular assessment (BP and HR) 

Measurement of body temperature 

ECOG performance status

Only for subjects included in study Part 1 (all comer): Blood (serum) samples 
collection for biomarker investigations, see Table 16-5 and Table 16-6

PK sampling (all subjects of study Part 1 and at least 12 subjects of study Part 2)

…
New text:
Day 3 

Update of concomitant therapy

Physical examination

Ask subject for changes in vision

Cardiovascular assessment (BP and HR) 

Measurement of body temperature 

ECOG performance status

Only for subjects included in study Part 1/ dose escalation (all comer): Blood 
(serum) samples collection for biomarker investigations, see Table 16-5

PK sampling (all subjects of study Part 1 and at least 12 subjects of study Part 2)

…
Section 7.3.1: Tumor evaluation – response assessment (RECIST)
This section was changed as a result of Modification 6.


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Old text:
In measurable lesions (i.e., at the primary site, visceral or nodal [in lymph nodes ≥2 cm] 
lesions), the objective response will be assessed by CT / MRI scan at the EOT visit and 
documented according to the revised RECIST guideline, Version 1.1 (RECIST, v1.1), see 
Section 16.8. The assessment will be done by the investigators. No central evaluation is 
planned for this study.
New text:
In measurable lesions (i.e., at the primary site, visceral or nodal [in lymph nodes ≥1,5 cm] 
lesions), the objective response will be assessed by CT / MRI scan at the EOT visit and 
documented according to the revised RECIST guideline, Version 1.1 (RECIST, v1.1), see 
Section 16.8. The assessment will be done by the investigators. No central evaluation is 
planned for this study.
Section 7.4.4: Biomarker investigations
This section was changed as a result of Modification 6.
Old text:
Biomarker analysis in blood (serum) samples 
Blood (serum) samples for the quantification of fibroblast growth factor 23 (FGF23), 
phosphate and calcium levels will be collected as follows:

Study Part 1 / dose escalation + MTD expansion (all comer)
-
Screening
-
Cycle 1:  Days 1*, 3*, 8*, and 15* 
-
Cycles 2-12:  Days 1, 8, 15
-
Cycles ≥13: Days 1 and 11
-
EOT visit

Study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN)
Screening
All Cycles:  Days 1*, 8*, and 15* 
EOT visit
*Blood collection before administration of morning dose only for Cycle 1 of Part 1 and Part 2.
…
New text:


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…
Biomarker analysis in blood (serum) samples 
Blood (serum) samples for the quantification of fibroblast growth factor 23 (FGF23), 
phosphate and calcium levels will be collected as follows:

Study Part 1 / dose escalation 
-
Screening
-
Cycle 1:  Days 1*, 3*, 8*, and 15* 
-
Cycles 2-12:  Days 1, 8, 15
-
Cycles ≥13: Days 1 and 11
-
EOT visit

Study Part 1 /  MTD expansion (all comer) and Study Part 2 / MTD expansion 
(sqNSCLC + LAC + BC + SCCHN)
Screening
Cycles 1-12:  Days 1*, 8*, 15*
Cycles ≥13: Days 1 and 11
EOT visit
*Blood collection before administration of morning dose only for Cycle 1 of Part 1 and Part 2.
…
Section 7.5.1.1: Definitions
This section was changed as a result of Modification 4.
Old text:
…
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 subject 
was at risk of death at the time of the event, it does not refer to an event which 
hypothetically might have caused death if it were more severe.
c) Requires insubject hospitalization or prolongation of existing hospitalization


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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 
(i.e. elective or scheduled surgery arranged prior to the start of the study)
-
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 
dependant on clinical judgment. In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedence.
Results in persistent or significant disability / incapacity
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions.
Is a congenital anomaly / birth defect
Is another medically important serious event as judged by the investigator
New text:
…
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):
Results in death
Is life-threatening
The term ‘life-threatening’ in the definition refers to an event in which the subject 
was at risk of death at the time of the event, it does not refer to an event which 
hypothetically might have caused death if it were more severe.
Requires insubject 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 
(i.e. elective or scheduled surgery arranged prior to the start of the study)
-
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 


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fulfill the criterion of ‘medically important’ and as such may be reportable as an SAE 
dependant on clinical judgment. In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedence.
Results in persistent or significant disability / incapacity
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions.
Is a congenital anomaly / birth defect
Is another medically important serious event as judged by the investigator
All SAEs occurring after the IC for study treatment eligibility has been obtained, until the 
end of the follow-up period must be handled via this process. All serious diagnoses, 
symptom(s), sign(s) or finding(s) that have a start date after signing the IC must be 
recorded as SAEs. This also includes all serious events with a start date during the pre-
treatment period for subject stratification (FGFR expression / FGFR mutation testing 
period), in case an invasive procedure was performed to obtain tumor material. A 
condition that was present before signing the IC for study treatment eligibility and 
worsens after signing the IC must also be recorded as an SAE if the serious criteria are 
met.
Section 7.5.1.3: Assessments and documentation of adverse events
This section was changed as a result of Modification 4.
Old text:
AEs observed, mentioned upon open questioning by a member of the investigator team or 
spontaneously reported by the subject, will be documented (see Section 11.1 for details). 
AEs will be documented event based (using the CTCAE v4.03 guidelines). The 
observation phase for AEs will start with signing the first Informed Consent and will end 
in general with the last visit of follow-up. Adverse events should be collected past 30-35 
days after the study treatment stop for all AEs that were ongoing at the end of treatment as 
well as new SAEs (information may be obtained via phone call). The investigator is 
responsible for the grading of each category mentioned in Section 9.5.1.2.
…
New text:
AEs observed, mentioned upon open questioning by a member of the investigator team or 
spontaneously reported by the subject, will be documented (see Section 11.1 for details). 
AEs will be documented event based (using the CTCAE v4.03 guidelines). The 
observation phase for AEs will start with signing the first Informed Consent and will end 
in general with the last visit of follow-up. All AEs identified after first IC during the pre-
treatment period for subject stratification (FGFR expression / FGFR mutation testing 
period) will not be documented in the eCRF, in case no invasive procedure will be 


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performed to obtain tumor material. Adverse events should be collected past 30-35 days 
after the study treatment stop for all AEs that were ongoing at the end of treatment as well 
as new SAEs (information may be obtained via phone call). The investigator is 
responsible for the grading of each category mentioned in Section 9.5.1.2.
…
Section 7.5.4.2: Laboratory examinations
This section was changed as a result of Modification 5.
Old text:
…
Blood tests:
Hematology and biochemistry parameters (for details see Table 16-4)
Serum creatinine concentration will be used to estimate the subject’s 
glomerular filtration rate (eGFR) at screening utilizing the Modification of 
Diet in Renal Disease (MDRD) equation, see Section 16.9.
Coagulation parameters only for subjects taking anticoagulants
Virology tests 
…
New text:
…
Blood tests:
-
Hematology and biochemistry parameters (for details see Table 16-4)
Serum creatinine concentration will be used to estimate the subject’s 
glomerular filtration rate (eGFR) at screening utilizing the Modification of 
Diet in Renal Disease (MDRD) equation, see Section 16.9.
-
Coagulation parameters for all subjects
-
Virology tests 
…
Section 9.1: Data recording
This section was changed as a result of Modification 4.


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Old text:
…

Data recorded during the FGFR expression / FGFR mutation testing period (MTD 
expansion cohorts only)
Limited data will be recorded for all subjects in the FGFR expression / FGFR 
mutation testing period as described below: 
-
Subject number
-
Demographic data
-
Cancer classification including primary diagnosis (all comer for study Part 1; 
sqNSCLC, LAC, BC or SCCHN for Part 2), complete medical / oncological 
history data and TNM classification
-
Life expectancy
-
ECOG Performance Status
-
Information on existence of an archival tumor biopsy specimen
-
Details on collection of fresh tumor material (if applicable)
-
Adverse event(s) 
New text:

Data recorded during the FGFR expression / FGFR mutation testing period (MTD 
expansion cohorts only)
Limited data will be recorded for all subjects in the FGFR expression / FGFR 
mutation testing period as described below: 
-
Subject number
-
Demographic data
-
Cancer classification including primary diagnosis (all comer for study Part 1; 
sqNSCLC, LAC, BC or SCCHN for Part 2), complete medical / oncological 
history data and TNM classification
-
Life expectancy
-
ECOG Performance Status
-
Information on existence of an archival tumor biopsy specimen
-
Details on collection of fresh tumor material (if applicable)
-
Adverse event(s) only in case an invasive procedure will be performed to obtain 
tumor material after informed consent


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This section was changed as a result of Modification 3.
Old text:

Data recorded from “only screened subjects (screening failures)” including pre-
screening
For screening failures, all items listed below must be documented within the eCRF:
-
Subject number
-
Date of birth
-
…
New text:

Data recorded from “only screened subjects (screening failures)” including pre-
screening
For screening failures, all items listed below must be documented within the eCRF:
-
Subject number
-
Date of informed consent
-
Date of birth


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Section 14.1: Study flow chart - amended
This section was changed as a result of Modification 5.
Old text:
Table 14-1:
Study flow chart: Pre-Treatment – Study Part 1 and Part 2 - amended
FGFR expression / 
FGFR mutation 
testing 
Screening
Measures / actions
Only for subjects 
recruited for MTD 
expansion cohorts 
(Part 1 and Part 2)  
Within 28 Days* 
Within 7 Days*
before first study drug 
administration
Signed informed consent
X(A1)
X(A2)
Limited inclusion criteria 
X
Inclusion / exclusion criteria
X
X
Demographic data
X(K)
X(K)
Documentation of the primary 
diagnosis (refractory, locally 
advanced or metastatic solid 
tumor) using the complete 
pathological report
X(K)
X(K)
Complete medical / oncological 
history
X(K)
X(K)
TNM classification
X(K)
X(K)
Concomitant diseases, NYHA 
grading
X
Review of baseline toxicities 
(X)
X
X
Baseline characteristics (smoking 
habits / history, alcohol 
consumption)
X
Previous therapy
X
Concomitant therapy
X
X
Physical examination 
X
Body height
X
Body weight / calculation of BMI(B)
X
Vital signs(C)
X
ECOG performance status
X
X
12-lead ECG(D)
X
Echocardiography or MUGA scan
X
Obtain pre-treatment biopsy(E)  
X
Continued


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Table 14-1: Study flow chart: Pre-Treatment – Study Part 1 and Part 2 - amended 
(Continued)
Measures / actions
FGFR expression / 
FGFR mutation 
testing 
Screening
Only for subjects 
recruited for MTD 
expansion cohorts 
(Part 1 and Part 2)  
Within 28 Days* 
Within 7 Days*
before first study drug 
administration
Obtain archival tissue sample or 
fresh tumor material for FGFR 
expression / FGFR mutation testing
X
Stratification of subjects to be 
enrolled in MTD expansion cohorts 
(Part 1 and Part 2)(F)  
X
Blood / urine collection for safety 
lab tests(G)
X
X
Blood (serum) samples collection 
for biomarker investigations(H)
X
Only females: Urine pregnancy 
test
X
Calculation of eGFR(I)
X
Ophthalmological examination at 
consultant
X
CT / MRI scans 
X
Documentation of lesion(s) 
according to RECIST v1.1
X
Adverse events(J)
(X)
X
X
*Pre-study examinations may require hospitalization for 1- 2 days.
(A1)
Informed consent for FGFR expression / FGFR mutation testing
(A2)
Informed consent for study treatment eligibility can be signed before 28-day screening phase.
(B)
BMI (body mass index) is calculated by dividing the subject’s weight by the square of his / her 
height (kg/cm2).
(C)
Vital signs (body temperature, respiration, systolic / diastolic blood pressure, heart rate); for 
methods of measurement, see Section 9.4.1.1 (Cardiovascular assessment) and 
Section9.5.3.3 (Vital signs). 
(D)
At screening, ECG readings (in the supine position) should be performed in triplicate in close 
sequence and not more than 2 minutes apart.
(E) 
A pre-treatment biopsy at screening will be obtained from all subjects who agreed on this. 
The biopsy sample will be sent to laboratory for biomarker evaluation, see Table 16-5, Table 
16-6 and Table 16-7
(F) 
For details, see Table 16-6 and Table 16-7. 
Continued


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Table 14-1: Study flow chart: Pre-Treatment – Study Part 1 and Part 2 - amended 
(Continued)
(G) 
Safety lab tests: Virology tests within 28 days before first study drug administration, all other 
blood and urine tests within 7 days before first study drug administration, for details 
see Table 16-4. (H)
Biomarker investigations in blood (serum) samples: see Table 16-5
- Table 16-7, and separate document e.g. Laboratory Manual for details.
(I)
For calculation of eGFR (estimated glomerular filtration rate), see Section 16.9.
(J)
Signs and symptoms that existed prior to signing informed consent should be recorded as 
medical history findings. Signs and symptoms worsened after the informed consent was 
signed as well as any sign or symptom that begins after the informed consent was signed 
(even if prior to start of study medication) should be recorded on an adverse event page of 
the eCRF using CTCAE v4.03.
(K)
Documentation has not to be provided twice for subjects enrolled in the MTD expansion 
cohorts.


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New text:
Table 14-1:
Study flow chart: Pre-Treatment – Study Part 1 and Part 2 - amended
FGFR expression / 
FGFR mutation 
testing 
Screening
Measures / actions
Only for subjects 
recruited for MTD 
expansion cohorts 
(Part 1 and Part 2)  
Within 28 Days* 
Within 7 Days*
before first study drug 
administration
Signed informed consent
X(A1)
X(A2)
Limited inclusion criteria 
X
Inclusion / exclusion criteria
X
X
Demographic data
X(K)
X(K)
Documentation of the primary 
diagnosis (refractory, locally 
advanced or metastatic solid 
tumor) using the complete 
pathological report
X(K)
X(K)
Complete medical / oncological 
history
X(K)
X(K)
TNM classification
X(K)
X(K)
Concomitant diseases, NYHA 
grading
X
Review of baseline toxicities 
(X)
X
X
Baseline characteristics (smoking 
habits / history, alcohol 
consumption)
X
Previous therapy
X
Concomitant therapy
X
X
Physical examination 
X
Body height
X
Body weight / calculation of BMI(B)
X
Vital signs(C)
X
ECOG performance status
X
X
12-lead ECG(D)
X
Echocardiography or MUGA scan
X
Obtain pre-treatment biopsy(E)  
X
Obtain archival tissue sample or 
fresh tumor material for FGFR 
expression / FGFR mutation testing
X
Continued


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Table 14-1: Study flow chart: Pre-Treatment – Study Part 1 and Part 2 - amended 
(Continued)
Measures / actions
FGFR expression / 
FGFR mutation 
testing 
Screening
Only for subjects 
recruited for MTD 
expansion cohorts 
(Part 1 and Part 2)  
Within 28 Days* 
Within 7 Days*
before first study drug 
administration
Stratification of subjects to be 
enrolled in MTD expansion cohorts 
(Part 1 and Part 2)(F)  
X
Blood / urine collection for safety 
lab tests(G)
X
X
Blood (serum) samples collection 
for biomarker investigations(H)
X
Only females: Urine pregnancy 
test
X
Calculation of eGFR(I)
X
Ophthalmological examination at 
consultant
X
CT / MRI scans 
X
Documentation of lesion(s) 
according to RECIST v1.1
X
Adverse events(J)
(X)
X
X
*Pre-study examinations may require hospitalization for 1- 2 days.
(A1)
Informed consent for FGFR expression / FGFR mutation testing
(A2)
Informed consent for study treatment eligibility can be signed before 28-day screening phase.
(B)
BMI (body mass index) is calculated by dividing the subject’s weight by the square of his / her 
height (kg/cm2).
(C)
Vital signs (body temperature, respiration, systolic / diastolic blood pressure, heart rate); for 
methods of measurement, see Section 9.4.1.1 (Cardiovascular assessment) and 
Section9.5.3.3 (Vital signs). 
(D)
At screening, ECG readings (in the supine position) should be performed in triplicate in close 
sequence and not more than 2 minutes apart.
(E) 
A pre-treatment biopsy at screening will be obtained from all subjects who agreed on this. 
The biopsy sample will be sent to laboratory for biomarker evaluation, see Table 16-5, Table 
16-6 and Table 16-7. 
(F) 
For details, see Table 16-6and Table 16-7. 
(G) 
Safety lab tests: Virology tests within 28 days before first study drug administration, all other 
blood and urine tests within 7 days before first study drug administration, for details 
see Table 16-4. 
Continued


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Table 14-1: Study flow chart: Pre-Treatment – Study Part 1 and Part 2 - amended 
(Continued)
(H)
Biomarker investigations in blood (serum) samples: see Table 16-5 - Table 16-7, and 
separate document e.g. Laboratory Manual for details.
(I)
For calculation of eGFR (estimated glomerular filtration rate), see Section 16.9.
(J)
Signs and symptoms that existed prior to signing informed consent should be recorded as 
medical history findings. Signs and symptoms worsened after the informed consent was 
signed as well as any sign or symptom that begins after the informed consent was signed 
(even if prior to start of study medication) should be recorded on an adverse event page of 
the eCRF using CTCAE v4.03. AE does only to be recorded for period of FGFR expression / 
FGFR mutation testing in pre-treatment in case an invasive procedure was performed to 
obtain tumor material.
(K)
Documentation has not to be provided twice for subjects enrolled in the MTD expansion 
cohorts.


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Section 14.2: Laboratory examinations - amended
This section was changed as a result of Modification 5.
Old text:
Table 14-4: Parameters and time points of laboratory examinations performed at local laboratory or study site (safety laboratory) –
Study Part 1 and Part 2 – amended 
Parameters
PRE-TREATMENT
TREATMENT
FOLLOW-UP
FGFR ex-
pression / FGFR 
mutation testing
Screen-
ing
Cycle 1
Cycles 2-12
Cycle ≥13
EOT
visit
FU 
visit
Day -3
Day 1
Day 8
Day 15 Day 1
Day 11
BLOOD
Hematology: Erythrocytes (RBC), hemoglobin, hematocrit, platelet 
count, MCV, MCH, MCHC, leucocytes (WBC), including differential 
WBC (absolute count of neutrophils, lymphocytes, monocytes, 
basophils, and eosinophils)
X
X
X
X
X
X
X
X
X
Coagulation: PT or PT-INR (obligatory at screening)  and PTT 
(aPTT)(A)
X
X
X
X
X
X
X
X
X
Biochemistry: AST / GOT, ALT / GPT, gamma-GT, AP, LDH, 
amylase, lipase, glucose, triglycerides, creatinine(B), BUN, uric acid, 
bilirubin (total & direct), total protein, albumin, sodium, potassium, 
chloride, CPK, calcium, phosphate
X
X
X
X
X
X
X
X
X
Virology: HBs-Ag, anti-HCV, anti-HIV 1+2 
X
URINE
Macroanalysis: Clarity of urine: clear, slightly clear, cloudy, or turbid
X
X
X
X
X
X
X
X
X
Urinalysis (dip stick): pH, blood, protein, glucose, bilirubin, 
urobilinogen, ketone, nitrite, leucocytes (or leucocyte esterase), 
specific gravity
X
X
X
X
X
X
X
X
X
Laboratory analysis(C): Protein and creatinine 
X
X
X
X
X
X
X
X
X
Microscopic urinalysis(D): Erythrocytes, leucocytes, epithelia cells, 
bacteria crystals, casts, bacteria and yeast 
X
X
X
X
X
X
X
X
X
Continued


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Table 14-4:
Parameters and time points of laboratory examinations performed at local laboratory or study site (safety laboratory) – Study 
Part 1 and Part 2 – amended (Continued)
Parameters
PRE-TREATMENT
TREATMENT
FOLLOW-UP
FGFR ex-
pression / FGFR 
mutation testing
Screen-
ing
Cycle 1
Cycles 2-12
Cycle ≥13
EOT
visit
FU 
visit
Day -3
Day 1
Day 8
Day 15 Day 1
Day 11
Pregnancy test(F)
X
A)
Only for subjects taking anticoagulant e.g. warfarin or heparin
(B)
The serum creatinine concentration is used to estimate the subject’s glomerular filtration rate (see Section 16.9)
(C)
Random urine sample preferably taken at mid-morning for the quantification of proteinuria by urinary protein/creatinine ratio
(D)
Only if urine appearance is turbid, or if protein, leukocytes, erythrocytes, or nitrite are out of normal range)
(F)
Only females of childbearing potential


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New text:
Table 14-4: Parameters and time points of laboratory examinations performed at local laboratory or study site (safety laboratory) – Study 
Part 1 and Part 2 – amended 
Parameters
PRE-TREATMENT
TREATMENT
FOLLOW-UP
FGFR ex-
pression / FGFR 
mutation testing
Screen-
ing
Cycle 1
Cycles 1-12
Cycle ≥13
EOT
visit
FU 
visit
Day -3
Day 1
Day 8
Day 15 Day 1
Day 11
BLOOD
Hematology: Erythrocytes (RBC), hemoglobin, hematocrit, platelet 
count, MCV, MCH, MCHC, leucocytes (WBC), including differential 
WBC (absolute count of neutrophils, lymphocytes, monocytes, 
basophils, and eosinophils)
X
X
X
X
X
X
X
X
Coagulation: PT or PT-INR (obligatory at screening)  and PTT 
(aPTT)(A)
X
X
X
X
Biochemistry: AST / GOT, ALT / GPT, gamma-GT, AP, LDH, 
amylase, lipase, glucose, triglycerides, creatinine(B), BUN, uric acid, 
bilirubin (total & direct), total protein, albumin, sodium, potassium, 
chloride, CPK, calcium, phosphate
X
X
X
X
X
X
X
X
Virology: HBs-Ag, anti-HCV, anti-HIV 1+2 
X
URINE
Macroanalysis: Clarity of urine: clear, slightly clear, cloudy, or turbid
X
X
X
X
X
X
X
X
Urinalysis (dip stick): pH, blood, protein, glucose, bilirubin, 
urobilinogen, ketone, nitrite, leucocytes (or leucocyte esterase), 
specific gravity
X
X
X
X
X
X
X
X
Laboratory analysis(C): Protein and creatinine 
X
X
X
X
X
X
X
X
Microscopic urinalysis(D): Erythrocytes, leucocytes, epithelia cells, 
bacteria crystals, casts, bacteria and yeast 
X
X
X
X
X
X
X
X
Pregnancy test(F)
X
Continued


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Table 14-4: Parameters and time points of laboratory examinations performed at local laboratory or study site (safety laboratory) – Study 
Part 1 and Part 2 – amended
(A)
For all subjects
(B)
The serum creatinine concentration is used to estimate the subject’s glomerular filtration rate (see Section 16.9)
(C)
Random urine sample preferably taken at mid-morning for the quantification of proteinuria by urinary protein/creatinine ratio
(D)
Only if urine appearance is turbid, or if protein, leukocytes, erythrocytes, or nitrite are out of normal range)
(F)
Only females of childbearing potential


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Section 14.2: Laboratory examinations - amended
This section was changed as a result of Modification 6.
Old text:
Table 14-6: Parameters and time points for biomarker investigations in study Part 1 / MTD expansion (all comer) - amended
Parameters
PRE-TREATMENT 
TREATMENT
FOLLOW-UP
FGFR expression / 
FGFR mutation 
testing 
Screening
Cycle 1
Cycles 2-12
Cycles ≥13
EOT visit
Day 1
Day 3
Day 8
Day 15
Day 1
Day 8
Day 15
Day 1
Day 11
Tumor tissue:
p-ERK1/2 levels
X(A)
X(B)
only Cycle 2
FGFR1/2/3 expression
X(C)
FGFR and FGFR 
pathway mutations
X(C)
Blood (serum) samples*:
FGF23
X
X
X
X
X
X
X
X
X
X
X
Phosphate, Calcium
X
X
X
X
X
X
X
X
X
X
X
p-ERK = phospho-extracellular signal–regulated kinase
FGFR 1/2/3
= fibroblast growth factor receptor 1, 2 and 3
FGF23 = fibroblast growth factor 23
* Blood (serum) samples to be collected before administration of the morning dose of BAY 1163877 only for Cycle 1.
(A)
An additional biopsy is not requested if a biopsy was already obtained for FGFR expression / FGFR mutation testing prior to the screening visit. Anticancer 
chemotherapy must have been stopped for at least 5 half-lives of the last applied therapy before the pre-treatment biopsy is taken. Mitomycin C, 
nitrosoureas or monoclonal antibodies with anticancer activity (e.g. bevacizumab or cetuximab etc.) should not be given within 6 weeks of pre-treatment 
biopsy for biomarker (p-ERK1/2) studies.
Continued


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Table 14-6: Parameters and time points for biomarker investigations in study Part 1 / MTD expansion (all comer) - amended
Parameters
PRE-TREATMENT 
TREATMENT
FOLLOW-UP
FGFR expression / 
FGFR mutation 
testing 
Screening
Cycle 1
Cycles 2-12
Cycles ≥13
EOT visit
Day 1
Day 3
Day 8
Day 15
Day 1
Day 8
Day 15
Day 1
Day 11
(B)
A second mandatory tumor biopsy must be obtained on Cycle 2, Day 1.
(C)
An archival or fresh tumor tissue specimen will be used for the quantification of fibroblast FGFR expression levels, necessary for subject stratification (see 
Section 7.1.1: Inclusion criteria). If no archival biopsy sample is available which has been handled and processed as described in the lab manual, collection 
of fresh tumor biopsy material is mandatory for stratification. 
The evaluation of FGFR pathway mutations is planned retrospectively for all subjects.


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New text:
Table 14-6: Parameters and time points for biomarker investigations in study Part 1 / MTD expansion (all comer) - amended
Parameters
PRE-TREATMENT 
TREATMENT
FOLLOW-UP
FGFR expression / 
FGFR mutation 
testing 
Screening
Cycles 1-12
Cycles ≥13
EOT visit
Day 1
Day 8
Day 15
Day 1
Day 11
Tumor tissue:
p-ERK1/2 levels
X(A)
X(B)
only Cycle 2
FGFR1/2/3 expression
X(C)
FGFR and FGFR 
pathway mutations
X(C)
Blood (serum) samples*:
FGF23
X
X
X
X
X
X
X
Phosphate, Calcium
X
X
X
X
X
X
X
p-ERK = phospho-extracellular signal–regulated kinase
FGFR 1/2/3
= fibroblast growth factor receptor 1, 2 and 3
FGF23 = fibroblast growth factor 23
* Blood (serum) samples to be collected before administration of the morning dose of BAY 1163877 only for Cycle 1.
(A)
An additional biopsy is not requested if a biopsy was already obtained for FGFR expression / FGFR mutation testing prior to the screening visit. Anticancer 
chemotherapy must have been stopped for at least 5 half-lives of the last applied therapy before the pre-treatment biopsy is taken. Mitomycin C, 
nitrosoureas or monoclonal antibodies with anticancer activity (e.g. bevacizumab or cetuximab etc.) should not be given within 6 weeks of pre-treatment 
biopsy for biomarker (p-ERK1/2) studies.
(B)
A second mandatory tumor biopsy must be obtained on Cycle 2, Day 1.
Continued


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Table 14-6: Parameters and time points for biomarker investigations in study Part 1 / MTD expansion (all comer) - amended
Parameters
PRE-TREATMENT 
TREATMENT
FOLLOW-UP
FGFR expression / 
FGFR mutation 
testing 
Screening
Cycles 1-12
Cycles ≥13
EOT visit
Day 1
Day 8
Day 15
Day 1
Day 11
(C)
An archival or fresh tumor tissue specimen will be used for the quantification of fibroblast FGFR expression levels, necessary for subject stratification (see 
Section 7.1.1: Inclusion criteria). If no archival biopsy sample is available which has been handled and processed as described in the lab manual, collection 
of fresh tumor biopsy material is mandatory for stratification. 
The evaluation of FGFR pathway mutations is planned retrospectively for all subjects.


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Section 14.2: Laboratory examinations - amended
This section was changed as a result of Modification 6. Old text:
Table 14-7: Parameters and time points for biomarker investigations in study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN) - amended
Parameters
PRE-TREATMENT
TREATMENT
FOLLOW-UP
FGFR expression / 
FGFR mutation testing
Screening
Cycles 2-12
Cycles ≥13
EOT visit
Day 1
Day 8
Day 15
Day 1
Day 11
Tumor tissue:
p-ERK1/2 levels
X(A)
X(B)
only Cycle 2
FGFR1/2/3 expression
X(C)
FGFR and FGFR pathway 
mutations
X(C)
Blood (serum) samples*:
FGF23
X
X
X
X
X
X
X
Phosphate, calcium
X
X
X
X
X
X
X
p-ERK
= phospho-extracellular signal–regulated kinase
FGFR 1/2/3
= fibroblast growth factor receptor 1, 2 and 3
FGF23
= fibroblast growth factor 23
* Blood (serum) samples to be collected before administration of the morning dose of BAY 1163877 only for Cycle 1.
(A)
A pre-treatment biopsy (e.g. endoscopic or ultrasound-guided biopsy) will be obtained at screening if the subject agreed on this. The pre-treatment biopsy 
is optional for subjects for whom an archival biopsy is available. An additional biopsy is not requested if a biopsy was already obtained for FGFR expression 
/ FGFR mutation testing prior to the screening visit.
Anticancer chemotherapy must have been stopped for at least 5 half-lives of the last applied therapy before the pre-treatment biopsy is taken. Mitomycin C, 
nitrosoureas or monoclonal antibodies with anticancer activity (e.g. bevacizumab or cetuximab etc.) should not be given within 6 weeks of pre-treatment 
biopsy for biomarker (p-ERK1/2) studies.
(B)
A second biopsy will be taken on Cycle 2, Day 1 if the subject agreed on this at screening (optional biopsy).
Continued


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Table 14-7: Parameters and time points for biomarker investigations in study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN) - amended
(C)
An archival tumor tissue specimen will be used for the quantification of fibroblast FGFR expression levels necessary for subject stratification (see 
Section 7.1.1: Inclusion criteria). If no archival biopsy is available which has been handled and processed as described in the lab manual, collection of fresh 
tumor biopsy material is mandatory for stratification. 
Samples of BC subjects will also be tested on activating FGFR3 mutation status for stratification. 
The evaluation of FGFR pathway mutations is planned retrospectively for all subjects.
p-ERK1/2 levels will only be analyzed if a subject is willing to undergo both a pre-treatment biopsy at screening and a second biopsy on Cycle 2, Day 1.


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New text:
Table 14–7: Parameters and time points for biomarker investigations in study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN) - amended
Parameters
PRE-TREATMENT
TREATMENT
FOLLOW-UP
FGFR expression / 
FGFR mutation testing
Screening
Cycles 1-12
Cycles ≥13
EOT visit
Day 1
Day 8
Day 15
Day 1
Day 11
Tumor tissue:
p-ERK1/2 levels
X(A)
X(B)
only Cycle 2
FGFR1/2/3 expression
X(C)
FGFR and FGFR pathway 
mutations
X(C)
Blood (serum) samples*:
FGF23
X
X
X
X
X
X
X
Phosphate, calcium
X
X
X
X
X
X
X
p-ERK
= phospho-extracellular signal–regulated kinase
FGFR 1/2/3
= fibroblast growth factor receptor 1, 2 and 3
FGF23
= fibroblast growth factor 23
* Blood (serum) samples to be collected before administration of the morning dose of BAY 1163877 only for Cycle 1.
(A)
A pre-treatment biopsy (e.g. endoscopic or ultrasound-guided biopsy) will be obtained at screening if the subject agreed on this. The pre-treatment biopsy 
is optional for subjects for whom an archival biopsy is available. An additional biopsy is not requested if a biopsy was already obtained for FGFR expression 
/ FGFR mutation testing prior to the screening visit.
Anticancer chemotherapy must have been stopped for at least 5 half-lives of the last applied therapy before the pre-treatment biopsy is taken. Mitomycin C, 
nitrosoureas or monoclonal antibodies with anticancer activity (e.g. bevacizumab or cetuximab etc.) should not be given within 6 weeks of pre-treatment 
biopsy for biomarker (p-ERK1/2) studies.
(B)
A second biopsy will be taken on Cycle 2, Day 1 if the subject agreed on this at screening (optional biopsy).
Continued


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Table 14–7: Parameters and time points for biomarker investigations in study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN) - amended
(C)
An archival tumor tissue specimen will be used for the quantification of fibroblast FGFR expression levels necessary for subject stratification (see 
Section 7.1.1: Inclusion criteria). If no archival biopsy is available which has been handled and processed as described in the lab manual, collection of 
fresh tumor biopsy material is mandatory for stratification. 
Samples of BC subjects will also be tested on activating FGFR3 mutation status for stratification. 
The evaluation of FGFR pathway mutations is planned retrospectively for all subjects.
p-ERK1/2 levels will only be analyzed if a subject is willing to undergo both a pre-treatment biopsy at screening and a second biopsy on Cycle 2, Day 1.


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15.5 Amendment 5
Date of amendment: 16 September 2016
15.5.1 Overview of changes
15.5.1.1
Modification 1: Increase in number of patients with BC
Description of modification to the study plan
The number of subjects with BC to be included will be increased to ensure 30 evaluable 
subjects completed Cycle 2. Selected safety-relevant in- and exclusion criteria will be 
modified. Moreover, the study will be performed worldwide.
Rationale for introducing the modification
In order to confirm the efficacy and safety signals in patients with relapsed or refractory 
bladder cancer overexpressing FGFR or with activating FGFR3 mutations the recruitment 
will be extended to ensure overall treatment of approximately 30 evaluable subjects..
Based on the current available overall safety database which shows good tolerability, 
some in- and exclusion criteria will be adapted.
List of CSP sections affected by this modification 
Synopsis, Sections: 6 Study design, 6.2 Justification of the study design, 7.1.1.2 Eligibility 
criteria for study treatment, 7.1.2.3 Exclusion criteria, 7.5.4 Echocardiography / MUGA 
scan, 10.7 Determination of sample size.
15.5.1.2
Modification 2: PK assessment in renally impaired subjects
Description of modification to the study plan
A maximum of 8 subjects with moderate renal impairment (Glomerular filtration rate 
(GFR)  30-59 mL/min/1.73 m2) will be included and the PK will be assessed. To allow 
recruitment of these subjects inclusion criteria are modified.
Rationale for introducing the modification
Assessment of PK in this patient population may allow dosing of BAY 1163877 in 
patients with moderate renal impairment.
List of CSP sections affected by this modification 
Synopsis, Sections: 6 Study design, 9.4.2.1 Drug measurement, 10.7 Determination of 
sample size, 16.1 Study flow chart
15.5.1.3
Modification 3: ECG recording
Description of modification to the study plan
All ECGs will be recorded as single ECGs.
Rationale for introducing the modification
Triplicate ECGs were collected in patients enrolled under the study protocol versions 1-5. 


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The established data base is expected to be sufficient to model changes of QT after 
BAY1163877 dosing, i.e. single ECGs for safety assessment are sufficient.
List of CSP sections affected by this modification 
Synopsis, Sections: 6 Study design, 9.1.2.1.2 Screening, 9.1.2.3.1 Cycle 1, 9.5.3.4
Electrocardiogram, 16.1 Study flow chart.
15.5.1.4
Modification 4: Biomarker assessment in serum
Description of modification to the study plan
Assessment of biomarkers in blood will no longer be performed.
Rationale for introducing the modification
A sufficient set of data was collected to correlate BAY1163877 dosing and changes of 
FGFR23. Serum calcium and phosphate will continue to be monitored in the safety 
assessments.
List of CSP sections affected by this modification 
Synopsis, Sections: 6 Study design, 9.1.2.1.2 Screening, 9.1.2.3.1 Cycle 1, 9.1.2.3.2
Subsequent Cycles (Cycles 2-13), 9.1.2.3.3 Subsequent Cycles (Cycles ≥13), 9.1.2.3.4
Follow up, 9.4.4 Biomarker investigation, 9.5.4.2 Laboratory examinations, 16.1 Study 
flow chart, 16.2 Laboratory examinations.
15.5.1.5
Modification 5: Dose administration
Description of modification to the study plan
BAY 1163877 can be administered regardless of food intake.
Rationale for introducing the modification
No changes of the PK of BAY 1163877 was observed after intake of food. 
List of CSP sections affected by this modification 
Sections 8.4.2.2 and 8.4.2.2.1.
15.5.1.6
Modification 6: Minor corrections/inconsistencies/change of sponsor 
name
Description of modification to the study plan
Minor text modifications and corrections of omissions or terminology were done. 
Moreover, section numbering was amended according to the current template (i.e. title 
page and synopsis were numbered at level 1). Therefore, all following section numbers 
changed accordingly.
Rationale for introducing the modification
These changes were done for clarification and to ensure correct and consistent wording. 
Moreover, the name of the sponsor Bayer Health Care AG was renamed to Bayer AG. The 
data management department of Nuvisan became part of Linical. 


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List of CSP sections affected by this modification 
Title page, Synopsis, Sections: 6 Study design, 8.2 Identity of study treatment, 8.9.1 Drug-
drug interaction relevant for BAY 1163877, 8.9.2 Prohibited concomitant medication, 
8.9.3 Permitted concomitant medication, 9.3.1 Tumor evaluation, 9.4.1.1 Cardiovasvular 
assessments, 9.5.3.2 Ophthalmological examination, 11.1 Data recording, 11.3 Data 
processin, 16.8 Response evaluation criteria in solid tumors.
15.5.2 Changes of protocol
In this section, all affected protocol sections are detailed; the sequence of the sections 
follows the structure of the original protocol. In the display of modifications, the “old 
text” refers to the protocol version preceding this amendment. Deletions are crossed out in 
the “old text”. Additions are underlined in the “new text”. Corrections of typing errors, 
omissions or terminology (minor corrections) are not highlighted in this amendment.
15.5.2.1
Title page
This section was changed as a result of Modifications 1 and 6.
Old text:
Title page
Integrated Clinical Study Protocol
No.  BAY 1163877 / 16443
Sponsor:
Bayer HealthCare AG,  D-51368 Leverkusen,  Germany
New text:
1
Title page
Integrated Clinical Study Protocol
No.  BAY 1163877 / 16443
Sponsor:
Sponsor (Non-US): Bayer AG, D-51368 Leverkusen,  
Germany
Sponsor (US territory): Bayer HealthCare Pharmaceuticals 
Inc., 100 Bayer Boulevard, P.O. Box 915, Whippany 
NJ 07981-0915, USA


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15.5.2.2
Synopsis
This section was changed as a result of Modifications 1, 2, 3, 4 and 6.
Old text:
Synopsis
Diagnosis and main criteria for 
inclusion

…..

Adequate bone marrow, liver and renal function as 
assessed by the following laboratory requirements 
conducted within 7 days of starting the study 
treatment:
-
Hemoglobin ≥ 9.0 g/dL; subjects taking 
chronic erythropoietin consistent with 
institutional guidelines can be included. 
-
…..
-
Amylase and lipase ≤ 2.5 x ULN
-
…
-
Glomerular filtration rate (GFR) 
≥60 mL/min/1.73 m2 according to the 
modified diet in renal disease (MDRD) 
abbreviated formula

….
Methodology 
Eligible cancer subjects will be enrolled at multiple 
centers in Europe and Asia. In total, the “on study” 
period for the subjects comprises 3 phases:
…
The complete duration of the study (Part 1 and Part 2) 
depends on the number of dose-escalation steps in 
Part 1 and will be approximately 2 years.
…
Electrocardiogram (ECG): 12-lead ECG readings will 
be performed at screening, on Cycle 1, Days -3 and -2 
(“tablet bridging cohort” and “food effect assessment” 
only), on Cycle 1, Days 1, 2, and 15, thereafter on 
Day 1 of each subsequent Cycle, and at the EOT visit. 
At screening and in Cycle 1, ECG readings should 
be done in triplicate. The triplicate ECGs will be 
recorded in close sequence and not more than 2 minutes 
apart. In all subsequent Cycles (Cycle ≥ 2) and at the 
EOT visit, ECG readings will be performed as single 


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readings.
Pharmacodynamic (PD) biomarkers: In an attempt to 
demonstrate the mechanism of action of BAY 1163877, 
biomarkers will be studied in blood (serum) and tissue 
samples.
Biomarker analysis in serum
Blood (serum) samples for quantification of fibroblast 
growth factor 23 (FGF23), phosphate and calcium 
levels will be collected at screening, on Days 1*, 8* and 
15* of Cycles 1-12, on Days 1 and 11 of Cycles ≥ 13, 
and at EOT visit. In subjects included in study Part 1 
(all comer) an additional blood (serum) sample will be 
collected on Cycle 1, Day 3*.
* Blood collection before administration of morning dose only for Cycle 1 
of Part 1 and Part 2.
Biomarker analysis in tumor tissue
…
Number of subjects
Approximately 200 subjects will be enrolled in the pre-
treatment phase of the study.
…

Study Part 2 / MTD expansion (sqNSCLC + 
LAC + BC + SCCHN): 
40 additional subjects will be enrolled to have 
20 evaluable subjects with sqNSCLC or LAC and a 
cohort of 20 evaluable subjects with BC or SCCHN 
treated at MTD (at least 8 subjects per indication).


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New text:
2
Synopsis
Diagnosis and main criteria for 
inclusion

…

Adequate bone marrow, liver and renal function 
as assessed by the following laboratory 
requirements conducted within 7 days of starting 
the study treatment:
-
…
-
Lipase ≤ 5 x ULN
-
…
-
Glomerular filtration rate (GFR) 
≥30 mL/min/1.73 m2 according to the modified 
diet in renal disease (MDRD) abbreviated 
formula

…
Methodology 
Eligible cancer subjects will be enrolled at multiple 
centers worldwide. In total, the “on study” period for 
the subjects comprises 3 phases:
…
The complete duration of the study (Part 1 and Part 2) 
depends on the number of dose-escalation steps in 
Part 1 and will be approximately 7 years.
…
Pharmacokinetics (PK):
…
In the MTD expansion cohorts, in a maximum of 8 
subjects with moderately impaired renal function at 
baseline (glomerular filtration rate [GFR] of 30 to 
59 mL/min/1.73 m2 according to the modified diet in 
renal disease [MDRD] abbreviated formula), serial PK 
blood samples will be collected on Cycle 1 Day 1 and 
Day 15.
…
Electrocardiogram (ECG): 12-lead ECG readings will 
be performed at screening, on Cycle 1, Days -3 and -2 
(“tablet bridging cohort” and “food effect assessment” 
only), on Cycle 1, Days 1, 2, and 15, thereafter on 


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Day 1 of each subsequent Cycle, and at the EOT visit. 
Pharmacodynamic (PD) biomarkers: In an attempt to 
demonstrate the mechanism of action of BAY 1163877, 
biomarkers will be studied in tissue samples.
Biomarker analysis in tumor tissue
…
Number of subjects
Subjects will be enrolled in the pre-treatment phase of 
the study to recruit enough subjects with present high 
FGFR expression levels for the following study parts.
….

Study Part 2 / MTD expansion (sqNSCLC + 
LAC + BC + SCCHN): 
Additional subjects will be enrolled to have 
20 evaluable subjects with sqNSCLC or LAC and a 
cohort of approximately 30 evaluable subjects with BC 
and at least 8 subjects with SCCHN treated at MTD.
15.5.2.3
6. Study design
This section was changed as a result of Modifications 1, 2, 3, 4 and 6.
Old text:
Design overview
This is a Phase I, first-in-human, open-label, non-randomized, multi-center, 2-part, dose-
escalation study of BAY 1163877 in sequential cohorts of subjects with refractory, locally 
advanced or metastatic solid tumors. The study will be conducted at multiple centers in 
Europe and Asia.
…
The complete duration of the study (Part 1 and Part 2) depends on the number of dose-
escalation steps in Part 1 and will be approximately 2 years.
…
It is expected that approximately 200 subjects will be enrolled in the pre-treatment phase 
of the study and approximately 92 subjects will be enrolled in the treatment phase.
…
Targeted / planned enrollment:
…

Study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN): 40 additional 


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subjects will be enrolled to have 20 evaluable subjects with sqNSCLC or LAC and 20
evaluable subjects with BC or SCCHN (at least 8 subjects per indication) treated at MTD.
PK assessments will be performed in all subjects participating in study Part 1 / dose 
escalation and MTD expansion (all comer). Additionally, PK assessments are planned in 
at least 12 subjects participating in study Part 2 / MTD expansion (sqNSCLC + LAC + BC 
+ SCCHN) such that valid PK data are available in 8 subjects. Food effect PK assessment 
is planned in approximately 8 subjects enrolled in the MTD expansion cohorts (study Part 
1 and Part 2). Subjects participating in “food effect assessment” in study Part 2 may be 
included in the total sample size of 12 if all protocol requirements are met.
…
Treatment: Subjects with PK assessment (all subjects of study Part 1 and at least 
12 subjects of study Part 2) will receive BAY 1163877 (tablet or solution) on a continuous 
schedule starting with single-dose administration on Cycle 1, Day 1, followed by a “drug-
free day” (to enable single dose PK assessments). Treatment with BAY 1163877 will 
resume on Day 3 of Cycle 1 if no protocol-defined dose-limiting toxicities (DLTs) are 
reported. Starting on Cycle 1, Day 3, the study drug will be self-administered twice daily 
for the remaining 19 days of Cycle 1. For subsequent cycles, study drug will be 
administered twice daily for 21 days until the maximum tolerated dose is determined.
…
Pharmacokinetics (PK):  Single- and multiple-dose PK of BAY 1163877 will be 
evaluated in plasma samples collected on Cycle 1, Day -3 in the “tablet bridging cohort”, 
and on Cycle 1, Days 1 and 15 in all subjects participating in Part 1 (all comer) and in at 
least 12 subjects participating in Part 2 (sqNSCLC + LAC + BC + SCCHN). In 
approximately 8 subjects enrolled in the MTD expansion cohorts (study Part 1 and Part 2), 
the effect of food on the PK of BAY 1163877 will be determined by comparing exposures 
on Cycle 1 Day -3 (administration after consumption of a high-fat, high-calorie breakfast) 
and Cycle 1 Day 1 (administration after an overnight fast of at least 8 hours), see 
Section 8.1.
…
Electrocardiogram (ECG): 12-lead ECG readings will be performed at screening, on 
Cycle 1, Days -3 and -2 (“tablet bridging cohort” and “food effect assessment”, only), on 
Cycle 1, Days 1, 2, and 15, thereafter on Day 1 of each subsequent Cycle, and at the EOT 
visit. At screening and in Cycle 1, ECG readings should be done in triplicate. The 
triplicate ECGs will be recorded in close sequence and not more than 2 minutes apart. In 
all subsequent Cycles (Cycle ≥ 2) and at the EOT visit, ECG readings will be performed 
as single readings. The time points for ECG readings and further details are provided in 
Section 9.5.3.4.
Pharmacodynamic (PD) biomarkers: In an attempt to demonstrate the mechanism of 
action of BAY 1163877 biomarkers will be studied in blood (serum) and tissue samples 
(for details see Section 9.4.4). 
Biomarker analysis in serum: Blood (serum) samples for quantification of fibroblast 
growth factor 23 (FGF23), phosphate and calcium levels will be collected at screening, on 


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Days 1, 8 and 15 of Cycles 1-12, on Days 1 and 11 of Cycles ≥13, and at EOT visit. In 
subjects included in study Part 1 (all comer) an additional blood (serum) sample will be 
collected on Cycle 1, Day 3. Biomarker analysis in tumor tissue: Biomarker analysis will 
be done at screening for subject stratification in the MTD expansion cohorts (Part 1: all 
comer; Part 2: sqNSCLC + LAC + BC + SCCHN) according to FGFR expression levels / 
FGFR mutation using either an archival tumor tissue specimen or fresh tumor biopsy 
material (see Section 7.1.1, inclusion criteria).
New text:
Design overview
This is a Phase I, first-in-human, open-label, non-randomized, multi-center, 2-part, dose-
escalation study of BAY 1163877 in sequential cohorts of subjects with refractory, locally 
advanced or metastatic solid tumors. The study will be conducted at multiple centers 
worldwide.
…
The complete duration of the study (Part 1 and Part 2) depends on the number of dose-
escalation steps in Part 1 and will be approximately 7 years.
…
Planned sample size:
Subjects will be enrolled in the pre-treatment phase of the study to recruit enough subjects 
with present high FGFR expression levels in the screening phase of the treatment phase.
…
Targeted / planned enrollment:
…

Study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN): additional 
subjects will be enrolled to have 20 evaluable subjects with sqNSCLC or LAC and 
approximately 30 evaluable subjects with BC and at least 8 subjects with SCCHN treated 
at MTD.
PK assessments will be performed in all subjects participating in study Part 1 / dose 
escalation and MTD expansion (all comer). Additionally, PK assessments are planned in 
at least 12 subjects participating in study Part 2 / MTD expansion (sqNSCLC + LAC + BC 
+ SCCHN) such that valid PK data are available in 8 subjects and in a maximum of 8 
subjects of the MTD expansion cohorts with impaired renal function at baseline. Food 
effect PK assessment is planned in approximately 8 subjects enrolled in the MTD 
expansion cohorts (study Part 1 and Part 2). Subjects participating in “food effect 
assessment” in study Part 2 may be included in the total sample size of 12 if all protocol 
requirements are met.
…
Treatment: Subjects with PK assessment (all subjects of study Part 1 and at least 
12 subjects of study Part 2 and a maximum of 8 subjects of the MTD expansion cohorts 


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with impaired renal function at baseline) will receive BAY 1163877 (tablet or solution) on 
a continuous schedule starting with single-dose administration on Cycle 1, Day 1, 
followed by a “drug-free day” (to enable single dose PK assessments). Treatment with 
BAY 1163877 will resume on Day 3 of Cycle 1 if no protocol-defined dose-limiting 
toxicities (DLTs) are reported. Starting on Cycle 1, Day 3, the study drug will be self-
administered twice daily for the remaining 19 days of Cycle 1. For subsequent cycles, 
study drug will be administered twice daily for 21 days until disease progression or as 
long as clinical benefit is assumed by the investigator or until unacceptable toxicity 
occurs.
…
Pharmacokinetics (PK):  Single- and multiple-dose PK of BAY 1163877 will be 
evaluated in plasma samples collected on Cycle 1, Day -3 in the “tablet bridging cohort”, 
and on Cycle 1, Days 1 and 15 in all subjects participating in Part 1 (all comer) and in at 
least 12 subjects participating in Part 2 (sqNSCLC + LAC + BC + SCCHN). In 
approximately 8 subjects enrolled in the MTD expansion cohorts (study Part 1 and Part 2), 
the effect of food on the PK of BAY 1163877 will be determined by comparing exposures 
on Cycle 1 Day -3 (administration after consumption of a high-fat, high-calorie breakfast) 
and Cycle 1 Day 1 (administration after an overnight fast of at least 8 hours), see 
Section 8.1.  In the MTD expansion cohorts, in a maximum of 8 subjects with moderately 
impaired renal function at baseline (glomerular filtration rate [GFR] of 30 to 59 
mL/min/1.73 m2 according to the modified diet in renal disease [MDRD] abbreviated 
formula), serial PK blood samples will be collected on Cycle 1 Day 1 and Day 15.
…
Electrocardiogram (ECG): 12-lead ECG readings will be performed at screening, on 
Cycle 1, Days -3 and -2 (“tablet bridging cohort” and “food effect assessment”, only), on 
Cycle 1, Days 1, 2, and 15, thereafter on Day 1 of each subsequent Cycle, and at the EOT 
visit. In all Cycles and at the EOT visit, ECG readings will be performed as single 
readings. The time points for ECG readings and further details are provided in 
Section 9.5.3.4.
Pharmacodynamic (PD) biomarkers: In an attempt to demonstrate the mechanism of 
action of BAY 1163877 biomarkers will be studied in tissue samples (for details see 
Section 9.4.4). 
Biomarker analysis in tumor tissue: Biomarker analysis will be done at screening for 
subject stratification in the MTD expansion cohorts (Part 1: all comer; Part 2: sqNSCLC + 
LAC + BC + SCCHN) according to FGFR expression levels / FGFR mutation using either 
an archival tumor tissue specimen or fresh tumor biopsy material (see Section 7.1.1, 
inclusion criteria).
15.5.2.4
6.2 Justification of the design
This section was changed as a result of Modification 1.
Old text:
The study will be conducted at multiple sites in Europe and Asia to ensure recruitment of a 


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sufficient number of subjects with advanced solid organ malignancies. The sites must be 
specialized in tumor assessment according to RECIST 1.1 and must be well equipped to 
conduct the efficacy and safety evaluations required by the protocol.
…
New text:
The study will be conducted at multiple sites worldwide to ensure recruitment of a 
sufficient number of subjects with advanced solid organ malignancies. The sites must be 
specialized in tumor assessment according to RECIST 1.1 and must be well equipped to 
conduct the efficacy and safety evaluations required by the protocol.
…
15.5.2.5
7.1.1.2
Eligibility criteria for study treatment
This section was changed as a result of Modification 1.
Old text:
…..

Adequate bone marrow, liver and renal function as assessed by the following 
laboratory requirements conducted within 7 days of starting the study treatment:
-
Hemoglobin ≥9.0 g/dL; subjects taking chronic erythropoietin consistent with 
institutional guidelines can be included. 
-
…..
-
Amylase and lipase ≤ 2.5 x ULN
-
…
-
Glomerular filtration rate (GFR) ≥60 mL/min/1.73 m2 according to the modified 
diet in renal disease (MDRD) abbreviated formula
….
New text:
…

Adequate bone marrow, liver and renal function as assessed by the following 
laboratory requirements conducted within 7 days of starting the study treatment:
-
…
-
Lipase ≤ 5 x ULN
-
…
-
Glomerular filtration rate (GFR) ≥30 mL/min/1.73 m2 according to the modified 
diet in renal disease (MDRD) abbreviated formula
…


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15.5.2.6
7.1.2.3
Exclusion criteria
This section was changed as a result of Modification 1.
Old text:
…
Medical and surgical history
…

History or current condition of an uncontrolled cardiovascular disease including 
congestive heart failure (CHF) > NYHA (New York Heart Association) Class 2, unstable 
angina (symptoms of angina at rest) or new-onset angina (within last 3 months) or 
myocardial infarction (MI) within past 6 months and cardiac arrhythmias requiring anti-
arrhythmic therapy (beta-blockers or digoxin are permitted)

Left ventricular ejection fraction (LVEF) < 50% as assessed by echocardiography 
performed at screening

Subjects with history and / or current evidence of endocrine alteration of 
calciumphosphate homeostasis (e.g. parathyroid disorder, history of parathyroidectomy, 
tumor lysis, tumoral calcinosis)

Prior pancreatitis, intra- or extrahepatic biliary obstruction within the previous 12 
months, or history of malignant obstruction requiring biliary stent unless stably treated 
with no prior obstruction or blockage of stent

Pericarditis 

Current evidence of corneal disorder / keratopathy including but not limited to 
bullous / band keratopathy, corneal abrasion, inflammation / ulceration, 
keratoconjunctivitis etc. (to be confirmed by ophthalmologic examination). Pre-existing 
cataract is not an exclusion criterion.

History of human immunodeficiency virus (HIV) infection or chronic 
hepatitis B or C 
…
Medication, drug use and special behavioral patterns

…

Concomitant therapies that cannot be discontinued or switched to a different 
medication prior to study entry that are known to increase serum calcium and / or 
phosphate levels, especially calcium, phosphate, vitamin D, parathyroid hormone 
(parathormone) are not permitted within 4 weeks prior to start of study treatment). 
Bisphosphonates, zolendronic acid or monoclonal anti-RANK ligand antibodies 
(denosumab) are allowed.

Anticancer chemotherapy or immunotherapy during the study or within 5-half-
lives prior to start of study treatment. Mitomycin C, nitrosoureas or monoclonal antibodies 


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with anticancer activity (e.g. bevacizumab or cetuximab etc.) should not be given within 6 
weeks of pre-treatment biopsy for biomarker (p-ERK1/2) studies. Acute toxic effects of 
previous anticancer chemotherapy or immunotherapy have to be normalized completely 
(excluding alopecia). Anticancer therapy is defined as any agent or combination of agents 
with clinically proven anti-tumor activity administered by any route with the purpose of 
affecting the malignancy, either directly or indirectly, including palliative and therapeutic 
endpoints.
…
Electrocardiogram (ECG), blood pressure, heart rate

Systolic / diastolic blood pressure ≤ 110/70 mmHg and heart rate ≥ 100/min 
(measured with the subject in a sitting position for at least 2 minutes). Measurements will 
be in duplicate and the mean value will be used for assessment.
New text:
…
Medical and surgical history
…

History or current condition of an uncontrolled cardiovascular disease including 
congestive heart failure (CHF) > NYHA (New York Heart Association) Class 2, unstable 
angina (symptoms of angina at rest) or new-onset angina (within last 3 months) or 
myocardial infarction (MI) within past 6 months and cardiac arrhythmias requiring anti-
arrhythmic therapy (beta-blockers or digoxin are permitted)

History of human immunodeficiency virus (HIV) infection or chronic 
hepatitis B or C 
…
Medication, drug use and special behavioral patterns

…

Concomitant therapies that cannot be discontinued or switched to a different 
medication prior to study entry that are known to increase serum phosphate levels are not 
permitted within 4 weeks prior to start of study treatment). 

Anticancer chemotherapy or immunotherapy during the study or within 5-half-
lives prior to start of study treatment. Mitomycin C, nitrosoureas or monoclonal antibodies 
with anticancer activity (e.g. bevacizumab or cetuximab etc.) should not be given within 6 
weeks before starting to receive study treatment or within 6 weeks of pre-treatment biopsy 
for biomarker (p-ERK1/2) studies. Acute toxic effects of previous anticancer 
chemotherapy or immunotherapy have to be normalized completely (excluding alopecia). 
Anticancer therapy is defined as any agent or combination of agents with clinically proven 
anti-tumor activity administered by any route with the purpose of affecting the 
malignancy, either directly or indirectly, including palliative and therapeutic endpoints.


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…
Electrocardiogram (ECG), blood pressure, heart rate

Systolic / diastolic blood pressure ≤ 100/60 mmHg and heart rate ≥ 100/min 
(measured with the subject in a sitting position for at least 2 minutes). 
15.5.2.7
8.2
Identity of study treatment
This section was changed as a result of Modification 6.
Old text:
Table 6-2:
Identity of test drug (IMP):  BAY 1163877 tablet formulation  
Generic name / brand name / INN
Not applicable
Substance code number(s)
BAY 1163877 as BAY 1213802
Material / formulation) number(s)
81820457 for BAY 1163877 HCL TAB 50.0 mg 
363 COAT
81820449 for BAY 1163877 HCL TAB 200.0 mg 
364 COAT
New text:
Table 8-2:
Identity of test drug (IMP):  BAY 1163877 tablet formulation  
Generic name / brand name / INN
Not applicable
Substance code number(s)
BAY 1163877 as BAY 1213802
Material / (formulation)
BAY 1163877 HCL TAB 50.0 mg 363 COAT
BAY 1163877 HCL TAB 200.0 mg 364 COAT
15.5.2.8
8.4.2.2
Mode of administration
This section was changed as a result of Modification 5.
Old text:
BAY 1163877 will be administered per os (p.o.) at least 1 hour before or 2 hours after a 
meal or snack. …
New text:
BAY 1163877 will be administered per os (p.o.). …
15.5.2.9
8.4.2.2.1 Food effect assessment
This section was changed as a result of Modification 5.
Old text:
…
Starting with Cycle 1, Day 3, BAY 1163877 will be taken twice daily (at least 1 hour 
before or 2 hours after a meal).
New text:
…


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Starting with Cycle 1, Day 3, BAY 1163877 will be taken twice daily.
15.5.2.10 8.9.1
Drug-drug interactions relevant for BAY 1163877 
This section was changed as a result of Modification 6.
Old text:
…
Initial in vitro study results indicate that BAY 1163877 is a mechanism-based 
(irreversible) inhibitor of CYP 3A4 and additional studies are planned to further 
investigate. Since several commonly used drugs are metabolized by CYP 3A4, subjects 
should be proactively closely monitored. 
…
New text:
…
Initial in vitro study results with BAY 1163877 indicate minor mechanism-based 
(irreversible) inhibition potential towards CYP 3A4. Since several commonly used drugs 
are metabolized by CYP 3A4, subjects should be proactively closely monitored for side 
effects of these comedications due to potentially increased systemic exposure. 
…
15.5.2.11 8.9.2
Prohibited concomitant therapy
This section was changed as a result of Modification 6.
Old text:
Concomitant therapy with the following medication is NOT allowed:

Anticancer chemotherapy or immunotherapy during the study or within 5-half-
lives prior to start of study treatment. Acute toxic effects of previous anticancer 
chemotherapy or immunotherapy have to be normalized completely (excluding alopecia, 
anemia and / or hypothyroidism). Anticancer therapy is defined as any agent or 
combination of agents with clinically proven anti-tumor activity administered by any route 
with the purpose of affecting the malignancy, either directly or indirectly, including 
palliative and therapeutic endpoints.
…
New text:
Concomitant therapy with the following medication is NOT allowed:

Anticancer chemotherapy or immunotherapy during the study or within 5-half-
lives prior to start of study treatment. Antibody treatment should not be given within 6 
weeks before starting to receive study treatment. Acute toxic effects of previous anticancer 
chemotherapy or immunotherapy have to be normalized completely (excluding alopecia, 
anemia and / or hypothyroidism). Anticancer therapy is defined as any agent or 


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combination of agents with clinically proven anti-tumor activity administered by any route 
with the purpose of affecting the malignancy, either directly or indirectly, including 
palliative and therapeutic endpoints.
…
15.5.2.12 8.9.3
Permitted concomitant therapy 
This section was changed as a result of Modification 6.
Old text:
…

Antiemetic therapy with 5-hydroxytryptamine-3-receptor antagonist and 
dexamethasone is allowed. 
…
New text:
…

Antiemetic therapy is allowed. 
…
15.5.2.13 9.1.2.1.2 Screening
This section was changed as a result of Modifications 3, 4 and 6.
Old text:
….
Within 28 Days Prior to First Dose of BAY 1163877  
…

Triplicate 12-lead ECG readings (see Section 9.5.3.4)
…
Within 7 Days Prior to First Dose of BAY 1163877 
…

Echocardiography or MUGA scan

Blood and urine collection for safety laboratory tests, for details see Table 16-4

Blood (serum) samples collection for biomarker investigations, see Section 14.2
…
New text:
…
Within 28 Days Prior to First Dose of BAY 1163877  


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…

Single 12-lead ECG reading (see Section 9.5.3.4) 
…
Within 7 Days Prior to First Dose of BAY 1163877 
…

Blood and urine collection for safety laboratory tests. In case of abnormal results 
caused by intercurrent diseases, short-term treatable conditions or other temporary health 
disorders, the investigator may decide to repeat the respective screening parameter(s). As a 
rule, up to 2 repetitions are acceptable, for details see Table 16-4
…
15.5.2.14 9.1.2.3.1 Cycle 1
This section was changed as a result of Modifications 3 and 4.
Old text:
…
Days 1-3 (possible overnight stay)
Day 1
…

Triplicate 12-lead ECG readings (see Section 9.5.3.4)
…

Blood (serum) samples collection for biomarker investigations, see Section 14.2

PK sampling (all subjects of study Part 1 and at least 12 subjects of study Part 2)
…
Day 2 

No administration of BAY 1163877 (“drug-free day”) for subjects with PK 
assessment (all subjects of study Part 1 and at least 12 subjects with PK assessment in 
study Part 2 [including “food effect assessment”]) 
…

Triplicate ECG readings (see Section 7.5.3.4) 
…

PK sampling (all subjects of study Part 1 and at least 12 subjects of study Part 2) 
…
Day 3
…


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
PK sampling (all subjects of study Part 1 and at least 12 subjects of study Part 2)
…
Day 8 ± 1 (Visit)
…

Blood (serum) samples collection for biomarker investigations, see Section 14.2. 
…
Day 15
…

Triplicate ECG readings (see Section 7.5.3.4) 
…

Blood (serum) samples collection for biomarker investigations, see Section 14.2. 

PK sampling (all subjects of study Part 1 and at least 12 subjects of study Part 2)
…
New text:
…
Days 1-3 (possible overnight stay)
Day 1
…

Single 12-lead ECG reading (see Section 9.5.3.4)

…

PK sampling (all subjects of study Part 1 and at least 12 subjects of study Part 2) 
and a maximum of 8 subjects of the MTD expansion cohorts with impaired renal function 
at baseline)
…
Day 2 

No administration of BAY 1163877 (“drug-free day”) for subjects with PK 
assessment (all subjects of study Part 1 and at least 12 subjects with PK 
assessment in study Part 2 and a maximum of 8 subjects with PK assessment in the 
MTD expansion cohorts with impaired renal function at baseline [including “food 
effect assessment”])
…

Single 12-lead ECG readings (see Section 9.5.3.4)
…


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
PK sampling (all subjects of study Part 1 and at least 12 subjects of study Part 2
and a maximum of 8 subjects of the MTD expansion cohorts with impaired renal 
function at baseline) 
…
Day 3
…

PK sampling (all subjects of study Part 1 and at least 12 subjects of study Part 2
and a maximum of 8 subjects of the MTD expansion cohorts with impaired renal 
function at baseline)
…
Day 15
…

ECG reading (see Section 7.5.3.4) 
…

PK sampling (all subjects of study Part 1 and at least 12 subjects of study Part 2
and a maximum of 8 subjects of the MTD expansion cohorts with impaired renal function 
at baseline)
…
15.5.2.15 9.1.2.3.2 Subsequent Cycles (Cycles 2-12) 
This section was changed as a result of Modification 4.
Deleted old text:
Day 1 (Visit)
…

Blood (serum) samples collection for biomarker investigations, see Section 14.2. 
…
Day 8 ± 1 and Day 15 ± 1 (Visits)
…

Blood (serum) samples collection for biomarker investigations, see Section 14.2. 
…
15.5.2.16 9.1.2.3.3 Subsequent Cycles (Cycles ≥13)
This section was changed as a result of Modification 4.
Deleted old text:


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Day 1 (Visit)
…

Blood (serum) samples collection for biomarker investigations, see Section 14.2. 
…
Day 11 (Visit)
…

Blood (serum) samples collection for biomarker investigations, see Section 14.2. 
…
15.5.2.17 9.1.2.3.4 Follow up
This section was changed as a result of Modification 4.
Deleted old text:
…
Within 0-14 Days of Last Study Drug Administration (EOT Visit)
…

Blood (serum) samples collection for biomarker investigations, see Section 14.2. 
…
15.5.2.18 9.3.1
Tumor evaluation - response assessment (RECIST)
This section was changed as a result of Modification 6.
Old text:
…
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. For a response 
to be scored as complete response (CR) or partial response (PR), the response must be 
confirmed by a repeat CT scan (with contrast) or MRI scan (with and without contrast) 
performed 8 weeks after the response was first determined. 
New text:
…
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. For a response 
to be scored as complete response (CR) or partial response (PR), the response must be 
confirmed by a repeat CT scan (with contrast) or MRI scan (with and without contrast) 
performed not earlier than 4 weeks after the response was first determined. 


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15.5.2.19 9.4.1.1
Cardiovascular assessment
This section was changed as a result of Modification 6.
Old text:
…
-
At screening, BP must be measured in both arms to see whether there is a difference 
in blood pressure readings between the subject’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) 
-
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 
readings should be obtained and averaged.
New text:
…
-
At screening, BP must be measured in both arms to see whether there is a difference 
in blood pressure readings between the subject’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) 
…
15.5.2.20 9.4.2.1
Drug measurements
This section was changed as a result of Modification 2.
Old text:
…
Pharmacokinetic assessments will be performed in all subjects enrolled in Part 1 (dose 
escalation and MTD expansion (all comer) cohorts). The plan is to perform 
pharmacokinetic assessments in at least 12 subjects in Part 2 MTD expansion cohort 
(sqNSCLC + LAC + BC + SCCHN) such that valid PK data are available in 8 subjects. 
“Food effect assessment” will be performed in approximately 8 subjects enrolled in the 
MTD expansion cohorts (study Part 1 and Part 2).  
Blood (plasma) samples for PK assessment of BAY 1163877 will be collected at the 
following time points:
…

Cycles 2-5, Day 1: exposure-response modelling 
…
New text:
…
Pharmacokinetic assessments will be performed in all subjects enrolled in Part 1 (dose 


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escalation and MTD expansion (all comer) cohorts). The plan is to perform 
pharmacokinetic assessments in at least 12 subjects in Part 2 MTD expansion cohort 
(sqNSCLC + LAC + BC + SCCHN) such that valid PK data are available in 8 subjects. 
“Food effect assessment” will be performed in approximately 8 subjects enrolled in the 
MTD expansion cohorts (study Part 1 and Part 2). In the MTD expansion cohorts 
pharmacokinetic assessments will be performed in a maximum of 8 subjects with 
moderately impaired renal function at baseline (glomerular filtration rate [GFR] of 30 to 
59 mL/min/1.73 m2 according to the modified diet in renal disease [MDRD] abbreviated 
formula).  
Blood (plasma) samples for PK assessment of BAY 1163877 will be collected at the 
following time points:
…

Cycles 2-5, Day 1: exposure-response modelling (not in subjects with impaired 
renal function)
…
15.5.2.21 9.4.4
Biomarker investigations
This section was changed as a result of Modification 4 and 6.
Old text:
Concentrations of FGF23 will be measured by a validated ELISA assay. Instructions for 
sample collection, processing, storage and shipment will be described in a separate 
document (e.g. lab manual). PD marker investigations
Pharmacodynamic (PD) biomarkers:
In an attempt to demonstrate the mechanism of action of BAY 1163877, biomarkers will 
be studied in blood (serum) and tissue samples.
Biomarker analysis in blood (serum) samples 
Blood (serum) samples for the quantification of fibroblast growth factor 23 (FGF23), 
phosphate and calcium levels will be collected as follows:

Study Part 1 / dose escalation 
-
Screening
-
Cycle 1:  Days 1*, 3*, 8*, and 15* 
-
Cycles 2-12:  Days 1, 8, 15
-
Cycles ≥13: Days 1 and 11
-
EOT visit
-
Study Part 1 /  MTD expansion (all comer) and Study Part 2 / MTD expansion 
(sqNSCLC + LAC + BC + SCCHN)
-
Screening


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-
Cycles 1-12:  Days 1*, 8*, 15*
-
Cycles ≥13: Days 1 and 11
-
EOT visit
*Blood collection before administration of morning dose only for Cycle 1 of Part 1 and Part 2.
…
New text:
Concentrations of FGF23 will be measured by a validated ELISA assay. Instructions for 
sample collection, processing, storage and shipment will be described in a separate 
document (e.g. lab manual). 
Pharmacodynamic (PD) biomarkers:
In an attempt to demonstrate the mechanism of action of BAY 1163877, biomarkers will 
be studied in tissue samples.
…
15.5.2.22 9.5.3.2
Ophthalmological examination
This section was changed as a result of Modification 6.
Old text:
… The ophthalmologist will describe examination findings on an examination worksheet 
provided by the investigational site. The worksheet will be transferred to the site where the 
data will be transcribed to the eCRF.
New text:
… The ophthalmologist will describe examination findings on an examination worksheet 
provided by the investigational site. Any findings qualifying as an adverse event will be 
recorded accordingly.
15.5.2.23 9.5.3.4
Electrocardiogram (ECG)
This section was changed as a result of Modification 3.
Old text:
For the assessment of possible drug effects on QT/ QTc interval duration at pre-defined 
time points at screening and in Cycle 1, standard 12-lead ECGs will be recorded in 
triplicates in selected subjects dosed with 50 mg and higher. The triplicate ECGs will be 
recorded in close sequence and not more than 2 minutes apart. 
Subjects will have a single ECG recording in all subsequent cycles.
12-lead ECG readings will be performed in the supine position at the following time 
points:

Screening (triplicate ECG readings)


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
Cycle 1, Day -3 and Day -2 (triplicate ECG readings [“tablet bridging cohort” and 
“food effect assessment” only])
-
before and 2, 3 (Day -3) and 24 (Day -2) hours after single-dose administration

Cycle 1, Day 1 and Day 2 (triplicate ECG readings)
-
before and 2, 3 (Day 1) and 24 (Day 2) hours after single-dose administration

Cycle 1, Day 15 (triplicate ECG readings)
-
before morning dose, and 2 and 3 hours thereafter 
…
New text:
For the assessment of possible drug effects on QT/ QTc interval duration at pre-defined 
time points at screening and in Cycle 1, standard 12-lead ECGs will be recorded in 
triplicates in selected subjects dosed with 50 mg and higher until implementation of 
Amendment 5. The triplicate ECGs will be recorded in close sequence and not more than 
2 minutes apart. 
Subjects will have a single ECG recording in all subsequent cycles.
12-lead ECG readings will be performed in the supine position at the following time
points:

Screening (single ECG reading) 

Cycle 1, Day -3 and Day -2 (triplicate ECG readings [“tablet bridging cohort” and 
“food effect assessment” only])
-
before and 2, 3 (Day -3) and 24 (Day -2) hours after single-dose administration

Cycle 1, Day 1 and Day 2 (single ECG reading) 
-
before and 2, 3 (Day 1) and 24 (Day 2) hours after single-dose administration

Cycle 1, Day 15 (single ECG reading) 
…
15.5.2.24 9.5.4
Echocardiography / MUGA scan
This section was changed as a result of Modification 1.
Old text:
An echocardiography or MUGA (multiple gated acquisition) scan is to be done at 
screening (within 7 days prior to first study drug administration) to ensure that only 
subjects with adequate cardiac function (LVEF ≥ 50%) participate in this study.
New text:
An echocardiography or MUGA (multiple gated acquisition) scan is to be done at 


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screening (within 7 days prior to first study drug administration) to ensure that only 
subjects with adequate cardiac function (LVEF ≥ 50%) participate in this study. This is no 
longer needed after implementation of Amendment 5.
15.5.2.25 9.5.3.6
Laboratory examinations 
This section was changed as a result of Modification 4.
Deleted old text:
…
The following laboratory analyses will be performed by analysis laboratories: 
Blood tests:
-
Blood (serum) samples for quantification of FGF23 levels will be collected prior to 
administration of study drug and during the study as shown in Section 16.2 in an 
attempt to demonstrate the mechanism of action of BAY 1163877.
…
15.5.2.26 10.7
Determination of sample size
This section was changed as a result of Modifications 1 and 2.
Old text:
…
In study Part 2 / MTD expansion, additional subjects will be included in order to obtain 
further safety and PK data at the MTD level in at least 40 subjects with sqNSCLC, LAC, 
BC and SCCHN.
New text:
…
In study Part 2 / MTD expansion, additional subjects will be included in order to obtain 
further safety and PK data at the MTD level in at least 20 subjects with sqNSCLC or 
LAC, approximately 30 subjects with BC and at least 8 subjects with SCCHN.
15.5.2.27 11.1
Data recording
This section was changed as a result of Modification 6.
Old text:
…
A CRO (Nuvisan) provides the investigational site with access to an internet / web-based 
electronic data capture (EDC) computer system (termed “Inform”).  Oracle has developed 
this system as a secured data entry tool that cannot be modified by investigative sites.  The 
customized application for this protocol was developed by Nuvisan and validated 
according to Nuvisan “Standard Operating Procedures”.  Edit checks and data logic 
checks are done at the point of entry and are validated by Nuvisan.  All data entered into 


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the system is transferred to a secure server maintained by Nuvisan. 
Access to the Inform EDC system at the site, at Nuvisan and at Bayer is password 
protected.  Study access is granted to site personnel only after they have been trained in 
the use of the Inform EDC System by Nuvisan personnel or after a web-based training, 
either at the investigational site or at the investigators’ meeting.  Nuvisan and Bayer 
personnel are also required to complete the training program before they are allowed to 
access the system.  All Inform EDC system training history is documented and maintained 
by Nuvisan. 
The Inform EDC System contains a system-generated audit trail that captures any changes 
made to a data field, including who made the change, and the date and time it was made.  
This information is available both at the investigator’s site and at Nuvisan.
…
New text:
A CRO (Linical, formerly part of Nuvisan) provides the investigational site with access to 
an internet / web-based electronic data capture (EDC) computer system (termed 
“Inform”). Oracle has developed this system as a secured data entry tool that cannot be 
modified by investigative sites. The customized application for this protocol was 
developed by Linical and validated according to Lincical “Standard Operating 
Procedures”. Edit checks and data logic checks are done at the point of entry and are 
validated by Linical. All data entered into the system is transferred to a secure server 
maintained by Linical. 
Access to the Inform EDC system at the site, at Linical and at Bayer is password 
protected. Study access is granted to site personnel only after they have been trained in 
the use of the Inform EDC System by Linical personnel or after a web-based training, 
either at the investigational site or at the investigators’ meeting. Linical and Bayer 
personnel are also required to complete the training program before they are allowed to 
access the system. All Inform EDC system training history is documented and maintained 
by Linical. 
The Inform EDC System contains a system-generated audit trail that captures any changes 
made to a data field, including who made the change, and the date and time it was 
made. This information is available both at the investigator’s site and at Linical. 
…
15.5.2.28 11.3
Data processing
This section was changed as a result of Modification 6.
Old text:
…
For data coding (e.g. AEs, medication), Nuvisan will transfer the verbatim terms and 
internationally recognized and accepted dictionaries will be used by the sponsor.
…


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New text:
…
For data coding (e.g. AEs, medication), Linical will transfer the verbatim terms and 
internationally recognized and accepted dictionaries will be used by the sponsor. 
…
15.5.2.29 16.1
Study flow chart 
This section was changed as a result of Modifications 2, 3 and 4.


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Old text:
Table 14-1: Study flow chart: Pre-Treatment – Study Part 1 and Part 2
Measures / actions
FGFR expression / 
FGFR mutation 
testing 
Screening
Only for subjects 
recruited for MTD 
expansion cohorts 
(Part 1 and Part 2)  
Within 28 Days* 
Within 7 Days*
before first study drug 
administration
…
Demographic data
X(K)
X(K)
Documentation of the primary 
diagnosis (refractory, locally 
advanced or metastatic solid 
tumor) using the complete 
pathological report
X(K)
X(K)
Complete medical / oncological 
history
X(K)
X(K)
TNM classification
X(K)
X(K)
…
Echocardiography or MUGA scan
X
…
Blood / urine collection for safety 
lab tests(G)
X
X
Blood (serum) samples collection 
for biomarker investigations(H)
X
Only females: Urine pregnancy 
test
X
Calculation of eGFR(I)
X
Ophthalmological examination at 
consultant
X
CT / MRI scans 
X
Documentation of lesion(s) 
according to RECIST v1.1
X
Adverse events(J)
(X)
X
X
(H)
Biomarker investigations in blood (serum) samples: see Table 16-5 - Table 16-7, and 
separate document e.g. Laboratory Manual for details.
(I)
For calculation of eGFR (estimated glomerular filtration rate), see Section 14.9.
(J)
Signs and symptoms that existed prior to signing informed consent should be recorded as 
medical history findings. Signs and symptoms worsened after the informed consent was 
signed as well as any sign or symptom that begins after the informed consent was signed 
(even if prior to start of study medication) should be recorded on an adverse event page of 
the eCRF using CTCAE v4.03. AE does only to be recorded for period of FGFR expression / 


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FGFR mutation testing in pre-treatment in case an invasive procedure was performed to 
obtain tumor material.
(K)
Documentation has not to be provided twice for subjects enrolled in the MTD expansion 
cohorts.
New text:
Table 16-1: Study flow chart: Pre-Treatment – Study Part 1 and Part 2 
Measures / actions
FGFR expression / 
FGFR mutation 
testing 
Screening
Only for subjects 
recruited for MTD 
expansion cohorts 
(Part 1 and Part 2)  
Within 28 Days* 
Within 7 Days*
before first study drug 
administration
…
Demographic data
X(J)
X(J)
Documentation of the primary 
diagnosis (refractory, locally 
advanced or metastatic solid 
tumor) using the complete 
pathological report
X(J)
X(J)
Complete medical / oncological 
history
X(J)
X(J)
TNM classification
X(J)
X(J)
…
Blood / urine collection for safety 
lab tests(G)
X
X
…
(H)
For calculation of eGFR (estimated glomerular filtration rate), see Section 16.9.
(I)
Signs and symptoms that existed prior to signing informed consent should be recorded as 
medical history findings. Signs and symptoms worsened after the informed consent was 
signed as well as any sign or symptom that begins after the informed consent was signed 
(even if prior to start of study medication) should be recorded on an adverse event page of 
the eCRF using CTCAE v4.03. AE does only to be recorded for period of FGFR expression / 
FGFR mutation testing in pre-treatment in case an invasive procedure was performed to 
obtain tumor material.
(J)
Documentation has not to be provided twice for subjects enrolled in the MTD expansion 
cohorts.


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Old text:
Table 14-3: Study flow chart: Treatment (Cycle ≥ 1) and Follow-up – Study Part 1 and Part 2 (continued)
Measures / actions
TREATMENT
FOLLOW-
UP
Cycle 1 
(21 days)
Cycles 2-12
(21 days)
Cycles ≥13
(21 days)
EOT Visit
Within 
0-14 days 
after last 
dose
FU-Visit / 
Phone Call(A)
At 30-35 days 
after last 
dose
Day (D)
D1
D2
D3
D8 ±1
D15
D1
D8 ±1 D15 ±1
D1
D1
1
…
12-lead ECG readings(D)
X
X
X
X
X
X
…
Blood (serum) samples collection for 
biomarker investigations(G)
X
(X)
X
X
X
X
X
X
X
X
24-hour urine collection(N)
X
Obtain tumor biopsy for biomarker 
tests(H)
X
(Cy 2 
only)
PK blood sampling(I)
XX
X
PK blood sampling for PK / PD 
modeling(J)
X
…
Dispense / return of BAY 1163877 and 
diary(K)
X
X
X
X
X
X
X
X
X
X


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Table 14-3: 
Study flow chart: Treatment (Cycle ≥ 1) and Follow-up – Study Part 1 and Part 2 (Continued)
Administration of BAY 1163877
if PK assessment (L)
X
Continuous, twice-daily administration 
Administration of BAY 1163877
if no PK assessment(M)
   Continuous, twice-daily administration
..
(D) In Cycle 1, all 12-lead ECGs should be performed in triplicate in close sequence and not more than 2 minutes apart. ECG readings will be 
performed at the following time points:
Cycle 1, Day 1 and Day 2 (triplicate ECG readings): before and 2, 3 (Day 1) and 24 (Day 2) hours after single-dose administration 
Cycle 1, Day 15 (triplicate ECG readings): before morning dose, and 2 and 3 hours thereafter 
Cycle ≥ 2, Day 1 (single ECG reading): after morning dose
EOT visit (single ECG reading)
(E) Safety laboratory tests, see Table 14-4
(F)
For calculation of eGFR (estimated glomerular filtration rate), see Section 14.9
(G) Biomarker investigations blood (serum) samples, see Table 14-5 - Table 14-7, and Laboratory Manual for details. 
(H)
A tumor biopsy on Cycle 2, Day 1 will be obtained from all subjects who agreed on this at screening. The biopsy sample will be send to 
laboratory for biomarker evaluation, see Table 14–5, Table 14 6and Table 14 7. 
A biopsy on Cycle 2, Day 1 is optional … 
…for subjects in study Part 1 / dose-escalation (all comer).
…for subjects in study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN).
A biopsy on Cycle 2, Day 1 is mandatory … 
…for subjects in study Part 1 / MTD expansion (all comer).
(I)
PK sampling will be done as follows (for details see Laboratory Manual):•

Cycle 1, Day 1: single-dose PK (all subjects of study Part 1 and at least 12 subjects of study Part 2)

pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 and 48 hour(s) after single-dose administration (48-hours sample before morning dose on Day 3)

Cycle 1, Day 15: multiple-dose PK (all subjects of study Part 1 and at least 12 subjects of study Part 2)
before and 0.5, 1, 2, 3, 4, 6, 8 and 12 hour(s) after morning dose on Cycle 1, Day 15 (12-hour sample before administration of evening dose)
(J)
All subjects participating in the MTD expansion cohorts (Part 1 or Part 2) will have 2 PK samples drawn for the purpose of exposure-
response modelling on Day 1 of Cycles 2, 3, 4, and 5 (1 blood sample just before the morning dose of BAY 1163877 and 1 blood sample 
between 0.5 and 1.5 hours post-dose). The dose needs to be taken under supervision and the time recorded.…


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(K) First oral administration of BAY 1163877 on Cycle 1 Day 1 will be done with a member of the site. To have complete control over the 
distribution and use of the study medication, the drug accountability must be performed before new medication is handed out to the subject. 
Return of BAY 1163877and diary at EOT visit.
(L)
Subjects with PK assessment (all subjects of study Part 1 and at least 12 subjects of study Part 2) will receive a single-dose of BAY 1163877 
on Cycle 1, Day 1 (morning), followed by a “drug-free day” (to enable single dose PK assessments). Subjects with “food effect assessment” 
in Part 1 and Part 2 take the morning dose after an overnight fast of at least 8 hours (see Section 8.4.2.2.1)….
(M) Subjects without PK assessment in study Part 2 will receive BAY 1163877 twice daily from Cycle 1, Day 1 ongoing.
(N) In approximately 8 subjects enrolled in MTD expansion cohorts (study Part 1 and Part 2), urine will be collected for 24 hours after dosing.
New text:
Table 16-3: Study flow chart: Treatment (Cycle ≥ 1) and Follow-up – Study Part 1 and Part 2 (continued)
Measures / actions
TREATMENT
FOLLOW-
UP
Cycle 1 
(21 days)
Cycles 2-12
(21 days)
Cycles ≥13
(21 days)
EOT Visit
Within 
0-14 days 
after last 
dose
FU-Visit / 
Phone Call(A)
At 30-35 days 
after last 
dose
Day (D)
D1
D2
D3
D8 ±1
D15
D1
D8 ±1 D15 ±1
D1
D1
1
…
12-lead ECG readings(D)
X
X
X
X
X
X
…
24-hour urine collection(M)
X
Obtain tumor biopsy for biomarker 
tests(G)
X
(Cy 2 
only)
PK blood sampling(H)
XX
X


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PK blood sampling for PK / PD 
modeling(I)
X
…
Dispense / return of BAY 1163877 and 
diary(J)
X
X
X
X
X
X
X
X
X
X
Administration of BAY 1163877
if PK assessment (M)
X
Continuous, twice-daily administration 
Administration of BAY 1163877
if no PK assessment(M)
   Continuous, twice-daily administration
…
(D) In Cycle 1, all 12-lead ECGs should be performed at the following time points:
Cycle 1, Day 1 and Day 2 (single ECG reading): before and 2, 3 (Day 1) and 24 (Day 2) hours after single-dose administration 
Cycle 1, Day 15 (single ECG reading): before morning dose, and 2 and 3 hours thereafter 
Cycle ≥2, Day 1 (single ECG reading): after morning dose
EOT visit (single ECG reading)
(E)
Safety laboratory tests, see Table 16-4
(F)
For calculation of eGFR (estimated glomerular filtration rate), see Section 16.9
(G) A tumor biopsy on Cycle 2, Day 1 will be obtained from all subjects who agreed on this at screening. The biopsy sample will be send to 
laboratory for biomarker evaluation, see Table 14–5, Table 14 6and Table 14 7. 
A biopsy on Cycle 2, Day 1 is optional … 
…for subjects in study Part 1 / dose-escalation (all comer).
…for subjects in study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN).
A biopsy on Cycle 2, Day 1 is mandatory … 
…for subjects in study Part 1 / MTD expansion (all comer).
(H) PK sampling will be done as follows (for details see Laboratory Manual):•

Cycle 1, Day 1: single-dose PK (all subjects of study Part 1 and at least 12 subjects of study Part 2 and a maximum of 8 subjects of the MTD 
expansion cohorts with impaired renal function at baseline)

pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 and 48 hour(s) after single-dose administration (48-hours sample before morning dose on Day 
3)

Cycle 1, Day 15: multiple-dose PK (all subjects of study Part 1 and at least 12 subjects of study Part 2 and a maximum of 8 subjects of the 


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MTD expansion cohorts with impaired renal function at baseline)
before and 0.5, 1, 2, 3, 4, 6, 8 and 12 hour(s) after morning dose on Cycle 1, Day 15 (12-hour sample before administration of evening 
dose)
(I)
All subjects participating in the MTD expansion cohorts (Part 1 or Part 2) will have 2 PK samples drawn for the purpose of exposure-
response modelling on Day 1 of Cycles 2, 3, 4, and 5 (1 blood sample just before the morning dose of BAY 1163877 and 1 blood sample 
between 0.5 and 1.5 hours post-dose). The dose needs to be taken under supervision and the time recorded.…
(J) First oral administration of BAY 1163877 on Cycle 1 Day 1 will be done with a member of the site. To have complete control over the 
distribution and use of the study medication, the drug accountability must be performed before new medication is handed out to the subject. 
Return of BAY 1163877and diary at EOT visit.
(K)
Subjects with PK assessment (all subjects of study Part 1 and at least 12 subjects of study Part 2 and a maximum of 8 subjects of the MTD 
expansion cohorts with impaired renal function at baseline) will receive a single-dose of BAY 1163877 on Cycle 1, Day 1 (morning), followed 
by a “drug-free day” (to enable single dose PK assessments). Subjects with “food effect assessment” in Part 1 and Part 2 take the morning 
dose after an overnight fast of at least 8 hours (see Section 8.4.2.2.1)….
(L)
Subjects without PK assessment in study Part 2 will receive BAY 1163877 twice daily from Cycle 1, Day 1 ongoing.
(M) In approximately 8 subjects enrolled in MTD expansion cohorts (study Part 1 and Part 2), urine will be collected for 24 hours after dosing.


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15.5.2.30 16.2
Laboratory examinations
This section was changed as a result of Modification 4.
Old text:
Table 14-7: Parameters and time points for biomarker investigations in study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN) 
Parameters
PRE-TREATMENT
TREATMENT
FOLLOW-UP
FGFR expression / 
FGFR mutation 
testing
Screening
Cycles 1-12
Cycles ≥13
EOT visit
Day 1
Day 8
Day 15
Day 1
Day 11
Tumor tissue:
p-ERK1/2 levels
X(A)
X(B)
only Cycle 2
FGFR1/2/3 expression
X(C)
FGFR and FGFR 
pathway mutations
X(C)
Blood (serum) samples*:
FGF23
X
X
X
X
X
X
X
Phosphate, calcium
X
X
X
X
X
X
X
p-ERK
= phospho-extracellular signal–regulated kinase
FGFR 1/2/3
= fibroblast growth factor receptor 1, 2 and 3
FGF23
= fibroblast growth factor 23
* Blood (serum) samples to be collected before administration of the morning dose of BAY 1163877 only for Cycle 1.
….


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New text:
Table 16-7: Parameters and time points for biomarker investigations in study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN) 
Parameters
PRE-TREATMENT
TREATMENT
FOLLOW-UP
FGFR expression / 
FGFR mutation 
testing
Screening
Cycles 1-12
Cycles ≥13
EOT visit
Day 1
Day 8
Day 15
Day 1
Day 11
Tumor tissue:
p-ERK1/2 levels
X(A)
X(B)
only Cycle 2
FGFR1/2/3 expression
X(C)
FGFR and FGFR 
pathway mutations
X(C)
p-ERK
= phospho-extracellular signal–regulated kinase
FGFR 1/2/3
= fibroblast growth factor receptor 1, 2 and 3
….


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15.5.2.31 16.8
Response evaluation criteria in solid tumors (RECIST v1.1)
This section was changed as a result of Modification 6.
Old text:
…
Table 14-10: Target and non-target lesion response
Target Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Response for this 
Category also Requires
CR
CR
No
CR
4-6 weeks Confirmation
CR
Non-CR/Non-PD
No
PR
4-6 weeks Confirmation
CR
Not evaluated
No
PR
4-6 weeks Confirmation
PR
Non-PD or not all 
evaluated
No
PR
4-6 weeks Confirmation
…
CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease;
Subjects with 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.
Table 14-11: Time-point response: Subjects with non-target disease only
Non-Target Lesions
New Lesions
Overall 
Response
Best Response also Requires
CR
No
CR
4-6 weeks Confirmation
…
CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease
a:  ‘Non-CR/non-PD’ is preferred over ‘SD’ for non-target disease because SD is increasingly used 
as an endpoint for assessment of efficacy in some trials, therefore, to assign this category 
when no lesions can be measured is not advised.


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New text:
Table 16-10: Target and non-target lesion response
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Response for this 
Category also Requires
CR
CR
No
CR
not earlier than 4 weeks 
Confirmation
CR
Non-CR/Non-PD
No
PR
not earlier than 4 weeks 
Confirmation
CR
Not evaluated
No
PR
not earlier than 4 weeks 
Confirmation
PR
Non-PD or not all 
evaluated
No
PR
not earlier than 4 weeks 
Confirmation
…
CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease;
Subjects with 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.
Table 16-11: Time-point response: Subjects with non-target disease only
Non-Target 
Lesions
New Lesions
Overall 
Response
Best Response also Requires
CR
No
CR
not earlier than 4 weeks 
Confirmation
…
CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease
a:  ‘Non-CR/non-PD’ is preferred over ‘SD’ for non-target disease because SD is increasingly 
used as an endpoint for assessment of efficacy in some trials, therefore, to assign this 
category when no lesions can be measured is not advised.


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15.6 Amendment 7
Date of amendment: 16 March 2017
15.6.1 Overview of changes
15.6.1.1
Modification 1: Change in Medical Expert and further clarifications
Description of modification to the study plan
The medical expert for this study changed. Moreover, minor changes were done for 
clarification.
Rationale for introducing the modification
Due to organizational reasons the medical expert for this study was changed.
List of CSP sections affected by this modification 
Sections 1, 5 and 16.3
15.6.1.2
Modification 2: Safety cohort
Description of modification to the study plan
A 3rd study part investigating the “Safety cohort” was included.
Rationale for introducing the modification
Preliminary safety data of patients with advanced cancer treated with BAY 1163877
showed a favorable safety profile (details can be found in the current version of the IB). 
However, sample size is still limited in selected indications (sqNSCLC, LAC, BC) and 
additional safety data  will be generated in Study Part 3 “Safety cohort”.
In parallel, changes of selected immune parameters will be assessed in Part 3. It was 
shown that FGFR3 expression is inversely correlated to PD-L1 expression in tumor tissue 
of patients with BC. This finding was confirmed in archival biopsy samples collected in 
study 16443. A similar correlation was detected in patients with sqNSCLC and LAC. It is 
assumed that a causal relationship between FGFR expression and T-cell exclusion leads to 
low PD-L1 levels. Potentially, inhibition of FGFR can overcome this interaction and 
render tumors targetable by the immune system. Preclinical models are not available due 
to limitations in mimicking immune responses in murine model systems.
List of CSP sections affected by this modification 
Sections 2, 3, 4, 6, 6.2, 7.1.1.1, 7.1.1.2, 7.1.2.2, 7.1.2.3, 8.1, 8.4.2, 8.4.2.1, 8.7, 9.1.2.1.1, 
9.1.2.1.2, 9.1.2.3.1, 9.1.2.3.2, 9.4.1.2, 9.4.4.1, 9.5.4.2, 10.7, 13.2, 14, 16.1 and 16.2.
15.6.1.3
Modification 3: Modifications of the criteria for dose modification 
and withdrawal and minor clarification/general instructions
Description of modification to the study plan
Changes done by the local Amendment 6 were included. 


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Liver toxicity criteria were modified and criteria for retinal detachment were added.
The protocol was modified to clarify that tissue mineralization and increased Ca x PO4 are 
different events. Furthermore investigators were instructed to carefully monitor patients 
with a GFR in the range of 30 mL/ min to 60 mL/min. Conditions when patients may 
continue treatment although they show disease progression were clarified. Possible drug 
interaction with respect to BCRP and/or P-gp was addressed.
Rationale for introducing the modification
Modifications were implemented to further reduce the risk of drug-induced toxicities.
List of CSP sections affected by this modification 
Sections 7.2.1, 8.4.3, 8.9.3 and 9.1.2.3.
15.6.2 Changes of protocol
In this section, all affected protocol sections are detailed; the sequence of the sections 
follows the structure of the original protocol. In the display of modifications, the “old 
text” refers to the protocol version preceding this amendment. Deletions are crossed out in 
the “old text”. Additions are underlined in the “new text”. Corrections of typing errors, 
omissions or terminology (minor corrections) are not highlighted in this amendment.
15.6.2.1
Title page
This section was changed as a result of Modification 1.
Old text:
Sponsor’s medical 
expert:
Bayer Pharma AG
Muellerstrasse 178, 13353 Berlin, Germany
Phone No: 
New text:
Sponsor’s medical 
expert:
Bayer AG
Muellerstrasse 178, 13353 Berlin, Germany
Phone No: 
Signature of the sponsor’s medically responsible person
Old text:
Name
Role
PPD
PPD
PPD
PPD
PPD


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New text:
Name
Role
15.6.2.2
Section 2 
Synopsis
This section was changed as a result of Modification 2.
Old text:
Diagnosis and main criteria for 
inclusion
Eligibility criteria for FGFR expression / FGFR 
mutation testing (only for MTD expansion cohorts of 
study Part 1 and Part 2)
…

Subjects with histologically or cytologically 
confirmed, refractory, locally advanced or 
metastatic solid tumors (all comer for study 
Part1; sqNSCLC, LAC, BC) who are not 
candidates for standard therapy.
…
Subjects enrolled in the MTD expansion cohorts of 
Study Part 1 and Part 2 must present high FGFR 
expression levels based on archival or fresh tumor 
biopsy specimen analysis.
…
(only for MTD expansion cohorts of study Part 1 
(all comer) and Part 2 (sqNSCLC + LAC +BC + 
SCCHN))
…
Note: Anticancer chemotherapy must have been 
stopped for at least 5 half-lives of the last applied 
therapy before the pre-treatment biopsy is taken.
…
PPD


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Methodology
…
Note: Treatment with BAY 1163877 at MTD in Part 1 
(expansion cohort “all comer”), Part 2 (expansion 
cohort “sqNSCLC + LAC + BC + SCCHN”) can 
run in parallel.
…
At home, subjects will document the intake of study 
drug (date and time of dosing as well as the 
administered dose) on a compliance sheet / paper diary 
(source document to verify treatment compliance). The 
complete duration of the study (Part 1 and Part 2) 
depends on the number of dose-escalation steps in 
Part 1 and will be approximately 7 years.
…
Pharmacokinetics PK):
…
In the MTD expansion cohorts, in a maximum of 8 
subjects with moderately impaired renal function at 
baseline (glomerular filtration rate [GFR] of 30 to 
59 mL/min/1.73 m2 according to the modified diet in 
renal disease [MDRD] abbreviated formula), serial PK 
blood samples will be collected on Cycle 1 Day 1 and 
Day 15.
…
Safety / tolerability: Safety will be assessed by close 
monitoring and timely assessment of adverse events 
(AEs), laboratory parameters (blood tests, urinalysis), 
vital signs (blood pressure, heart rate), subject’s 
medical condition (physical examination including 
weight), vision tests, general well-being and activities 
of daily life (Eastern Cooperative Oncology Group 
(ECOG) performance status).
…
Biomarker analysis in tumor tissue
Biomarker analysis will be done at screening for subject 
stratification in the MTD expansion cohorts (Part 1: all 
comer; Part 2: sqNSCLC + LAC + BC + SCCHN)
according to FGFR expression levels / FGFR mutation 
using either an archival or fresh tumor biopsy material 
(see inclusion criteria).


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Analysis of phospho-extracellular signal-regulated 
kinase 1/2 levels, (p-ERK1/2) will be done at screening 
and on Cycle 2, Day 1 for all subjects who are willing 
to undergo a biopsy both at screening and on Cycle 2, 
Day 1.
…
Number of subjects

Study Part 2 / MTD expansion (sqNSCLC + 
LAC + BC + SCCHN): 
Additional subjects will be enrolled to have 
20 evaluable subjects with sqNSCLC or LAC and a 
cohort of approximately 30 evaluable subjects with BC 
and at least 8 subjects with SCCHN treated at MTD.
New text:
Study objective(s)
Exploratory objectives
To evaluate selected immune parameters
Dose(s)
Study Part 3 / MTD expansion “Safety cohort”
(sqNSCLC + LAC + BC):

Subjects receive the MTD of BAY 1163877 
determined in study Part 1.
Duration of treatment
Duration and dosing schedule for subjects of study 
Part 3: 
Subjects will receive BAY 1163877 twice daily from 
Cycle 1, Day 1 ongoing. Evidence of tumor 
progression, unacceptable toxicity, consent 
withdrawal or subject’s withdrawal from the study at 
the discretion of the Investigator may lead to 
termination of treatment.
Diagnosis and main criteria for 
inclusion
Eligibility criteria for FGFR expression / FGFR 
mutation testing (only for MTD expansion cohorts of 
study Part 1, Part 2, and Part 3)
…

Subjects with histologically or cytologically 
confirmed, refractory, locally advanced or 
metastatic solid tumors (all comer for study 
Part1; sqNSCLC, LAC, BC or SCCHN for Part 
2; sqNSCLC, LAC, or BC for Part 3) who are 


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not candidates for standard therapy.
…

Subjects enrolled in the MTD expansion cohorts 
of Study Part 1, Part 2, and Part 3 must present 
high FGFR expression levels based on archival 
or fresh tumor biopsy specimen analysis.
…
(only for MTD expansion cohorts of study 
Part 1 (all comer), Part 2 (sqNSCLC + LAC 
+BC + SCCHN) and Part 3 (sqNSCLC + 
LAC + BC)
…
Note: Anticancer chemotherapy must have been 
stopped for at least 5 half-lives of the last applied 
therapy before the pre-treatment biopsy for 
biomarker (p-ERK1/2) studies is taken.
…

Only for study Part 3: Subjects consent to 
undergo a paired biopsy at screening and 
between Cycle 2, Day 1 and Cycle 2, Day 21
Study design
Study Part 3 will expand the safety database and in 
parallel will collect additional efficacy data and explore 
changes of selected immune parameters during 
treatment with BAY 1163877 at the MTD identified in 
Part 1 in subjects with sqNSCLC, LAC, and BC.
Methodology 
Study Part 3 / MTD expansion “Safety cohort”
(sqNSCLC + LAC + BC):
Individual number of 21-day cycles with continuous 
BAY 1163877 monotherapy (tablet) until disease 
progression or as long as clinical benefit is assumed by 
the investigator or until unacceptable toxicity occurs.  
…
Note: Treatment with BAY 1163877 at MTD in Part 1 
(expansion cohort “all comer”), and Part 2 (expansion 
cohort “sqNSCLC + LAC + BC + SCCHN”) and Part 3 
(expansion cohort “Safety cohort”, sqNSCLC + LAC + 
BC) can run in parallel.
…
At home, subjects will document the intake of study 
drug (date and time of dosing as well as the 
administered dose) on a compliance sheet / paper diary 


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(source document to verify treatment compliance). The 
complete duration of the study (Part 1, Part 2 and Part 
3) depends on the number of dose-escalation steps in 
Part 1 and will be approximately 7 years.
Pharmacokinetics (PK)
…
In all subjects participating in Study Part 3, multiple 
dose PK of BAY 1163877 will be evaluated in plasma 
samples collected on Cycle 1, Day 15 (up to 12 hours 
after dosing).
…
In the MTD expansion cohorts, in approximately 8 
subjects with moderately impaired renal function at 
baseline (glomerular filtration rate [GFR] of 30 to 
59 mL/min/1.73 m2 according to the modified diet in 
renal disease [MDRD] abbreviated formula), serial PK 
blood samples will be collected on Cycle 1 Day 1 and 
Day 15.
…
Safety / tolerability: Safety will be assessed by close 
monitoring and timely assessment of adverse events 
(AEs), laboratory parameters (blood tests, urinalysis), 
vital signs (blood pressure, heart rate), subject’s 
medical condition (physical examination including 
weight), ophtalmological examination, general well-
being and activities of daily life (Eastern Cooperative 
Oncology Group (ECOG) performance status).
…
Biomarker analysis in tumor tissue
…
Biomarker analysis will be done at screening for subject 
stratification in the MTD expansion cohorts (Part 1: all 
comer; Part 2: sqNSCLC + LAC + BC + SCCHN; Part 
3: “Safety cohort” sqNSCLC + LAC + BC) according 
to FGFR expression levels / FGFR mutation using 
either an archival or fresh tumor biopsy material (see 
inclusion criteria).
Analysis of phospho-extracellular signal-regulated 
kinase 1/2 levels, (p-ERK1/2) will be done at screening 


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and on Cycle 2, Day 1 for all subjects of study Part 1 
and Part 2 who are willing to undergo a biopsy both at 
screening and on Cycle 2, Day 1.
Priming of immune response (only in Part 3 “Safety 
cohort”): Selected parameters of immune response will 
be measured in fresh tumor tissue at baseline and 
between Cycle 2, Day 1 and Cycle 2, Day 21 and 
peripheral blood at the following timepoints: at 
baseline; Cycle 1, Day 8; Cycle 2, Day 1; Cycle 2, Day 
15; and on the day of the second biopsy.
Number of subjects

Study Part 2 / MTD expansion (sqNSCLC + 
LAC + BC + SCCHN): 
Additional subjects will be enrolled to have 
20 evaluable subjects with sqNSCLC or LAC and a 
cohort of at least 30, up to a maximum of 50 evaluable 
subjects with BC and at least 8 subjects with SCCHN 
treated at MTD

Study Part 3 / MTD expansion “Safety cohort”
(sqNSCLC + LAC + BC):
Additional subjects will be enrolled to have 
approximately 20 subjects with sqNSCLC or LAC and 
approximately 20 subjects with BC treated at MTD.
15.6.2.3
Section 3
Introduction
This section was changed as a result of Modification 2.
Rationale of the study
Additional text:
It was shown that FGFR3 expression is inversely correlated to programmed death-ligand 1 
(PD-L1) expression and T cell infiltration in tumor tissue of patients with BC(40). This 
finding was confirmed in archival biopsy samples collected in study 16443. A similar 
correlation was detected in patients with sqNSCLC and LAC in study 16443.
It is assumed that a causal relationship between FGFR expression and T cell exclusion 
leads to low PD-L1 levels and decreased responsiveness towards inhibition of the PD-L1 
axis. Potentially, inhibition of FGFR can overcome this interaction and render tumors 
targetable by the immune system.
Immune responses and the tumor microenvironment are inadequately reflected in 
preclinical cancer models. We therefore aim to analyze selected immune parameters 
before and during BAY1163877 treatment in paired biopsies and in serum of biomarker-
selected patients. Fresh tumor tissue will be used to assess immune parameters indicating a 
T cell response against the tumor tissue. This will be done by performing gene expression 


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profiling (nCounter PanCancer Immune Profiling Panel) and immunohistochemistry for 
CD8+ T cell infiltration and PD-L1 expression on the tumor tissue. Peripheral blood will 
be used to collect serum to determine cytokine levels (IL-6, IFN-gamma, and other 
cytokines if needed). Aim of the assessment of peripheral blood is to search for changes in 
this easily accessible specimen that reflect the immune response in the tumor tissue.
15.6.2.4
Section 4
Study objectives
This section was changed as a result of Modification 2.
New text:
Exploratory objective:

To evaluate selected immune parameters.
15.6.2.5
Section 5
Investigator (s) and other study participants
This section was changed as a result of Modification 1.
Old text:
Sponsor’s Medical Expert
Name:
Title:
Address:
Bayer Pharma AG
Muellerstr, 178
13353 Berlin, Germany
Telephone No:
Fax No:
New text:
Sponsor’s Medical Expert
Name:
Title:
Address:
Bayer AG
Muellerstr, 178
13353 Berlin, Germany
Telephone No:
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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15.6.2.6
Section 6
Study design
This section was changed as a result of Modification 2.
Old text:
Design overview
…

Study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN): additional 
subjects will be enrolled to have 20 evaluable subjects with sqNSCLC or LAC and 
approximately 30 evaluable subjects with BC and at least 8 subjects with SCCHN treated 
at MTD. 
…
The complete duration of the study (Part 1, and Part 2) depends on the number of dose-
escalation steps in Part 1 and will be approximately 7 years.10
…
PK assessments will be performed in all subjects participating in study Part 1 / dose 
escalation and MTD expansion (all comer). Additionally, PK assessments are planned in 
at least 12 subjects participating in study Part 2 / MTD expansion (sqNSCLC + LAC + BC 
+ SCCHN) such that valid PK data are available in 8 subjects and in a maximum of 8 
subjects of the MTD expansion cohorts with impaired renal function at baseline.
…
All subjects participating in either of the 2 MTD expansion cohorts (Part 1 and Part 2) will 
have 2 PK samples drawn for the purpose of exposure-response modeling on Day 1 of 
Cycles 2, 3, 4, and 5 (1 blood sample just before the morning dose of BAY 1163877 and 
1 blood sample between 0.5 and 1.5 hours post-dose).
Figure 6-1: Schematic presentation of the treatment design
§ The first study (screening) visit is scheduled within 7 days / within 28 days before administration of the first 
dose of BAY 1163877 (written informed consent for study treatment eligibility). 
Subjects recruited for Part 1 or Part 2 MTD expansion cohorts have their first study visit before study 
(screening) visit to perform a biomarker analysis for subject stratification (mandatory written informed consent 
for FGFR expression / FGFR mutation testing). Those subjects who are eligible for participation in the MTD 
expansion cohort must additionally sign the informed consent for study treatment eligibility at the screening 
visit.
…

Pre-treatment 
-
Testing for FGFR expression and FGFR mutation (only for subjects recruited for 
Part 1 or Part 2 MTD expansion cohorts)
…

Treatment ….
Note: Treatment with BAY 1163877 at MTD in Part 1 (expansion cohort “all comer”) and 


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Part 2 (expansion cohort “sqNSCLC + LAC + BC + SCCHN”) can run in parallel.
…
Treatment: Subjects with PK assessment (all subjects of study Part 1 and at least 
12 subjects of study Part 2 and a maximum of 8 subjects of the MTD expansion cohorts 
with impaired renal function at baseline) will receive BAY 1163877 (tablet or solution) on 
a continuous schedule starting with single-dose administration on Cycle 1, Day 1, 
followed by a “drug-free day” (to enable single dose PK assessments).
…
Pharmacokinetics (PK): …
In the MTD expansion cohorts, in a maximum of 8 subjects with moderately impaired 
renal function at baseline (glomerular filtration rate [GFR] of 30 to 59 mL/min/1.73 m2
according to the modified diet in renal disease [MDRD] abbreviated formula), serial PK 
blood samples will be collected on Cycle 1 Day 1 and Day 15.
…
Safety /tolerability: ….
Safety will be assessed by close monitoring and timely assessment of adverse events 
(AEs), laboratory parameters (blood tests, urinalysis), vital signs (blood pressure, heart 
rate), subject’s medical condition (physical examination including weight), vision tests,
general well-being and activities of daily life (Eastern Cooperative Oncology Group 
(ECOG) performance status). 
…
Pharmacodynamic (PD) biomarkers: …
Biomarker analysis in tumor tissue: Biomarker analysis will be done at screening for 
subject stratification in the MTD expansion cohorts (Part 1: all comer; Part 2: sqNSCLC + 
LAC + BC + SCCHN) according to FGFR expression levels / FGFR mutation using either 
an archival tumor tissue specimen or fresh tumor biopsy material (see Section 7.1.1, 
inclusion criteria).
Analysis of phospho-extracellular signal-regulated kinase 1/2 levels, (p-ERK1/2) will be 
done at screening and on Cycle 2, Day 1 for all subjects who are willing to undergo a 
biopsy both at screening and on Cycle 2, Day 1.
New text:
Design overview
…
Study Part 3 will expand the safety database for patients on treatment with  BAY1163877 
at the MTD identified in Part 1 with sqNSCLC, LAC, and BC. In parallel, in Part 3 
additional efficacy data will be collected and changes of selected immune parameters will 
be assessed


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The complete duration of the study (Part 1, and Part 2, and Part 3) depends on the number 
of dose-escalation steps in Part 1 and will be approximately 7 years.
…

Study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN): additional 
subjects will be enrolled to have 20 evaluable subjects with sqNSCLC or LAC and of at 
least 30, up to a maximum of 50 evaluable subjects with BC and at least 8 subjects with 
SCCHN treated at MTD. 
•
Study Part 3 / MTD expansion “Safety cohort” (sqNSCLC + LAC + BC): 
additional subjects will be enrolled to have approximately 20 subjects with sqNSCLC or 
LAC and approximately 20 subjects with BC treated at MTD.
…
PK assessments will be performed in all subjects participating in study Part 1 / dose 
escalation and MTD expansion (all comer) and study Part 3/ MTD expansion “Safety 
cohort”. Additionally, PK assessments are planned in at least 12 subjects participating in 
study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN) such that valid PK 
data are available in 8 subjects and in approximately 8 subjects of the MTD expansion 
cohorts with impaired renal function at baseline.
…
All subjects participating in either of the 3 MTD expansion cohorts (Part 1, Part 2 and Part 
3 despite subjects with impaired renal function) will have 2 PK samples drawn for the 
purpose of exposure-response modeling on Day 1 of Cycles 2, 3, 4, and 5 (1 blood sample 
just before the morning dose of BAY 1163877 and 1 blood sample between 0.5 and 1.5 
hours post-dose). Subjects in Part 3 will provide one PK sample within 1 hour of biopsy 
collection in Cycle 2.
Figure 6-1: Schematic presentation of the treatment design
§ The first study (screening) visit is scheduled within 7 days / within 28 days before administration of the first 
dose of BAY 1163877 (written informed consent for study treatment eligibility). 
Subjects recruited for Part 1,Part 2, or Part 3 MTD expansion cohorts have their first study visit before study 
(screening) visit to perform a biomarker analysis for subject stratification (mandatory written informed consent 
for FGFR expression / FGFR mutation testing). Those subjects who are eligible for participation in the MTD 
expansion cohort must additionally sign the informed consent for study treatment eligibility at the screening 
visit.
…

Pre-treatment 
-
Testing for FGFR expression and FGFR mutation (only for subjects recruited for 
Part 1, Part 2 or Part 3 MTD expansion cohorts)
…

Treatment 
…
-
Study Part 3 / MTD expansion “Safety cohort” (sqNSCLC + LAC + BC): 


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Individual number of 21-day Cycles with continuous BAY 1163877 monotherapy 
(tablet) until disease progression or as long as clinical benefit is assumed by the 
investigator or until unacceptable toxicity occurs. 
Note: Treatment with BAY 1163877 at MTD in Part 1 (expansion cohort “all comer”),  
Part 2 (expansion cohort “sqNSCLC + LAC + BC + SCCHN”), and Part 3 (expansion 
cohort “Safety cohort”, sqNSCLC + LAC + BC”) can run in parallel.
…
Treatment: Subjects with PK assessment (all subjects of study Part 1 and 3 and at least 
12 subjects of study Part 2 and approximately 8 subjects of the MTD expansion cohorts 
with impaired renal function at baseline) will receive BAY 1163877 (tablet or solution) on 
a continuous schedule starting with single-dose administration on Cycle 1, Day 1, 
followed by a “drug-free day” (to enable single dose PK assessments, except for subjects 
in Part 3 who will receive BAY 1163877 twice daily continuously with no “drug free 
day”).
…
Pharmacokinetics (PK): …
In the MTD expansion cohorts, in approximately 8 subjects with moderately impaired 
renal function at baseline (glomerular filtration rate [GFR] of 30 to 59 mL/min/1.73 m2
according to the modified diet in renal disease [MDRD] abbreviated formula), serial PK 
blood samples will be collected on Cycle 1 Day 1 and Day 15. In all subjects participating 
in Study Part 3/”Safety cohort”, multiple dose PK of BAY 1163877 will be evaluated in 
plasma samples collected on Cycle 1, Day 15.
…
Safety /tolerability: ….
Safety will be assessed by close monitoring and timely assessment of adverse events 
(AEs), laboratory parameters (blood tests, urinalysis), vital signs (blood pressure, heart 
rate), subject’s medical condition (physical examination including weight), 
ophthalmological examination, general well-being and activities of daily life (Eastern 
Cooperative Oncology Group (ECOG) performance status). 
…
Assessment of immune priming (Part 3): Selected parameters of immune response will 
be measured in fresh tumor tissue at baseline and again between Cycle 2, Day 1 and Cycle 
2, Day 21; and in peripheral blood at the following timepoints: at baseline; Cycle 1, Day 
8; Cycle 2, Day 1; Cycle 2, Day 15; and on the day of the second biopsy.
Fresh tumor tissue will be used to assess immune parameters indicating a T cell response 
against the tumor tissue. This will be done by performing gene expression profiling 
(nCounter PanCancer Immune Profiling Panel) and immunohistochemistry for CD8+ T 
cell infiltration and PD-L1 expression on the tumor tissue. Peripheral blood will be used to 
collect serum to determine cytokine levels (IL-6, IFN-gamma, and other cytokines if 


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needed). Aim of the assessment of peripheral blood is to search for changes in this easily 
accessible specimen that reflect the immune response in the tumor tissue.
…
Pharmacodynamic (PD) biomarkers: …
Biomarker analysis in tumor tissue: Biomarker analysis will be done at screening for 
subject stratification in the MTD expansion cohorts (Part 1: all comer; Part 2: sqNSCLC + 
LAC + BC + SCCHN; Part 3: sqNSCLC + LAC + BC) according to FGFR expression 
levels / FGFR mutation using either an archival tumor tissue specimen or fresh tumor 
biopsy material (see Section 7.1.1, inclusion criteria).
Analysis of phospho-extracellular signal-regulated kinase 1/2 levels, (p-ERK1/2) will be 
done at screening and on Cycle 2, Day 1 for all subjects of study Part 1 and Part 2 who are 
willing to undergo a biopsy both at screening and on Cycle 2, Day 1.
15.6.2.7
Section 6.2
Justification of the design
This section was changed as a result of Modification 2.
New text:
Study Part 3 / “Safety cohort” (sqNSCLC + LAC + BC)
Preliminary safety data of patients with advanced cancer treated with BAY 1163877
showed a favorable safety profile (details can be found in the current version of the IB). 
However, sample size is still limited in selected indications (sqNSCLC, LAC, BC) and 
additional safety data  will be generated in Study Part 3 “Safety cohort”. In parallel, 
additional efficacy data will be collected and changes of selected immune parameters will 
be assessed in Part 3.
It was shown that FGFR3 expression is inversely correlated to programmed death-ligand 1 
(PD-L1) expression and T cell infiltration in tumor tissue of patients with BC (40). This 
finding was confirmed in archival biopsy samples collected in study 16443. A similar 
correlation was detected in patients with sqNSCLC and LAC in study 16443.
Recently, the PD1 and PD-L1 inactivating antibodies received accelerated approval by the 
FDA for patients with BC. It was demonstrated that patients with a low expression of PD-
L1 had a smaller chance to respond to atezolizumab treatment. 
It is assumed that a causal relationship between FGFR expression and T cell exclusion 
leads to low PD-L1 levels and decreased responsiveness towards inhibition of the PD-L1 
axis. Potentially, inhibition of FGFR can overcome this interaction and render tumors 
targetable by the immune system.
Immune responses and the tumor microenvironment are inadequately reflected in 
preclinical cancer models. We therefore aim to analyze selected immune parameters 
before and during BAY1163877 treatment in paired biopsies and in serum of biomarker-
selected cancer patients. Fresh tumor tissue will be used to assess immune parameters 
indicating a T cell response against the tumor tissue. This will be done by performing gene 
expression profiling (nCounter PanCancer Immune Profiling Panel) and 


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immunohistochemistry for CD8+ T cell infiltration and PD-L1 expression on the tumor 
tissue. Peripheral blood will be used to collect serum to determine cytokine levels (IL-6, 
IFN-gamma, and other cytokines if needed). Aim of the assessment of peripheral blood is 
to search for changes in this easily accessible specimen that reflect the immune response 
in the tumor tissue. 
15.6.2.8
Section 7.1.1.1 Eligibility criteria for FGFR expression / FGFR 
mutation testing (only for MTD expansion cohorts of study Part 1 
and Part 2)
This section was changed as a result of Modification 2.
Old text:
7.1.1.1 Eligibility criteria for FGFR expression / FGFR mutation testing (only for 
MTD expansion cohorts of study Part 1 and Part 2)
…

Subjects with histologically or cytologically confirmed, refractory, locally 
advanced or metastatic solid tumors (all comer for study Part1; sqNSCLC, LAC, BC or 
SCCHN for Part 2) who are not candidates for standard therapy. 
New text:
7.1.1.1 Eligibility criteria for FGFR expression / FGFR mutation testing (only for 
MTD expansion cohorts of study Part 1, Part 2 and Part 3)
…

Subjects with histologically or cytologically confirmed, refractory, locally 
advanced or metastatic solid tumors (all comer for study Part1; sqNSCLC, LAC, BC or 
SCCHN for Part 2; sqNSCLC, LAC, or BC for Part 3) who are not candidates for standard 
therapy. 
15.6.2.9
Section 7.1.1.2 Eligibility criteria for study treatment 
This section was changed as a result of Modification 2.
Old text:

Subjects enrolled in the MTD expansion cohorts of Study Part 1 and Part 2 must 
present high FGFR expression levels based on archival or fresh tumor biopsy specimen 
analysis.
Bladder cancer subjects with low overall FGFR expression levels can be included if 
activating FGFR3 mutations are confirmed. 
(only for MTD expansion cohorts of study Part 1 (all comer) and Part 2 (sqNSCLC + 
LAC +BC + SCCHN))
…
Note: Anticancer chemotherapy must have been stopped for at least 5 half-lives of the last 
applied therapy before the pre-treatment biopsy is taken. Mitomycin C, nitrosoureas or 


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monoclonal antibodies with anticancer activity (e.g. bevacizumab or cetuximab etc.) 
should not be given within 6 weeks of pre-treatment biopsy for biomarker (p-ERK1/2) 
studies.
New text:

Subjects enrolled in the MTD expansion cohorts of Study Part 1, Part 2 and Part 3
must present high FGFR expression levels based on archival or fresh tumor biopsy 
specimen analysis.
Bladder cancer subjects with low overall FGFR expression levels can be included if 
activating FGFR3 mutations are confirmed. 
(only for MTD expansion cohorts of study Part 1 (all comer), Part 2 (sqNSCLC + 
LAC +BC + SCCHN) and Part 3 (sqNSCLC + LAC + BC)).
….
Note: Anticancer chemotherapy must have been stopped for at least 5 half-lives of the last 
applied therapy before the pre-treatment biopsy for biomarker (p-ERK1/2) studies is 
taken. Mitomycin C, nitrosoureas or monoclonal antibodies with anticancer activity (e.g. 
bevacizumab or cetuximab etc.) should not be given within 6 weeks of pre-treatment 
biopsy for biomarker (p-ERK1/2) studies.
…

Subjects consent to undergo paired biopsies at screening and between Cycle 2, Day 
1 and Cycle 2, Day 21
(only for Study Part 3 / MTD expansion “Safety cohort” (sqNSCLC + LAC + BC))
15.6.2.10 Section 7.1.2.2 Exclusion criteria for FGFR expression / FGFR 
mutation testing (only for MTD expansion cohorts of study Part 2)
This section was changed as a result of Modification 2.
Old section heading:
Exclusion criteria for FGFR expression / FGFR mutation testing (only for MTD expansion 
cohorts of study Part 2)
New section heading:
Exclusion criteria for FGFR expression / FGFR mutation testing (only for MTD expansion 
cohorts of study Part 2 and Part 3)
15.6.2.11 Section 7.1.2.3 Exclusion criteria 
This section was changed as a result of Modification 2.
Old text:

FGFR testing shows low FGFR expression levels
(only for MTD expansion cohorts of study Part 1 (all comer) and Part 2 (sqNSCLC + LAC 
+ SCCHN))

No consent for mandatory paired biopsies for biomarker


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(only for MTD expansion cohorts of study Part 1 (all comer))

FGFR expression / FGFR mutation testing shows low FGFR expression levels and
absence of activating mutation in FGFR3 gene 
(only for Part 2 (BC))
…
New text:

FGFR testing shows low FGFR expression levels
(only for MTD expansion cohorts of study Part 1 (all comer), Part 2 (sqNSCLC + LAC + 
SCCHN) and Part 3 (sqNSCLC + LAC))

No consent for mandatory paired biopsies for biomarker (Part 1) or assessment of 
immune parameters (Part 3)
(only for MTD expansion cohorts of study Part 1 (all comer) and study Part 3 (sqNSCLC+ 
LAC + BC)

FGFR expression / FGFR mutation testing shows low FGFR expression levels and
absence of activating mutation in FGFR3 gene 
(only for Part 2 and Part 3 (BC))
…
15.6.2.12 Section 7.2.1
Withdrawal
This section was changes as a result of Modification 3.
Old text

Tumor progression
Subjects with documented disease progression, unless the investigator (in consultation 
with the sponsor) deems that continued treatment is appropriate.
New text:
- Retinal detachment of grade 2 or higher according to CTCAE v4.03 
- AST/ALT > 3xULN with concomitant bilirubin > 2xULN in the absence of 
another reason for these elevations
- AST/ALT > 8xULN or AST/ALT > 5xULN for > 2 weeks if no other reason is 
found for these elevations

Tumor progression
- Subjects with documented disease progression, unless the investigator (in 
consultation with the sponsor) deems that continued treatment is appropriate. 
Patients may continue if they experience clinical benefit as assessed by the 
investigator, do not exhibit rapid disease progression and have stable performance 
status.  In addition, treatment beyond progression should not delay an imminent 
intervention to prevent serious complications of disease progression (e.g. CNS 
metastases).


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15.6.2.13 Section 8.1
Treatments to be administered
This section was changed as a result of Modification 2.
New text:
Investigational medicinal product (IMP) – test drug
In study Part 3 / MTD expansion “Safety cohort” (sqNSCLC + LAC + BC), subjects will 
be treated with the MTD of BAY 1163877 determined in study Part 1. 
15.6.2.14 Section 8.4.2
Selection and timing of dose for each subject
This section was changed as a result of Modification 2.
Old text:
Extent and duration of drug exposure of the individual subject in study Part 2 / dose 
expansion (sqNSCLC + LAC + BC + SCCHN) are given in Section 6.
New text:
Extent and duration of drug exposure of the individual subject in study Part 2 / dose 
expansion (sqNSCLC + LAC + BC + SCCHN) and study Part 3 / dose expansion “Safety 
cohort” (sqNSCLC + LAC + BC) are given in Section 6.
15.6.2.15 8.4.2.1
Dosing schedule
This section was changed as a result of Modification 2.
New text:
Study Part 3 / MTD expansion “Safety cohort” (sqNSCLC + LAC  + BC):

Subjects will receive BAY 1163877 twice daily from Cycle 1, Day 1 ongoing.
15.6.2.16 8.4.3
Dose modification and delays
This section was changed as a result of Modification 3.
Old text:
Liver toxicity
Table 8-6:
Dose modifications of BAY 1163877 for liver toxicity
a
If all values remain stable for 2 cycles, dose re-escalation may be considered at the 
discretion of the investigator. After re-escalation, AST, ALT, and bilirubin should be 
checked weekly for at least 4 weeks.
Tissue mineralization
Dose modifications of BAY 1163877 for tissue mineralization are presented in Table 8-7. 
Tissue mineralization refers to Ca x PO4 ≥ 70 mg²/dL² considered possibly related to 
BAY 1163877.


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Table 8-7:
Dose modifications of BAY 1163877 for tissue mineralization
Toxicity
Modification schedule
Ca x PO4 (≥ 70 mg²/dL²)
Hold BAY 1163877, treat with phosphate
chelators until recovery, to Ca x PO4 < 70 mg²/dL². 
Resume same dose level, continue phosphate chelators 
and check weekly for at least 4 weeks.
- 1st reappearance
Hold BAY 1163877, treat with phosphate 
chelators until recovery to Ca x PO4 < 70 mg²/dL², 
then reduce 1 dose level, continue phosphate chelator 
and check weekly for at least 4 weeks.
- 2nd reappearance
Hold BAY 1163877 until recovery to
Ca x PO4 < 70 mg²/dL²,
then reduce 1 additional dose level, continue phosphate 
chelators and check weekly for at least 4 weeks.
- 3rd reappearance
Withdraw subject from study treatment.
…
New text:
…
Table 8-6:
Dose modifications of BAY 1163877 for liver toxicity
a
Dose will not be re-escalated after dose reduction for toxicity.
Patients with AST/ALT > 3xULN with concomitant bilirubin > 2xULN in the absence of 
another reason for these elevations have to permanently discontinue study drug.  
Permanent discontinuation also applies to patients with AST/ALT > 8xULN or AST/ALT 
> 5xULN for > 2 weeks if no other reason is found for these elevations.
Increased Ca x PO4
Dose modifications of BAY 1163877 for Ca x PO4 ≥ 70 mg²/dL² considered possibly 
related to BAY 1163877 are presented in Table 8-7.


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Table 8-7:
Dose modifications of BAY 1163877 for increased Ca x PO4
Toxicity
Modification schedule
Ca x PO4 (≥ 70 mg²/dL²)
Hold BAY 1163877, treat with phosphate
chelators and check twice weekly until recovery, to Ca x 
PO4 < 70 mg²/dL². 
Resume same dose level, continue phosphate chelators and 
check tweekly for at least 4 weeks.
- 1st reappearance
Hold BAY 1163877, treat with phosphate 
chelators and check twice weekly until recovery to Ca x PO4 
< 70 mg²/dL², 
then reduce 1 dose level, continue phosphate chelator and 
check weekly for at least 4 weeks.
- 2nd reappearance
Hold BAY 1163877 and check twice weekly until recovery to
Ca x PO4 < 70 mg²/dL²,
then reduce 1 additional dose level, continue phosphate 
chelators and check weekly for at least 4 weeks.
- 3rd reappearance
Withdraw subject from study treatment.
…
In patients with hyperphosphatemia (Ca x PO4 ≥ 70 mg²/dL²), the serum phosphate and 
calsium levels have to be checked twice weekly until resolution (Ca x PO4 < 70 mg²/dL²).
In patients with hypocalcemia, an additional 12-lead ECG has to be obtained on the day of 
detection of hypocalcemia.
Retinal detachment
Patients that experience retinal detachment of grade 2 or higher according to CTCAE 
v4.03 have to be permanently discontinued from study treatment.  
15.6.2.17 Section 8.7
Treatment compliance
This section was changed as a result of Modification 2.
Old text: 
A compliance of at least 80% is required, meaning documented intake of at least 80% of 
the planned study medication (80 % = 32 doses or 16 days in Cycle 1 with PK assessment 
and 34 doses or 17 days in ≥ Cycles 2 and in Cycle 1 without PK assessment.
New text:
A compliance of at least 80% is required, meaning documented intake of at least 80% of 
the planned study medication (80 % = 32 doses or 16 days in Cycle 1 with PK assessment 
[Part 1 and Part 2 only] and 34 doses or 17 days in ≥ Cycles 2 and in Cycle 1 without PK 
assessment [including Part 3]).  
15.6.2.18 Section 8.9.3
Permitted concomitant therapy
This section was changed as a result of Modification 3.


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New text:

In view of the maximum dose of 800 mg b.i.d., a risk for clinically relevant drug 
interaction due to inhibition of BCRP and/or P-gp in the intestine for drugs with a low 
bioavailability limited by P-gp and BCRP cannot be ruled out.  However, based on the 
maximum achievable plasma BAY 1163877 concentration, risk of clinically relevant drug 
interaction due to systemic inhibition of BCRP and P-gp is regarded as low.
15.6.2.19 Section 9.1.2.1.1
FGFR expression / FGFR mutation testing 
(MTD expansion cohorts only)
This section was changed as a result of Modification 2.
Old text:
A separate subject information sheet / informed consent form (SIS / ICF) for FGFR 
expression / FGFR mutation testing must be signed by all subjects recruited for study
Part 1 or Part 2 MTD expansion cohort (see Section 13.2). 
New text:
A separate subject information sheet / informed consent form (SIS / ICF) for FGFR 
expression / FGFR mutation testing must be signed by all subjects recruited for study
Part 1, Part 2 MTD expansion cohort or Part 3 (see Section 13.2). 
15.6.2.20 Section 9.1.2.1.2
Screening 
This section was changed as a result of Modification 2.
Old text:

Demographic data (already collected for subjects of Part 1 or Part 2 MTD 
expansion cohorts, see Section 9.1.2.1.1)

Documentation of the primary diagnosis (refractory, locally advanced or metastatic 
solid tumor) using the complete pathological report (already done for subjects of Part 1 or
Part 2 MTD expansion cohorts, see Section 9.1.2.1.1)

Complete medical / oncological history, TNM classification (see Section 9.2.3) 
(already done for subjects of Part 1 or Part 2 MTD expansion cohorts, see Section 
9.1.2.1.1)
…

ECOG performance status assessment (also for subjects of Part 1, Part 2 MTD 
expansion cohorts, see Section 9.1.2.1.1)
…
Note 1: A biopsy is mandatory for all subjects in the MTD expansion cohort of Part 1 and 
Part 2 for whom no archival biopsy is available for FGFR expression / FGFR mutation 
testing. …


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Note 2: Anticancer chemotherapy must have been stopped for at least 5 half-lives of the 
last applied therapy before the pre-treatment biopsy is taken….
New text:
Within 28 Days Prior to First Dose of BAY 1163877  

Demographic data (already collected for subjects of Part 1, Part 2 or Part 3 MTD 
expansion cohorts, see Section 9.1.2.1.1)

Documentation of the primary diagnosis (refractory, locally advanced or metastatic 
solid tumor) using the complete pathological report (already done for subjects of Part 1, or 
Part 2 or Part 3 MTD expansion cohorts, see Section 9.1.2.1.1)

Complete medical / oncological history, TNM classification (see Section 9.2.3) 
(already done for subjects of Part 1, Part 2 or Part 3 MTD expansion cohorts, see Section 
9.1.2.1.1)
…

ECOG performance status assessment (also for subjects of Part 1, Part 2 or Part 3
MTD expansion cohorts, see Section 9.1.2.1.1)
…

Obtain pre-treatment biopsy: 
…
-
mandatory for all subjects in the study Part 3 / MTD expansion cohort “Safety 
cohort” (sqNSCLC + LAC + BC)
-
Note 1: A biopsy is mandatory for all subjects in the MTD expansion cohort of 
Part 1, Part 2 and Part 3 for whom no archival biopsy is available for FGFR 
expression / FGFR mutation testing.
-
Note 2: Anticancer chemotherapy must have been stopped for at least 5 half-lives 
of the last applied therapy before the pre-treatment biopsy for biomarker (p-
ERK1/2) studies is taken….
Within 7 Days Prior to First Dose of BAY 1163877  
…

Only for subjects in Part 3: peripheral blood sample collection for determination of 
cytokine levels in serum.
15.6.2.21 Section 9.1.2.3 Treatment
This section was changed as a result of Modification 3.
New text: 
…


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Patients with an estimated GFR in the range 30 mL/ min to 60 mL/min should be carefully 
monitored for signs of increased toxicity. 
15.6.2.22 Section 9.1.2.3.1
Cycle 1
This section was changed as a result of Modification 2.
Old text
Day 1

PK sampling (all subjects of study Part 1 and at least 12 subjects of study Part 2 
and a maximum of 8 subjects of the MTD expansion cohorts with impaired renal function 
at baseline)
…
Oral administration of BAY 1163877 (single dosing for subjects with PK
assessment, twice daily dosing for subjects without PK assessment
Day 2
No administration of BAY 1163877 (“drug-free day”) for subjects with PK 
assessment (all subjects of study Part 1 and at least 12 subjects with PK assessment in 
study Part 2 and a maximum of 8 subjects with PK assessment in the MTD expansion 
cohorts with impaired renal function at baseline [including “food effect assessment”])

Twice daily administration of BAY 1163877 for subjects without PK assessment 
(remaining subjects of study Part 2)
…

PK sampling (all subjects of study Part 1 and at least 12 subjects of study Part 2
and a maximum of 8 subjects of the MTD expansion cohorts with impaired renal function 
at baseline) 
…
Day 3
…

PK sampling (all subjects of study Part 1 and at least 12 subjects of study Part 2 
and a maximum of 8 subjects of the MTD expansion cohorts with impaired renal function 
at baseline)
…
Days 15 (Visit) 

PK sampling (all subjects of study Part 1 and at least 12 subjects of study Part 2 
and a maximum of 8 subjects of the MTD expansion cohorts with impaired renal function 
at baseline)


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New text
Day 1

PK sampling (all subjects of study Part 1 and at least 12 subjects of study Part 2 
and approximately 8 subjects of the MTD expansion cohorts with impaired renal function 
at baseline)
Oral administration of BAY 1163877 (single dosing for subjects with PK
assessment, twice daily dosing for subjects without PK assessment and for subject 
in Part 3)
Day 2
No administration of BAY 1163877 (“drug-free day”) for subjects with PK 
assessment (all subjects of study Part 1 and at least 12 subjects with PK assessment in 
study Part 2 and approximately 8 subjects with PK assessment in the MTD expansion 
cohorts with impaired renal function at baseline [including “food effect assessment”])

Twice daily administration of BAY 1163877 for subjects without PK assessment 
(remaining subjects of study Part 2) and for subjects of Part 3
…

PK sampling (all subjects of study Part 1 and at least 12 subjects of study Part 2 
and approximately 8 subjects of the MTD expansion cohorts with impaired renal function 
at baseline) 
…
Day 3
…

PK sampling (all subjects of study Part 1 and at least 12 subjects of study Part 2 
and approximately 8 subjects of the MTD expansion cohorts with impaired renal function 
at baseline)
…
Day 8±1 (Visit)

Only for subjects in Part 3: Collection of peripheral blood for determination of 
cytokine levels
…
Days 15 (Visit) 

PK sampling (all subjects of study Part 1, 3 and at least 12 subjects of study Part 2 
and approximately 8 subjects of the MTD expansion cohorts with impaired renal 
function at baseline)


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15.6.2.23 Section 9.1.2.3.2
Subsequent Cycles (Cycles 2-12) 
This section was changed as a result of Modification 2.
Old text:
Day 1 (Visit) 

Only on Day 1 of Cycles 2, 3, 4 and 5: Blood (plasma) sample collection for 
exposure-response modelling at pre-dose and between 0.5 and 1.5 hours post-dose in all 
subjects participating in the MTD expansion cohorts of study Part 1 and part 2 , see Table 
16-3. The dose needs to be taken under supervision and the time recorded. 

Only on Day 1 of Cycle 2: Obtain second biopsy: mandatory for all subjects in the 
MTD expansion cohort of Part 1 (all comer), voluntary for all other subjects, and send to 
laboratory, see Section 16.2.

New text:
Day 1 (Visit) 

Only for subjects in Part 3 in Cycle 2: peripheral blood sample collection for 
determination of cytokine levels.

Only on Day 1 of Cycles 2, 3, 4 and 5: Blood (plasma) sample collection for 
exposure-response modelling at pre-dose and between 0.5 and 1.5 hours post-dose in all 
subjects participating in the MTD expansion cohorts of study Part 1, Part 2, and Part 3 , 
see Table 16-3 (not in subjects with impaired renal function). The dose needs to be taken 
under supervision and the time recorded. 

Only on Day 1 of Cycle 2: Obtain second biopsy: mandatory for all subjects in the 
MTD expansion cohort of Part 1 (all comer), voluntary for subjects in the dose escalation 
cohorts of study Part 1 (all comer) and in the MTD expansion cohort of Part 2, and send to 
laboratory, see Section 16.2.

Mandatory for all subjects in study Part 3 / MTD expansion “Safety cohort”
(sqNSCLC + LAC + BC): Between Day 1 and Day 21 of Cycle 2: Obtain second biopsy
and send to laboratory, see Section 16.2; obtain peripheral blood for determination of 
cytokine levels. Subjects in Part 3 will provide one PK sample within 1 hour of biopsy 
collection in Cycle 2.
…
Day 8 ± 1 and Day 15 ± 1 (Visits)

Only for subjects in Part 3 on Day 15 in Cycle 2: peripheral blood sample collection 
for determination of cytokine levels.


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15.6.2.24 Section 9.4.1.2 Assessment of immune priming
This section was added as a result of Modification 2.
New text:
Assessment of immune response will be done at screening and during treatment for 
subjects in the “Safety cohort” (Part 3: sqNSCLC + LAC + BC). For gene expression 
profiling (nCounter PanCancer Immune Profiling Panel) and immunohistochemistry for 
CD8+ T cell infiltration and PD-L1 expression afresh tumor biospy (e.g. obtained by 
endoscopic or ultrasound guided biopsy) will be collected as follows:

Study Part 3 / “Safety cohort” (sqNSCLC + LAC + BC):
Screening: Biopsy is mandatory 
Between Cycle 2, Day 1 and Cycle 2, Day 21:  Biopsy is mandatory
Peripheral blood will be collected for determination of cytokine levels (IL-6, IFN-gamm, 
and others if needed) at the following timepoints: at baseline; Cycle 1, Day 8; Cycle 2, 
Day 1; Cycle 2, Day 15; and on the day of the second biopsy..
15.6.2.25 Section 9.4.2.1 Drug measurement
This section was changed as a result of Modification 2.
Old text:
… In the MTD expansion cohorts pharmacokinetic assessments will be performed in a 
total of 8 subjects with moderately impaired renal function at baseline (glomerular 
filtration rate [GFR] of 30 to 59 mL/min/1.73 m2 according to the modified diet in renal 
disease [MDRD] abbreviated formula).
New text:
… In the MTD expansion cohorts pharmacokinetic assessments will be performed in 
approximately 8 subjects with moderately impaired renal function at baseline (glomerular 
filtration rate [GFR] of 30 to 59 mL/min/1.73 m2 according to the modified diet in renal 
disease [MDRD] abbreviated formula). In all subjects participating in study Part 3/ MTD 
expansion “Safety cohort”, multiple dose pharmacokinetics (on Cycle 1 Day 15) will be 
performed.
…

Cycle 2: Subjects in Part 3/ MTD expansion “Safety cohort” will provide one PK 
sample within 1 hour of biopsy collection in Cycle 2.
15.6.2.26 Section 9.4.4
Biomarker investigation
Old text:
…
Anticancer chemotherapy must have been stopped for at least 5 half-lives of the last 
applied therapy before the pre-treatment biopsy is taken….


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New text:
Biomarker analysis will be done at pre-screening for subject stratification in the MTD 
expansion cohorts (Part 1: all comer; Part 2: sqNSCLC + LAC + BC + SCCHN; Part 3
sqNSCLC + LAC + BC) according to FGFR expression levels / FGFR mutation using 
either an archival tumor tissue specimen or fresh tumor biopsy material (see Section 7.1.1: 
Inclusion criteria, and Section 9.4.4.1: Predictive marker investigation).
….
Anticancer chemotherapy must have been stopped for at least 5 half-lives of the last 
applied therapy before the pre-treatment biopsy for biomarker (p-ERK1/2) studies is 
taken….
15.6.2.27 Section 9.4.4.1 Predictive marker investigations
This section was changed as a result of Modification 2.
New text: 
Prediction Biomarker:
For subjects to be enrolled in study Part 1 / MTD expansion (all comer), and subjects to be 
enrolled in Study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN) and 
subjects to be enrolled in Study Part 3 MTD expansion (sqNSCLC + LAC + BC) 
biomarker analysis will be done prior study start (subject stratification) on either a fresh or 
archival tumor biopsy sample to confirm high fibroblast growth factor receptor (FGFR) 
expression levels / FGFR mutation (see Section 7.1.1: Inclusion criteria).  
Rationale for the quantification of tumor FGFR-1 -2- and -3 levels 
…
We therefore consider to stratify sqNSCLC, LAC, BC and SCCHN subjects to be enrolled 
in study Part 2 and Part 3 / MTD expansion by the quantification of total FGFR mRNA 
expression levels in archival tissue samples in order to exclude subjects that are unlikely to 
benefit from BAY1163877 therapy due to low overall FGFR target expression levels.
Rationale for the detection of genetic alterations in FGFR encoding genes and in 
FGFR pathway downstream signaling molecules
In subjects included in study Part 1 / MTD expansion (all comer), Part 2 / MTD expansion 
(sqNSCLC + LAC + BC + SCCHN) and Part 3 / MTD expansion “Safety cohort”
(sqNSCLC + LAC + BC), genetic testing of tumor tissue may be necessary if a subject 
lacks a treatment response to BAY 1163877 despite FGFR overexpression in tumor. …. 
Existence of such FGFR downstream pathway activating mutations in the case of lack of 
response to BAY 1163877 treatment - despite high total FGFR mRNA tumor expression 
levels - should be evaluated retrospectively in subjects enrolled in study Part 1 / MTD 
expansion (all comer), Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN) and 
Part 3 / MTD expansion “Safety cohort” (sqNSCLC + LAC + BC).
…


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15.6.2.28 Section 9.5.4.2 Laboratory examinations
This section was changed as a result of Modification 2.
New text:
Blood and urine samples for the safety laboratory tests, biomarker investigations, and gene 
expression profiling and cytokine levels will be collected by a member of the 
investigator’s team.
The laboratory test results will be made promptly available to the investigator except for 
the biomarker parameters and cytokine levels, which will be analyzed in batches where 
appropriate.
…
-
Gene expression profiling (nCounter PanCancer Immune Profiling Panel)
-
Immunhistochemistry for CD8+ T cell infiltration and PD-L1 expression
Peripheral Blood:
-
Collection of serum to determine cytokine levels (IL-6, IFN-gamma, and others if 
needed)
Subjects with BC with low overall FGFR expression levels can only be included in study 
Part 2 or Part 3 if an activating mutation in FGFR3 gene has been confirmed at screening.
15.6.2.29 Section 10.5
Planned interim analysis
This section was changed as a result of Modification 2.
New text:
No interim analysis is planned during dose expansion at MTD in study Part 1 (MTD 
expansion cohort “all comer”), study Part 2 (MTD expansion cohort “sqNSCLC + LAC + 
BC + SCCHN”) or study part 3 (MTD expansion cohort “Safety cohort”).
15.6.2.30 Section 10.7
Determination of sample size 
This section was changed as a result of Modification 2.
Old text
In study Part 2 / MTD expansion, additional subjects will be included in order to obtain 
further safety and PK data at the MTD level in at least 20 subjects with sqNSCLC or 
LAC, approximately 30 subjects with BC and at least 8 subjects with SCCHN.
New text:
In study Part 2 / MTD expansion, additional subjects will be included in order to obtain 
further safety and PK data at the MTD level in at least 20 subjects with sqNSCLC or 
LAC, at least 30, up to a maximum of 50 evaluable subjects with BC and at least 8 
subjects with SCCHN.


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In study Part 3 / MTD expansion “Safety cohort”, additional subjects will be included to 
expand the safety database, to collect additional efficacy data, and to assess changes of the 
immune parameters following treatment at the MTD level in approximately 20 subjects 
with sqNSCLC or LAC, and approximately 20 subjects with BC.
15.6.2.31 Section 11.1
Data recording
This section was changed as a result of Modification 2.
New text:
…
-
Cancer classification including primary diagnosis (all comer for study Part 1; 
sqNSCLC, LAC, BC or SCCHN for Part 2; sqNSCLC, LAC or BC for Part 3), 
complete medical / oncological history data and TNM classification
…
15.6.2.32 Section 13.2
Subject information and consent
This section was changed as a result of Modification 2.
New text:
SIS / ICF for FGFR expression / FGFR mutation testing
For subject stratification in the MTD expansion cohorts (Part 1: all comer; Part 2: 
sqNSCLC + LAC + BC + SCCHN, Part 3: sqNSCLC + LAC + BC), a separate SIS / ICF 
will be provided to subjects for FGFR expression / FGFR mutation testing.
15.6.2.33 Section 13.3
Publication policy
According to modification 6 of Amendment 5 the name of the sponsor Bayer Health Care 
AG was renamed to Bayer AG. Section 13.3 was now amended accordingly.
Old text:
All data and results and all intellectual property rights in the data and results derived from 
the trial will be the property of the Bayer HealthCare, who may utilize the data in various 
ways, such as for submission to government regulatory authorities or disclosure to other 
investigators. The investigator, whilst free to utilize data derived from the trial for 
scientific purposes, must discuss any publication with Bayer HealthCare prior to release 
and obtain written consent of Bayer HealthCare on the intended publication. Bayer 
HealthCare recognizes the right of the investigator to publish the results upon completion 
of the trial. However, the investigator must send a draft manuscript of the publication or 
abstract to Bayer HealthCare 30 days in advance of submission in order to obtain approval 
prior to submission of the final version for publication. This will be reviewed promptly 
and approval will not be withheld unreasonably. In case of a difference of opinion 
between Bayer HealthCare AG and the investigator(s), the contents of the publication will 
be discussed in order to find a solution that satisfies all parties.
New text:


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All data and results and all intellectual property rights in the data and results derived from 
the trial will be the property of the Bayer AG, who may utilize the data in various ways, 
such as for submission to government regulatory authorities or disclosure to other 
investigators. The investigator, whilst free to utilize data derived from the trial for 
scientific purposes, must discuss any publication with Bayer AG prior to release and 
obtain written consent of Bayer AG on the intended publication. Bayer AG recognizes the 
right of the investigator to publish the results upon completion of the trial. However, the 
investigator must send a draft manuscript of the publication or abstract to Bayer AG
30 days in advance of submission in order to obtain approval prior to submission of the
final version for publication. This will be reviewed promptly and approval will not be 
withheld unreasonably. In case of a difference of opinion between Bayer AG and the 
investigator(s), the contents of the publication will be discussed in order to find a solution 
that satisfies all parties.
15.6.2.34 Section 14 
Reference list 
This section was changed as a result of Modification 2.
New reference:
(40)
Sweis RF, Spranger S, Bao R, Paner GP, Stadler WM, Steinberg G, Gajewski TF. 
Molecular Drivers of the Non-T-cell-Inflamed Tumor Microenvironment in 
Urothelial Bladder Cancer. Cancer Immunol Res. 2016 Jul;4(7):563-8. doi: 
10.1158/2326-6066.CIR-15-0274. Epub 2016 May 17.
15.6.2.35 Section 16.1 
Study flow chart
This section was changed as a result of Modification 2.
New text:
Table 16-1: Study flow chart: Pre-Treatment – Study Part 1, and Part 2 and Part 3
FGFR expression / 
FGFR mutation 
testing 
Screening
Measures / actions
Only for subjects 
recruited for MTD 
expansion cohorts 
(Part 1, Part 2, Part 3)  
Within 28 Days* 
Within 7 Days*
before first study drug 
administration
Stratification of subjects to be 
enrolled in MTD expansion cohorts 
(Part 1, Part 2 and Part 3)(F)  
Part 3 only: Peripheral blood 
collection for serum cytokine level
(K)
X
(E) 
A pre-treatment biopsy at screening will be obtained from all subjects who agreed on this. 
For subjects in Part 3 the fresh biopsy for immune response is mandatory. The biopsy 
sample will be sent to laboratory for biomarker evaluation, see Table 16 5, Table 16 6 and 
Table 16 7.
(K)
For details see Table 16 8


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Table 16-3:
Study flow chart: Treatment (Cycle ≥ 1) and Follow-up – Study Part 1, Part 2 and Part 3 (continued)
Measures / actions
TREATMENT
FOLLOW-UP
Cycle 1 
(21 days)
Cycles 2-12
(21 days)
Cycles ≥13
(21 days)
EOT Visit
Within 
0-14 days 
after last 
dose
FU-Visit / 
Phone Call(A)
At 30-35 days 
after last dose
Day (D)
D1
D2
D3
D8 ±1
D15
D1
D8 ±1
D15 ±1
D1
D11
Part 3 only: obtain fresh tumor biopsy (G)
X
(Between Day 1 to Day 21)
Part 3 only: peripheral blood collection (N)
X
XN
XN
PK blood sampling (H)
XX
X
XH
(G)
..
A biopsy in Cycle 2, between Days 1 and 21 inclusively is mandatory …
… for subjects in Part 3 / MTD expansion (sqNCSLC + LAC + BC)”.
(H)
PK sampling will be done as follows (for details see Laboratory Manual):•
Cycle 1, Day 1: single-dose PK (all subjects of study Part 1 and at least 12 subjects of study Part 2 and approximately 8 subjects of the MTD expansion 
cohorts with impaired renal function at baseline
…
Cycle 1, Day 15: multiple-dose PK (all subjects of study Part 1 and 3 and at least 12 subjects of study Part 2 and approximately 8 subjects of the MTD
Cycle 2: Subjects in Part 3/ MTD expansion “Safety cohort” will provide one PK sample within 1 hour of biopsy collection in Cycle 2
(I)
All subjects participating in the MTD expansion cohorts (Part 1, Part 2 or Part 3 [not in subjects with impaired renal function]) will have 2 PK samples 
drawn for the purpose of exposure-response modeling on Day 1 of Cycles 2, 3, 4, and 5 (1 blood sample just before the morning dose of BAY 1163877 
and 1 blood sample between 0.5 and 1.5 hours post-dose). The dose needs to be taken under supervision and the time recorded.
(K)
Subjects with PK assessment (all subjects of study Part 1 and at least 12 subjects of study Part 2 and approximately 8 subjects of the MTD expansion 
cohorts with impaired renal function at baseline) will receive a single-dose of BAY 1163877 on Cycle 1, Day 1 (morning),…
(L)
Subjects without PK assessment in study Part 2 and subjects in study Part 3 will receive BAY 1163877 twice daily from Cycle 1, Day 1 ongoing.
(N)
Peripheral blood sample for determination of serum cytokine level will be collected at the following timepoints: at baseline; Cycle 1, Day 8; Cycle 2, Day 
1; Cycle 2, Day 15; and at day of second biopsy, for details see Table 16-8


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15.6.2.36 Section 16.2
Laboratory examinations
This section was changed as a result of Modification 2.
New text:
Table 16-4: Parameters and time points of laboratory examinations performed at local laboratory or study site (safety laboratory) – Study Part 1,  
Part 2 and Part 3


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Table 16-8: Parameters and time points for biomarker investigations in study Part 3 / MTD expansion ”Safety cohort”
(sqNSCLC + LAC + BC)
Parameters
PRE-TREATMENT 
TREATMENT
FGFR expression / 
FGFR mutation 
testing
Screening
Cycle 1
Cycle 2
Day 1
Day 8
Day 15
Day 1
Day 8
Day 15
Fresh tumor biopsy
X(A)
X(B)
Peripheral blood samples (B) 
X
X
X(C)
X
Tumor tissue for FGFR 
expression
FGFR1/2/3 expression
FGFR and FGFR pathway 
mutations
X(D)
X(D)
(A)
An additional biopsy is not requested if a fresh biopsy was already obtained for FGFR expression / FGFR mutation testing prior to the screening 
visit. 
(B)
A second mandatory tumor biopsy must be obtained between Cycle 2, Day 1 and Cycle 2, Day 21. 
(C)
Peripheral blood will be collected for determination of serum cytokine levels at the following timepoints: at baseline; Cycle 1, Day 8; Cycle 2, Day 1; 
Cycle 2, Day 15; and on the day of the second biopsy
(D)
An archival or fresh tumor tissue specimen will be used for the quantification of fibroblast FGFR expression levels, necessary for subject 
stratification (see Section 7.1.1: Inclusion criteria). If no archival biopsy sample is available which has been handled and processed as described in 
the lab manual, collection of fresh tumor biopsy material is mandatory for stratification. 
The evaluation of FGFR pathway mutations is planned retrospectively for all subjects.


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15.6.2.37 Section 16.3
Listing of instructions and manuals
This section was changed as a result of Modifications 1.
Old text:
Sample Handling Procedure Sheet / Manuals
Instructions for handling of biologic samples for safety laboratory evaluations and PK 
assessments are given in the sample handling procedure sheet in the study file and / or
Laboratory Manual. These documents comprise all relevant measures for the sampling, 
handling, storage and shipment of the biomatrices (e.g. blood-plasma, urine etc.) including 
sampling. It is provided by the department responsible for bioanalysis.
New text:
Instructions for handling of biologic samples for safety laboratory evaluations and PK 
assessments are given in a separate document (e.g. Laboratory Manual). These document 
comprises all relevant measures for the sampling, handling, storage and shipment of the 
biomatrices (e.g. blood-plasma, urine etc.). 
15.7 Amendment 9
Amendment no.9 is a global amendment forming integrated protocol version 8.0, dated 17 
Oct 2018.
Overall rationale for the amendment
The protocol was amended to allow patients a possibility to continue treatment with 
rogaratinib and/or follow-up in a roll-over study after the study completion.
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
6.3 End of study, 8.2 Identity 
of study treatment, 8.8 Post-
study therapy, 10.1 General 
considerations, 12 Premature 
termination of the study
Protocol was modified to 
introduce a roll-over study.
A roll-over study was 
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.


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16 Appendices
16.1 Study flow chart - amended
Table 16-1, Table 16-2 and Table 16-3 in the following provide flow charts presenting the 
time points for the study related measures / actions.


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Table 16-1: Study flow chart: Pre-Treatment – Study Part 1,  Part 2 and Part 3- amended
FGFR expression / 
FGFR mutation 
testing 
Screening
Measures / actions
Only for subjects 
recruited for MTD 
expansion cohorts 
(Part 1, Part 2, Part 
3)  
Within 28 Days* 
Within 7 Days*
before first study drug 
administration
Signed informed consent
X(A1)
X(A2)
Limited inclusion criteria 
X
Inclusion / exclusion criteria
X
X
Demographic data
X(J)
X(J)
Documentation of the primary 
diagnosis (refractory, locally 
advanced or metastatic solid 
tumor) using the complete 
pathological report
X(J)
X(J)
Complete medical / oncological 
history
X(J)
X(J)
TNM classification
X(J)
X(J)
Concomitant diseases, NYHA 
grading
X
Review of baseline toxicities 
(X)
X
X
Baseline characteristics (smoking 
habits / history, alcohol 
consumption)
X
Previous therapy
X
Concomitant therapy
X
X
Physical examination 
X
Body height
X
Body weight / calculation of BMI(B)
X
Vital signs(C)
X
ECOG performance status
X
X
12-lead ECG(D)
X
Obtain pre-treatment biopsy(E)  
X
Obtain archival tissue sample or 
fresh tumor material for FGFR 
expression / FGFR mutation testing
X
Continued


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Table 16-1: Study flow chart: Pre-Treatment – Study Part 1, Part 2 and Part 3 - amended91
Measures / actions
FGFR expression / 
FGFR mutation 
testing 
Screening
Only for subjects 
recruited for MTD 
expansion cohorts 
(Part 1,  Part 2 and 
Part 3)  
Within 28 Days* 
Within 7 Days*
before first study drug 
administration
Stratification of subjects to be 
enrolled in MTD expansion cohorts 
(Part 1, Part 2 and Part 3)(F)  
X
Blood / urine collection for safety 
lab tests(G)
X
X
Part 3 only: Peripheral blood 
collection for serum cytokine 
level(K)
X
Only females: Urine pregnancy 
test
X
Calculation of eGFR(H)
X
Ophthalmological examination at 
consultant
X
CT / MRI scans 
X
Documentation of lesion(s) 
according to RECIST v1.1
X
Adverse events(I)
(X)
X
X
*Pre-study examinations may require hospitalization for 1- 2 days.
(A1)
Informed consent for FGFR expression / FGFR mutation testing
(A2)
Informed consent for study treatment eligibility can be signed before 28-day screening phase.
(B)
BMI (body mass index) is calculated by dividing the subject’s weight by the square of his / her 
height (kg/cm2).
(C)
Vital signs (body temperature, respiration, systolic / diastolic blood pressure, heart rate); for 
methods of measurement, see Section 9.4.1.1 (Cardiovascular assessment) and 
Section9.5.3.3 (Vital signs). 
(D)
At screening, single ECG readings (in the supine position) should be performed.
(E) 
A pre-treatment biopsy at screening will be obtained from all subjects who agreed on this. For 
subjects in Part 3 the fresh biopsy is mandatory. The biopsy sample will be sent to laboratory 
for biomarker evaluation, see Table 16-5, Table 16-6 and Table 16-7. 
                                                
91 Table 16-1 was modified by Amendment 7, see section 15.6.2.35


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Table 16-1: Study flow chart: Pre-Treatment – Study Part 1, Part 2 and Part 3 
(Continued)
((F) 
For details, see Table 16-6 and Table 16-7
(G) 
Safety lab tests: Virology tests within 28 days before first study drug administration, all other 
blood and urine tests within 7 days before first study drug administration, for details 
see Table 16-4. H)
For calculation of eGFR (estimated glomerular filtration rate), see 
Section 16.9.
(I)
Signs and symptoms that existed prior to signing informed consent should be recorded as 
medical history findings. Signs and symptoms worsened after the informed consent was 
signed as well as any sign or symptom that begins after the informed consent was signed 
(even if prior to start of study medication) should be recorded on an adverse event page of 
the eCRF using CTCAE v4.03. AE does only to be recorded for period of FGFR expression / 
FGFR mutation testing in pre-treatment in case an invasive procedure was performed to 
obtain tumor material.
(J)
Documentation has not to be provided twice for subjects enrolled in the MTD expansion 
cohorts.
(K)
For details see Table 16-8


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Table 16-2: Study flow chart: Treatment (Cycle 1, Day -3 to Day -1) – Study Part 1 
and Part 2 
Measures / actions
TREATMENT 
(only for “tablet bridging cohort” 
(Part 1) and for “food effect 
assessment” (Part 1 and Part 2))
Cycle 1
Day -3
Day -2
Day -1
Concomitant medication
X
X
X
Physical examination 
X
X
X
Ask subject for changes in vision(A)
X
X
X
Cardiovascular assessment(B)
XX
X
Body temperature
X
X
X
Body weight
X
12-lead ECG readings(C)
X
X
ECOG performance status
X
X
X
Blood / urine collection for safety lab tests(D)
X
Calculation of eGFR(E)
X
PK blood sampling(F)
XX
Administration of BAY 1163877 (single dose) after a 
high-fat, high-calorie breakfast(G)
X
Administration of BAY 1163877 tablet (single dose)(H)
X
Toxicities / AE assessment
X
X
X
(A) 
If change in vision is reported by subject an ophthalmological examination must be performed 
(see Section 9.5.3.2)
(B)
Cardiovascular assessment: Blood pressure (BP) and heart rate (HR) will be measured as 
follows (see Section 9.4.1.1): before and 0.5, 1, 2, 3, 4, 6, 8, 12 (Day -3), 24 (Day -2) and
48 (Day -1) hour(s) after single-dose administration.
If a reduction of systolic BP below 90 mmHg or an increase in HR to more than 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, subject’s 
blood pressure will be measured before collection of the PK sample.
(C) 
12-lead ECGs should be performed in triplicate in close sequence and not more than 
2 minutes apart. ECG readings will be performed at the following time points: 
before and 2, 3 (Day -3) and 24 (Day -2) hours after single-dose administration. 
(D)
Safety laboratory tests, see Table 16-4
(E)
For calculation of eGFR (estimated glomerular filtration rate), see Section 16.9
(F)
PK sampling will be done as follows (for details see separate document e.g. Laboratory 
Manual):

pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12 (Day -3), 24 (Day -2) and 48 (Day -1) hour(s) 
after single-dose administration
Continued


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Table 16-2: Study flow chart: Treatment (Cycle 1, Day -3 to Day -1 – Study Part 1 and 
Part 2 (Continued)
(G)
Only for subjects with “food effect assessment” in Part 1 and Part 2:  Oral administration of a 
single dose of BAY 1163877 immediately (within 5 minutes) after consumption of a high-fat, 
high-calorie breakfast (supervised by a member of the site), see Section 8.4.2.2.1.
(H)
Only for subjects included in the “tablet bridging cohort” of Part 1 / dose escalation: 
Oral administration of BAY 1163877 tablet formulation on Cycle 1, Day -3 will be done by a 
member of the site.


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Table 16-3: Study flow chart: Treatment (Cycle ≥ 1) and Follow-up – Study Part 1, Part 2 and Part 3 (continued) - amended
Measures / actions
TREATMENT
FOLLOW-UP
Cycle 1 
(21 days)
Cycles 2-12
(21 days)
Cycles ≥13
(21 days)
EOT Visit
Within 
0-14 days after 
last dose
FU-Visit / 
Phone Call(A)
At 30-35 days 
after last dose
Day (D)
D1
D2
D3
D8 ±1
D15
D1
D8 ±1
D15 ±1
D1
D11
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
Physical examination 
X
X
X
X
X
X
X
X
X
X
X
X
Ask subject for changes in vision(B)
X
X
X
X
X
X
X
X
X
X
X
X
Cardiovascular assessment(C)
XX
X
X
X
X
X
X
X
X
X
X
Body temperature
X
X
X
X
X
X
X
X
Body weight
X
X
X
X
12-lead ECG readings(D)
X
X
X
X
X
X
ECOG performance status
X
X
X
X
X
X
X
X
X
X
X
Blood / urine collection for safety lab tests(E)
X
X
X
X
X
X
X
X
X
Calculation of eGFR(F)
X
X
X
X
X
X
X
X
X
24-hour urine collection(M)
X
Obtain tumor biopsy for biomarker tests(G)
X
(Cy 2 
only)
Part 3 only: obtain fresh tumor biopsy (G)
X (Between Day 1 to Day 21)
Part 3 only: peripheral blood collection (N)
X
XN
X
PK blood sampling(H)
XX
X
XH
PK blood sampling for PK / PD modeling(I)
X
Ophthalmological examination
Every 2nd cycle
X
CT / MRI scans and documentation of 
response according to RECIST v1.1
End of Cycle 2, then after every 3rd
cycle


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Table 16-3: 
Study flow chart: Treatment (Cycle ≥ 1) and Follow-up – Study Part 1, Part 2 and Part 3 (Continued) - amended
Measures / actions
TREATMENT
FOLLOW-UP
Cycle 1 
(21 days)
Cycles 2-12
(21 days)
Cycles ≥13
(21 days)
EOT Visit
Within 
0-14 days after 
last dose
FU-Visit / 
Phone Call(A)
At 30-35 days 
after last dose
Day (D)
D1
D2
D3
D8 ±1
D15
D1
D8 ±1
D15 ±1
D1
D11
Dispense / return of BAY 1163877 and diary(J)
X
X
X
X
X
X
X
X
X
X
Administration of BAY 1163877
if PK assessment (K)
X
Continuous, twice-daily administration 
Administration of BAY 1163877
if no PK assessment(L)
   Continuous, twice-daily administration
Toxicities / AE assessment
X
X
X
X
X
X
X
X
X
X
X
X
A time window of 1 day is allowed on visits with no PK sampling. 
(A)
FU-Visit will be performed for subjects who have not started a new treatment. For subjects who have started a new antitumor treatment, only a phone call 
will be made. 
(B)
If change in vision is reported by subject an ophthalmological examination (see Section 9.5.3.2) must be performed
(C)
Cardiovascular assessment: Blood pressure (BP) and heart rate (HR) will be measured as follows (see Section 9.4.1.1):

Cycle 1, Day 1 and Day 2: before and 0.5, 1, 2, 3, 4, 6, 8, 12 (Day 1), and 24 (Day 2) hour(s) after single-dose administration

Cycle 1, Day 3: before and 1 and 2 hour(s) after morning dose

Cycle 1, Day 8: (one measurement)

Cycle 1, Day 15: before and 0.5, 1, 2, 3, 4, 6, 8 and 12 hour(s) after morning dose (12-hour measurement before evening dose)

Cycle ≥ 2: each visit (one measurement)

Follow up : EOT visit (one measurement) and FU-visit (one measurement)
If a reduction of systolic BP below 90 mmHg or an increase in HR to more than 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, subject’s blood pressure will be measured before 
collection of the PK sample.
Continued


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Table 16-3:
Study flow chart: Treatment (Cycle ≥1) and Follow-up – Study Part 1, Part 2 and Part 3 (Continued) - amended
(D)
In Cycle 1, all 12-lead ECGs should be performed at the following time points:
Cycle 1, Day 1 and Day 2 (single ECG reading): before and 2, 3 (Day 1) and 24 (Day 2) hours after single-dose administration 
Cycle 1, Day 15 (single ECG reading): before morning dose, and 2 and 3 hours thereafter 
Cycle ≥ 2, Day 1 (single ECG reading): after morning dose
EOT visit (single ECG reading)
(E)
Safety laboratory tests, see Table 16-4
(F)
For calculation of eGFR (estimated glomerular filtration rate), see Section 16.9
(G)
A tumor biopsy on Cycle 2, Day 1 will be obtained from all subjects who agreed on this at screening. The biopsy sample will be send to laboratory for 
biomarker evaluation, see Table 16-5, Table 16-6 and Table 16-7. 
A biopsy on Cycle 2, Day 1 is optional … 
…for subjects in study Part 1 / dose-escalation (all comer).
…for subjects in study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN).
A biopsy on Cycle 2, Day 1 is mandatory … 
…for subjects in study Part 1 / MTD expansion (all comer).
A biopsy in Cycle 2, between Days 1 and 21 inclusively is mandatory …
… for subjects in Part 3 / MTD expansion (sqNCSLC + LAC + BC)”
(H)
PK sampling will be done as follows (for details see Laboratory Manual):•

Cycle 1, Day 1: single-dose PK (all subjects of study Part 1 and at least 12 subjects of study Part 2 and approximately 8 subjects of the MTD expansion 
cohorts with impaired renal function at baseline)

pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 and 48 hour(s) after single-dose administration (48-hours sample before morning dose on Day 3)

Cycle 1, Day 15: multiple-dose PK (all subjects of study Part 1 and 3 and at least 12 subjects of study Part 2 and approximately 8 subjects of the MTD 
expansion cohorts with impaired renal function at baseline)
before and 0.5, 1, 2, 3, 4, 6, 8 and 12 hour(s) after morning dose on Cycle 1, Day 15 (12-hour sample before administration of evening dose)
Cycle 2: Subjects in Part 3/ ”Safety cohort” will provide one PK sample within 1 hour of biopsy collection in Cycle 2
(I)
All subjects participating in the MTD expansion cohorts (Part 1, Part 2 or Part 3 [not in subjects with impaired renal function]) will have 2 PK samples 
drawn for the purpose of exposure-response modeling on Day 1 of Cycles 2, 3, 4, and 5 (1 blood sample just before the morning dose of BAY 1163877 
and 1 blood sample between 0.5 and 1.5 hours post-dose). The dose needs to be taken under supervision and the time recorded.


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Table 16-3:
Study flow chart: Treatment (Cycle ≥1) and Follow-up – Study Part 1, Part 2 and Part 3 (Continued)
(J) 
First oral administration of BAY 1163877 on Cycle 1 Day 1 will be done with a member of the site. To have complete control over the distribution and use 
of the study medication, the drug accountability must be performed before new medication is handed out to the subject. Return of BAY 1163877and diary 
at EOT visit.
(K) 
Subjects with PK assessment (all subjects of study Part 1 and at least 12 subjects of study Part 2 and approximately 8 subjects of the MTD expansion 
cohorts with impaired renal function at baseline) will receive a single-dose of BAY 1163877 on Cycle 1, Day 1 (morning), followed by a “drug-free day” (to 
enable single dose PK assessments). Subjects with “food effect assessment” in Part 1 and Part 2 take the morning dose after an overnight fast of at least 
8 hours (see Section 8.4.2.2.1). 
Treatment with BAY 1163877 will resume on Day 3 of Cycle 1 if no protocol-defined dose-limiting toxicities (DLTs) are reported. Starting on Cycle 1, 
Day 3, the study drug will be self-administered twice daily for the remaining 19 days of Cycle 1. For subsequent cycles, study drug will be administered 
twice daily for 21 days each Cycle.
(L)
Subjects without PK assessment in study Part 2 and subjects in study Part 3 will receive BAY 1163877 twice daily from Cycle 1, Day 1 ongoing.
(M)
In approximately 8 subjects enrolled in MTD expansion cohorts (study Part 1 and Part 2), urine will be collected for 24 hours after dosing.
(N)
Peripheral blood sample for determination of serum cytokine level will be collected at the following timepoints: at baseline; Cycle 1, Day 8; Cycle 2, Day 1; 
Cycle 2, Day 15; and at day of second biopsy, for details see Table 16-8
92
                                                
92 Table 16-3 was modified by Amendment 7, see section 15.6.2.35


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16.2 Laboratory examinations - amended
Table 16-4, Table 16-5, Table 16-6, Table 16-7 and Table 16-8 provide the parameters and 
time points for the laboratory examinations (safety laboratory tests, biomarker investigations, 
cytokines) to be performed during the study. Instructions for biomarker and PK sample 
collection, processing, storage and shipment will be described in a separate document (e.g. lab 
manual).


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Table 16-4: Parameters and time points of laboratory examinations performed at local laboratory or study site (safety laboratory) – Study Part 1, Part 
2 and Part 3 - amended 93
Parameters
PRE-TREATMENT
TREATMENT
FOLLOW-UP
FGFR ex-
pression / FGFR 
mutation testing
Screen-
ing
Cycle 1
Cycles 1-12
Cycle ≥13
EOT
visit
FU 
visit
Day -3
Day 1
Day 8
Day 15 Day 1
Day 11
BLOOD
Hematology: Erythrocytes (RBC), hemoglobin, hematocrit, platelet 
count, MCV, MCH, MCHC, leucocytes (WBC), including differential 
WBC (absolute count of neutrophils, lymphocytes, monocytes, 
basophils, and eosinophils)
X
X
X
X
X
X
X
X
Coagulation: PT or PT-INR (obligatory at screening)  and PTT 
(aPTT)(A)
X
X
X
X
Biochemistry: AST / GOT, ALT / GPT, gamma-GT, AP, LDH, 
amylase, lipase, glucose, triglycerides, creatinine(B), BUN, uric acid, 
bilirubin (total & direct), total protein, albumin, sodium, potassium, 
chloride, CPK, calcium, phosphate
X
X
X
X
X
X
X
X
Virology: HBs-Ag, anti-HCV, anti-HIV 1+2 
X
URINE
Macroanalysis: Clarity of urine: clear, slightly clear, cloudy, or turbid
X
X
X
X
X
X
X
X
Urinalysis (dip stick): pH, blood, protein, glucose, bilirubin, 
urobilinogen, ketone, nitrite, leucocytes (or leucocyte esterase), 
specific gravity
X
X
X
X
X
X
X
X
Laboratory analysis(C): Protein and creatinine 
X
X
X
X
X
X
X
X
Microscopic urinalysis(D): Erythrocytes, leucocytes, epithelia cells, 
bacteria crystals, casts, bacteria and yeast 
X
X
X
X
X
X
X
X
Pregnancy test(F)
X
                                                
93 Part 3 added by Amendment 7


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Table 16-4:
Parameters and time points of laboratory examinations performed at local laboratory or study site (safety laboratory) – Study 
Part 1, Part 2 and Part 3
(A)
For all subjects
(B)
The serum creatinine concentration is used to estimate the subject’s glomerular filtration rate (see Section 16.9)
(C)
Random urine sample preferably taken at mid-morning for the quantification of proteinuria by urinary protein/creatinine ratio
(D)
Only if urine appearance is turbid, or if protein, leukocytes, erythrocytes, or nitrite are out of normal range)
(F)
Only females of childbearing potential


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Table 16-5: Parameters and time points for biomarker investigations in study Part 1 / dose escalation (all comer) 
Parameters
PRE-TREATMENT
TREATMENT
FOLLOW-
UP
FGFR expression 
/ FGFR mutation 
testing
Screening
Cycle 1
Cycles 2-12
Cycles ≥13
EOT visit
Day 1
Day 3
Day 8
Day 15
Day 1
Day 8
Day 15
Day 1
Day 11
Tumor tissue:
p-ERK1/2 levels 
X(A)
X(B)
only Cycle 2
Blood (serum) samples*:
FGF23
X
X
X
X
X
X
X
X
X
X
X
Phosphate, Calcium
X
X
X
X
X
X
X
X
X
X
X
p-ERK = phospho-extracellular signal–regulated kinase
FGF23 = fibroblast growth factor 23
* Blood (serum) samples to be collected before administration of the morning dose of BAY 1163877 only for Cycle 1.
(A)
A pre-treatment biopsy (e.g. endoscopic or ultrasound-guided biopsy) will be obtained at screening if the subject agreed on this (optional biopsy).
Anticancer chemotherapy must have been stopped for at least 5 half-lives of the last applied therapy before the pre-treatment biopsy is taken. Mitomycin C, 
nitrosoureas or monoclonal antibodies with anticancer activity (e.g. bevacizumab or cetuximab etc.) should not be given within 6 weeks of pre-treatment 
biopsy for biomarker (p-ERK1/2) studies.
(B)
A second biopsy may be taken on Cycle 2, Day 1 if the subject agreed on this at screening (optional biopsy).
p-ERK1/2 levels will only be analyzed if a subject is willing to undergo both a pre-treatment biopsy at screening and a second biopsy on Cycle 2, Day 1.


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Table 16-6: Parameters and time points for biomarker investigations in study Part 1 / MTD expansion (all comer)
Parameters
PRE-TREATMENT 
TREATMENT
FOLLOW-UP
FGFR expression / 
FGFR mutation 
testing 
Screening
Cycles 1-12
Cycles ≥13
EOT visit
Day 1
Day 8
Day 15
Day 1
Day 11
Tumor tissue:
p-ERK1/2 levels
X(A)
X(B)
only Cycle 2
FGFR1/2/3 expression
X(C)
FGFR and FGFR 
pathway mutations
X(C)
Blood (serum) 
samples*:
FGF23
X
X
X
X
X
X
X
Phosphate, Calcium
X
X
X
X
X
X
X
p-ERK = phospho-extracellular signal–regulated kinase
FGFR 1/2/3
= fibroblast growth factor receptor 1, 2 and 3
FGF23 = fibroblast growth factor 23
* Blood (serum) samples to be collected before administration of the morning dose of BAY 1163877 only for Cycle 1.
(A)
An additional biopsy is not requested if a biopsy was already obtained for FGFR expression / FGFR mutation testing prior to the screening visit. 
Anticancer chemotherapy must have been stopped for at least 5 half-lives of the last applied therapy before the pre-treatment biopsy is taken. 
Mitomycin C, nitrosoureas or monoclonal antibodies with anticancer activity (e.g. bevacizumab or cetuximab etc.) should not be given within 6 weeks of 
pre-treatment biopsy for biomarker (p-ERK1/2) studies.
(B)
A second mandatory tumor biopsy must be obtained on Cycle 2, Day 1.
(C)
An archival or fresh tumor tissue specimen will be used for the quantification of fibroblast FGFR expression levels, necessary for subject stratification 
(see Section 7.1.1: Inclusion criteria). If no archival biopsy sample is available which has been handled and processed as described in the lab manual, 
collection of fresh tumor biopsy material is mandatory for stratification. 
The evaluation of FGFR pathway mutations is planned retrospectively for all subjects.


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Table 16-7: Parameters and time points for biomarker investigations in study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN) 
Parameters
PRE-TREATMENT
TREATMENT
FOLLOW-UP
FGFR expression / 
FGFR mutation testing
Screening
Cycles 1-12
Cycles ≥13
EOT visit
Day 1
Day 8
Day 15
Day 1
Day 11
Tumor tissue:
p-ERK1/2 levels
X(A)
X(B)
only Cycle 2
FGFR1/2/3 expression
X(C)
FGFR and FGFR pathway 
mutations
X(C)
p-ERK
= phospho-extracellular signal–regulated kinase
FGFR 1/2/3
= fibroblast growth factor receptor 1, 2 and 3
(A)
A pre-treatment biopsy (e.g. endoscopic or ultrasound-guided biopsy) will be obtained at screening if the subject agreed on this. The pre-treatment biopsy 
is optional for subjects for whom an archival biopsy is available. An additional biopsy is not requested if a biopsy was already obtained for FGFR expression 
/ FGFR mutation testing prior to the screening visit.
Anticancer chemotherapy must have been stopped for at least 5 half-lives of the last applied therapy before the pre-treatment biopsy is taken. Mitomycin C, 
nitrosoureas or monoclonal antibodies with anticancer activity (e.g. bevacizumab or cetuximab etc.) should not be given within 6 weeks of pre-treatment 
biopsy for biomarker (p-ERK1/2) studies.
(B)
A second biopsy will be taken on Cycle 2, Day 1 if the subject agreed on this at screening (optional biopsy).
(C)
An archival tumor tissue specimen will be used for the quantification of fibroblast FGFR expression levels necessary for subject stratification (see 
Section 7.1.1: Inclusion criteria). If no archival biopsy is available which has been handled and processed as described in the lab manual, collection of fresh 
tumor biopsy material is mandatory for stratification. 
Samples of BC subjects will also be tested on activating FGFR3 mutation status for stratification. 
The evaluation of FGFR pathway mutations is planned retrospectively for all subjects.
p-ERK1/2 levels will only be analyzed if a subject is willing to undergo both a pre-treatment biopsy at screening and a second biopsy on Cycle 2, Day 1.


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94
Table 16-8: Parameters and time points for biomarker investigations in study Part 3 / MTD expansion ”Safety cohort” (sqNSCLC + 
LAC + BC)
Parameters
PRE-TREATMENT 
TREATMENT
FGFR expression / 
FGFR mutation 
testing
Screening
Cycle 1
Cycle 2
Day 1
Day 8
Day 15
Day 1
Day 8
Day 15
Fresh tumor biopsy
X(A)
X(B)
Peripheral blood samples 
(B) 
X
X
X(C)
X
Tumor tissue for FGFR 
expression
FGFR1/2/3 expression
FGFR and FGFR pathway 
mutations
X(D)
X(D)
(A)
An additional biopsy is not requested if a fresh biopsy was already obtained for FGFR expression / FGFR mutation testing prior to the screening visit. 
(B)
A second mandatory tumor biopsy must be obtained between Cycle 2, Day 1 and Cycle 2, Day 21. 
(C)
Peripheral blood will be collected for determination of serum cytokine levels at the following timepoints: at baseline; Cycle 1, Day 8; Cycle 2, Day 1; Cycle 
2, Day 15; and on the day of the second biopsy
(D)
An archival or fresh tumor tissue specimen will be used for the quantification of fibroblast FGFR expression levels, necessary for subject stratification (see 
Section 7.1.1: Inclusion criteria). If no archival biopsy sample is available which has been handled and processed as described in the lab manual, collection 
of fresh tumor biopsy material is mandatory for stratification. 
The evaluation of FGFR pathway mutations is planned retrospectively for all subjects.
                                                
94 Table 16-8 was added by Amendment 7, see section 15.6.2.36


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16.3 Listing of instructions and manuals - amended
Instructions for handling of biologic samples for safety laboratory evaluations and PK 
assessments are given in a separate document (e.g. Laboratory Manual). This document 
comprises all relevant measures for the sampling, handling, storage and shipment of the 
biomatrices (e.g. blood-plasma, urine etc.). 95
                                                
95 This section was amended for clarification by Amendment 7 


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16.4 Model-based dose-response analysis of the DLT rates 
16.4.1 Statistical model
The analysis is based on a method reported by Tibaldi et al (2008) (37).
A range of daily doses will be tested, including possibly 100, 200, 300, 400, 500, 600, 700, 
800, 900, 1000 and 1100mg. Additional or alternative dose levels may be chosen. These 
possible dose levels are labeled as d = 1, …, N, where N is the maximum number of dose 
levels for the study. The probability, p, of observing a subject with DLTs during cycle 1 is 
modeled as a function of dose:
d
p
p




)
1
log(
.
The prior distribution on and determine the prior distribution on the probability of DLT as 
a function of dose. Prior distributions were elicited. All of the following distributions are 
independent. The following prior distributions are used in the trial:
1)
sd
-3,
N(µ
~



,
and
0.003)
sd
0.0015,
(µ
N
~




.
Based on these distributions, 100 dose-DLT curves from the prior distribution were simulated 
(see Figure 16-1).  
The prior probability distribution for the MTD is summarized in Table 16-9.


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Figure 16-1:100 random observations (curves) 
from the prior distribution
Table 16-9: Prior probability distribution of MTD
MTD range
Prior probability
≤100mg
10.8%
Between 100 and 300mg
17.4%
Between 300 and 600mg
25.0%
Between 600 and 1100mg
19.7%
> 1100mg
27.1%
Given any set of data, the prior distribution can be updated, yielding a posterior distribution of 
the parameters. From this posterior distribution many different quantities of relevance can be 
calculated:

E(p|d) = Posterior mean probability of DLT for dose d.

Td = (tolerable) Probability that the DLT rate is below 0.20, Pr(p <0.20| d), for a dose 
d.

Qd = Probability of dose d being the MTD
0
200
400
600
800
1000
0
20
40
60
80
100
Dose (mg)
Pr(DLT) (%)


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
MTD: the dose at which the predicted DLT rate is 20%: 




)
8.0
/
2.0
log(
MTD
Note that, in this model, the MTD is a parameter. It has a probability distribution. A 
consequence of the Bayesian modeling is the probability, Qd, which is the probability that a
dose is the MTD. This is a powerful question that cannot be answered from a frequentist 
perspective.
16.4.2 Trial simulation details
The trial design for purposes of simulation is as follows:
1. Three subjects are assigned to d = 1 (100mg)
2. Pursue the following dose escalation process up to when first DLT is observed: 
a.
2-fold dose escalation testing doses up to 1100 mg in cohorts of 3 subjects.
3. If at least one DLT is reported, fit Bayesian model and select next dose as the dose d at 
which Qd is maximum, or the maximum allowed dose if any of the following 
constraints are met:
If 2 DLTs in a cohort of size 3, d must be lower than or equal to that dose.
If 3 DLTs out of 3 or at least 4 DLTs out of 6, d must be lower than that dose.
Dose d must be at most 2-fold larger than the maximum dose tested.
Repeat 3, again assigning 3 subjects / cohort to this dose. Terminate study when any of the 
following stopping rules happen:
1. MTD precisely estimated: CV (MTD) calculated as the inter-quartile range over the 
median is lower than 40% 
2. Maximum possible dose is safe TN > 80%
3. Minimum dose tested (100mg) is toxic (TN < 20%)
4. Total sample size for next dose is already equal to 9.
16.4.3 Simulation scenarios
Five dose-DLT profiles were considered in order to evaluate the operational characteristics of 
that adaptive dose escalation trial. The 5 scenarios are:
Scenario A – Maximum dose safe:  This scenario represents a negative scenario under 
which all doses are safe and the true MTD is larger than the maximum possible dose 
(MTD=10,000 mg). 
Scenario B - Late MTD:  This is a scenario is which the MTD is 500 mg. The probability of 
a DLT is gradually increasing across all dose levels.
Scenario C – Early MTD:  In this scenario, the rate of DLT progression is faster over doses 


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so that the MTD appears sooner (200 mg).
Scenario D - Toxic: Under this scenario, all doses are toxic, with a DLT rate of 39% at the 
lowest dose and increasing to 100% at the highest dose level.
Scenario E - Peak:  In this scenario there is a step function in the probability of DLT’s 
occurring very early in the dose escalation process. The first doses up to 300 mg are very safe 
(p=5%), and all subsequent doses are toxic (p=80%).
Figure 16-2:Dose versus DLT rates simulation scenarios
16.4.4 Operational characteristics
We used 1000 trial simulations in order to monitor the following properties of the adaptive 
design under the 5 scenarios:

Accuracy and precision of the MTD

Probability of archiving each of the 3 stopping rules (MTD precision, last dose is safe, 
max. sample size).

Total sample size

Number and proportion of subjects being under-dosed and over-dosed (i.e., relative to 
DLT rate
dose (mg)
A: safe
B: Late MTD
C: early MTD
D: Toxic
E: Peak


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the true MTD)

Patient distribution across dose levels
16.4.5 Simulation results
Scenario A – Maximum dose safe: 
When all doses are safe, the study has 87.4% probability to report a mean MTD larger than 
1100mg. It has 75.3% probability to conclude that the maximum dose has a DLT rate of 
below 20% with 80% confidence. The expected mean standard deviation (±sd) sample size 
is 20.3±2.0 patients in 6.8±0.7 cohorts.
The predicted patient distribution by dose is reported in Figure 16-3 for all 5 scenarii. Under 
scenario A, as expected, the maximum dose escalation scheme of a 2-fold increase is 
performed for most simulations. The top dose (1100mg) is, on average (±sd), administered to 
8.1±1.7 patients.
Scenario B – Late MTD: 
When the true MTD is 500mg, the mean relative bias in the MTD estimate was 26.3%. The 
study has 81.9% chances to yield a CV (MTD) < 40%. It reaches the cap of N=9 subjects per 
dose in another 17.9%. At study end, the mean CV of the MTD is 40.1%. The expected mean 
(±sd) sample size is 18.1±4.4 patients in 6.0±1.5 cohorts. The expected mean (±sd) number of 
subjects being over-dosed (i.e., at doses larger than 500 mg) is 5.5±3.3.
As shown in Figure 16-3, dose escalation progresses up to 400 mg in a similar way as for 
scenario 1 with fewer patients being overdosed at 800 mg or 1100 mg and additional subjects 
receiving a dose of 300 mg.
Scenario C – Early MTD: 
When the true MTD is 200mg, the mean relative bias in the MTD estimate was 35.5%. The 
study has 27.8% chances to yield a CV (MTD) <40% and it reaches the cap of N=9 subjects 
per dose in another 70.9%. At study end, the mean CV of the MTD is 50.0%. The expected 
mean (±sd) sample size is 19.6±6.5 patients in 6.5±2.2 cohorts. The expected mean (±sd) 
number of subjects being over-dosed (i.e., at doses larger than 200mg) is 7.7±6.0.
As shown in Figure 16-3, under scenario C, maximum dose escalation progresses as expected 
up to 400mg. Then adaptation occurs around the MTD between doses from 100 to 300mg 
with a peak at 200mg (N=6.2±2.7). 
Scenario D – Toxic: 
When the DLT rate ranges from 39 to 100%, the study has 57.9% chances to declare that the 
DLT rate at the lowest dose (100mg) is at least 20% with 80% probability. In another 40.9%, 
the study will stop when the cap of N=9 subjects per dose is reached. The expected mean 
(±sd) sample size is 17.0±9.7 patients in 5.7±3.2 cohorts.
As shown in Figure 16-3, under scenario D, the majority of patients receive doses up to 
400mg where the predicted DLT rate is 68.0%.


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Scenario E – Peak: 
When doses up to and including 300 mg are very safe but larger doses are very toxic, the first 
doses up to 400mg are administered in most patients, as expected. Then adaptation occurs in 
the 200 -300mg interval. The expected mean (±sd) total sample size is 19.7±4.5 patients in 
6.5±1.5 cohorts. The expected mean (±sd) number of subjects being over-dosed (i.e., at doses 
larger than 300mg) is 4.1± 2.4. Most of these over-dosed patients receive a maximum dose of 
400 mg.


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Figure 16-3:Predicted mean + sd number of patients per dose by scenario


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16.5 National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 4.03 (CTCAE v4.03)
This study will utilize the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE), Version 4.03 (CTCAE v4.03: June 14, 2010), for toxicity / adverse 
event and serious adverse event reporting. 
All appropriate treatment areas should have access to a copy of the CTCAE v4.03.
A copy of CTCAE v4.03 can be downloaded from 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf
(copy link into browser)


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16.6 Tumor node metastases (TNM) classification
The International Union Against Cancer (UICC), Tumor Node Metastasis (TNM) 
Classification of Malignant Tumors (7th edition) will utilized for grading and staging of 
tumors.
All appropriate treatment areas should have access to a copy of the UICC-TNM v 7.
UICC - TNM Classification of Malignant Tumours
Author(s):
L. H. Sobin, MD, M. K. Gospodarowicz, MD, Prof. Dr. med. Ch. Wittekind
Publisher:
Wiley-Blackwell - A John Wiley & Sons, Ltd., Publication, December 2009
ISBN: 978-1-4443-3241-4
Also available as online version (TNM online)
http://www.wileyanduicc.com/
(copy link into browser)


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16.7 Eastern Cooperative Oncology Group (ECOG) performance status
These scales and criteria are used to assess how a subject's disease is progressing and how the 
disease affects the daily living abilities of the subject.
Table 16-10: ECOG Performance Status
Grade
Description
0
Fully active, able to carry on all pre-disease performance without restriction. 
(Karnofsky 90-100)
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. (Karnofsky 70-80)
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. (Karnofsky 50-60)
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. (Karnofsky 30-40)
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
(Karnofsky 10-20)
5
Dead
ECOG Performance based on Oken et al. (1982) in Am. J. Clin. Oncol. (36).


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16.8 Response evaluation criteria in solid tumors (RECIST v1.1) - amended
Response and progression will be evaluated in this trial using the new international criteria 
proposed by the RECIST committee. Changes in only the largest diameter (unidimensional 
measurement) of the tumor lesions are used in the RECIST criteria for determination of tumor 
response. Additionally, per the RECIST working group, CT scan (with contrast) is currently 
the best available and reproducible method to measure lesions selected for response 
assessment.
Measurable disease: Measurable lesions are defined as those that can 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 5 mm)

10 mm caliper measurement by clinical exam (lesions that cannot be accurately
measured with calipers should be recorded as non-measurable).

20 mm by chest x-ray.
-
Malignant lymph node: To be considered pathologically enlarged and measurable, a 
lymph node must be 15mm 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. Lymph nodes 10 mm are non-
pathological. Lymph nodes measuring 10 mm to 15 mm are considered non-target. 
Non-measurable disease: Non-measurable disease is defined as all other lesions (or sites of 
disease), including small lesions (longest diameter 10 mm or pathological lymph nodes with 
10 mm to 15 mm in short axis) as well as truly non-measurable lesions. Lesions 
considered to be truly non-measurable include: leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitic involvement of the skin or lung, inflammatory 
breast disease, abdominal masses/abdominal organomegaly identified by physical exam that is 
not measurable by reproducible imaging techniques.
Special considerations
Bone lesions: Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as CT scan or 
MRI can be considered as measurable lesions if the soft tissue component meets the definition 
of measurable disease. Blastic bone lesions are considered non-measurable disease. Note: 
Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these can be used to confirm the presence or disappearance 
of bone lesions.
Cystic lesions: Lesions that meet the criteria to be radiographically defined as simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
because they are, by definition, simple cysts. Cystic lesions thought to represent cystic 
metastases can be considered as measurable lesions, if they meet the definition of measurable 


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disease. However, if non-cystic lesions are present in the same subject, these are preferred for 
selection as target lesions.
Lesions with prior local treatment: Tumor lesions situated in a previously irradiated area, or 
in an area subjected to other loco-regional therapy, are usually not considered measurable 
unless there has been demonstrated progression in the lesion.
Measurement of lesions: All measurements should be recorded in metric notation, using 
calipers if clinically assessed. All baseline evaluations should be performed as close as 
possible to the treatment start and never more than 4 weeks before the beginning of the 
treatment.
Target lesions: When more than one measurable lesion is present at baseline, all measurable 
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 be recorded and 
measured at baseline. This means that, in instances where subjects have only one or two organ 
sites involved, a maximum of two or 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, and should be those that lend themselves to reproducible 
repeated measurements. In situations in which the largest lesion does not lend itself to 
reproducible measurement, the next largest lesion that can be measured reproducibly should 
be selected. 
Lymph nodes as target lesions: Pathological nodes, which are defined as measurable and may 
be identified as target lesions, must meet the criterion of a short axis of 15 mm by CT scan. 
Only the short axis of these nodes will contribute to the baseline sum. The short axis of the 
node is the diameter normally used by radiologists to judge if a node is involved by solid 
tumor. Nodal size is normally reported as two dimensions in the plane in which the image is 
obtained (for CT scan, this is almost always the axial plane; for MRI, the plane of acquisition 
may be axial, sagittal or coronal). The smaller of these measures is the short axis. All other 
pathological nodes (those with short axis 10 mm but 15 mm) should be considered non-
target lesions. Nodes that have a short axis 10 mm are considered non-pathological and 
should not be recorded or followed.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of 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 of diameters will be used as reference to further characterize the objective 
tumor response in the measurable dimension of the disease. 
Non-target lesions: All other lesions (or sites of disease), including pathological lymph 
nodes, should be identified as non-target lesions and should also be recorded at baseline. 
Measurements are not required but these lesions should be noted at baseline and should be 
followed as “present”, “absent”, or in rare cases, “unequivocal progression”. 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’). 


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Best response
All subjects will have their best response on trial classified as outlined below and 
summarized in Table 16-11, Table 16-12 and Table 16-13.
Evaluation of response in target lesions

Complete response (CR): disappearance of all target lesions (both target and non-
target). Any pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to
10 mm.

Partial response (PR): at least a 30% decrease in the sum of diameters of target 
lesions taking as the reference the baseline sum of diameters.

Stable disease (SD): steady state of disease. Neither sufficient shrinkage to qualify for 
PR nor sufficient increase to qualify for PD, taking as a reference, the smallest sum of 
diameters while in the trial.

Progressive disease (PD): at least a 20% increase in the sum of diameters of the 
target lesions, taking as a references the smallest sum on study (this includes the 
baseline sum if that is the smallest on trial). In addition to a relative increase of 20%, 
the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of 
new lesions will also constitute PD.
Special notes on assessment of target lesions
Lymph nodes: Lymph nodes identified as target lesions should always have the actual short 
axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study. This means that when 
lymph nodes are included as target lesions, the ‘sum’ of lesions may not be zero, even if 
complete response criteria are met, because a normal lymph node is defined as having a short 
axis of 10mm. For PR, SD and PD, the actual short axis measurement of the nodes is to be 
included in the sum of target lesions
Target lesions that become too small to measure
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (e.g., 2 mm). 
However, sometimes lesions or lymph nodes that are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’. When this occurs, it is 
important that a value be recorded on the case report form. If it is the opinion of the 
radiologist that the lesion has likely disappeared, the measurement should be recorded as 
0 mm. If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned. 
Evaluation of response in non-target lesions
Complete response: Disappearance of all non-target lesions and normalization of 


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tumor marker level. All lymph nodes must be non-pathological in size (10 mm short axis).
Non-CR / Non-PR: Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits.
Progressive disease: Unequivocal progression of existing non-target lesions. (Note: 
the appearance of one or more new lesions is also considered progression.)
Disease progression in subjects with only non-measurable disease
For subjects with only non-measurable disease, disease progression is defined as development 
of new lesions or “unequivocal progression” of existing lesions. Because worsening in non-
target disease cannot be easily quantified (by definition: if all lesions are truly non-
measurable), a useful test that can be applied when assessing subjects for unequivocal 
progression is to consider if the increase in overall disease burden, based on the change in 
non-measurable disease, is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease, i.e., an increase in tumor burden representing an additional 
73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable 
lesion). If ‘unequivocal progression’ is seen, the subject should be considered to have had 
overall PD at that point.
New lesions
The appearance of new malignant lesions denotes disease progression; however, the finding 
of a new lesion should be unequivocal, i.e., not attributable to differences in scanning 
technique, change in imaging modality or findings thought to represent something other than 
tumor (e.g., some ‘new’ bone lesions may be simply healing or flare of pre-existing lesions). 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. If a new lesion is 
equivocal (e.g., because of small size), continued therapy and follow-up evaluation will 
clarify if it represents truly new disease. If repeat scans confirm there is definitely a new 
lesion, then progression should be declared using the date of the initial scan.


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Table 16-11: Target and non-target lesion response - amended
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Response for this 
Category also Requires
CR
CR
No
CR
not earlier than 4 weeks 
confirmation
CR
Non-CR/Non-PD
No
PR
not earlier than 4 weeks 
confirmation
CR
Not evaluated
No
PR
not earlier than 4 weeks 
confirmation
PR
Non-PD or not all 
evaluated
No
PR
not earlier than 4 weeks 
confirmation
SD
Non-PD or not all 
evaluated
No
SD
Documented at least once > 6 
weeks from baseline
PD
Any
Yes or No
PD
—
Any
PD
Yes or No
PD
—
Any
Any
Yes
PD
—
Not all 
evaluated
Non-PD
No
Unevaluable
—
CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease;
Subjects with 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.
Table 16-12: Time-point response: Subjects with non-target disease only -
amended
Non-Target 
Lesions
New Lesions
Overall Response
Best Response also Requires
CR
No
CR
not earlier than 4 weeks 
confirmation
Non-CR / Non-PD
No
Non-CR  /Non-PDa
—
Unequivocal PD
Yes and No
PD
—
Any
Yes
PD
—
CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease
a:  ‘Non-CR/non-PD’ is preferred over ‘SD’ for non-target disease because SD is increasingly used 
as an endpoint for assessment of efficacy in some trials, therefore, to assign this category 
when no lesions can be measured is not advised.


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Table 16-13: Best overall response when confirmation of CR or PR is required
Overall Response First 
Time-point
Overall Response 
Subsequent Time-point
Best Overall Response
CR
CR
CR
CR
PR
SD, PD or PRa
CR
SD
SD provided minimum criteria for SD 
duration met, otherwise PD
CR
PD
SD provided minimum criteria for SD 
duration met, otherwise PD
CR
NE
SD provided minimum criteria for SD 
duration met, otherwise NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD 
duration met, otherwise PD
PR
NE
SD provided minimum criteria for SD 
duration met, otherwise NE
NE
NE
NE
CR=complete response; NE=non-evaluable; PD=progressive disease; PR=partial response; 
SD=stable disease.
a:  If a CR is truly met at the first time point, then any disease seen at a subsequent time point, 
even disease meeting PR criteria relative to baseline, makes the disease PD at that point 
(because the disease must have re-appeared after CR). Best response would depend on 
whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely present and, in fact, the subject 
had PR, or CR at the first time point. Under this circumstances, the original CR should be 
changed to PR and the best response is PR.
Response duration
Response duration will be measured from the time that measurement criteria for CR/PR 
(whichever is first recorded) are first met until the first date that recurrent disease or PD is 
objectively documented.
Stable disease duration
Stable disease duration will be measured from the time of start of therapy until the criteria for 
progression are met, taking as a reference the smallest measurements recorded since the start 
of treatment.


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Methods of measurement
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.
Clinical lesions - Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules, palpable lymph nodes). In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended. When lesions can be evaluated by both clinical exam and imaging, imaging 
evaluation should be undertaken because it is more objective and may also be reviewed at the 
end of the study.
Chest x-ray - Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, because CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung.
CT / MRI – CT scan is the best currently available and reproducible method to measure 
target lesions selected for response assessment. MRI is acceptable in certain situations (e.g., 
for body scans). CT scans should be performed with cuts of 5 mm or less in slice thickness, 
contiguously. This applies to the chest, abdomen and pelvis. Head and 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 radiation exposure at CT, MRI may be 
used instead of CT in selected instances.
Endoscopy / laparoscopy - The utilization of these techniques for objective tumor evaluation 
is not advised. However, they can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint.
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 subject 
to be considered in complete response. Because tumor markers are disease specific, 
instructions for their measurement should be incorporated.
Cytology / histology - These techniques can be used to differentiate between PR and CR in 
rare cases if required by protocol (for example, residual lesions in tumor types such as germ 
cell tumors, where known residual benign tumors can remain). When effusions are known to 
be a potential adverse effect of treatment (e.g., with certain taxane compounds or 
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


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disease) and progressive disease.
Bone lesions: Bone scan, PET scan or plain films are not considered adequate imaging 
techniques to measure bone lesions. However, these can be used to confirm the presence or 
disappearance of bone lesions.


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16.9 Estimation of renal function
Estimated glomerular filtration rate (eGFR) using Modification of Diet in Renal Disease 
(MDRD) equation
The glomerular filtration rate (GFR) will be estimated using the variables serum creatinine, 
age (years), race, and gender.
The equation does not require weight because the results are reported normalized to 1.73 m2
body surface area, which is an accepted average adult surface area.
All laboratories should be using creatinine (Cr) methods calibrated to be IDMS (isotope 
dilution mass spectrometry) traceable.
For creatinine in mg/dL; age in years
Men:
eGFR (mL/min/1.73 m2)* = 175  x  (serum creatinine)-1.154 x  age-0.203
Women: eGFR (mL/min/1.73 m2)* = 175  x  (serum creatinine)-1.154  x  age-0.203 x 0.742
For creatinine in µmol/L; age in years
Men:
eGFR (mL/min/1.73 m2)* = 175  x  (serum creatinine / 88.4)-1.154  x  age-0.203
Women: eGFR (mL/min/1.73 m2)* = 175  x  (serum creatinine / 88.4)-1.154  x  age-0.203 x 0.742
* For African Americans, multiply by 1.212 (eGFR x 1.212)
The calculator for SI units (for outside the U.S) or for conventional units (for use primarily in 
the USA) provided by the National Kidney Disease Education Program should be used by the 
investigator to calculate subject’s eGFR (see link below):
http://nkdep.nih.gov/lab-evaluation/gfr-calculators/adults-SI-units.shtml
http://nkdep.nih.gov/lab-evaluation/gfr-calculators/adults-conventional-unit.shtml


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16.10 New York Heart Association (NYHA) classification
The stages of heart failure will be assessed according to the New York Heart Association 
(NYHA) functional classification system. This system relates symptoms to everyday activities 
and the subject's quality of life.
Table 16-14: New York Heart Association (NYHA) classification
Class
Subject symptoms
Class I (mild)
No limitation of physical activity. Ordinary physical activity does not 
cause undue fatigue, palpitation, or dyspnea (shortness of breath).
Class II (mild)
Slight limitation of physical activity. Comfortable at rest, but ordinary 
physical activity results in fatigue, palpitation, or dyspnea.
Class III (moderate)
Marked limitation of physical activity. Comfortable at rest, but less than 
ordinary activity causes fatigue, palpitation, or dyspnea.
Class IV (severe)
Unable to carry out any physical activity without discomfort. Symptoms 
of cardiac insufficiency at rest. If any physical activity is undertaken, 
discomfort is increased.


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16.11 CYP 3A4 inhibitors and inducers
Table 16-15 provides an overview of strong CYP3A4 inhibitors and inducers (source: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIntera
ctionsLabeling/ucm093664.htm).
Table 16-15: An overview of strong CYP3A4 inhibitors and inducers
Strong CYP 3A4 Inhibitors
Strong CYP 3A4 Inducers
Boceprevir
Clarithromycin
Conivaptan
Grapefruit juice
Indinavir
Itraconazole
Ketoconazole
Lopinavir / Ritonavir
Mibefradil (withdrawn in US)
Nefazodone
Nelfinavir
Posaconazole
Ritonavir
Saquinavir
Telaprevir
Telithromycin
Voriconazole
Avasimibe
Carbamazepine
Phenytoin
Rifampin
St. John’s wort

SAP_001.pdf: 
 
Document Type: Statistical Analysis Plan 
Official Title: 
An open label, non-randomized, Phase I dose escalation study to 
characterize safety, tolerability, pharmacokinetics and maximum 
tolerated dose of BAY 1163877 in subjects with refractory, 
locally advanced or metastatic solid tumors 
NCT Number: 
NCT01976741 
Document Date: 
11 Dec 2019 
 


Statistical Analysis Plan (Supplement)
BAY 1163877/16443
Page: 1 of 20:
Title page
An open label, non-randomized, Phase I dose escalation study to 
characterize safety, tolerability, pharmacokinetics and maximum 
tolerated dose of BAY 1163877 in subjects with refractory, locally 
advanced or metastatic solid tumors
Phase I dose escalation pan-FGFR inhibitor (Rogaratinib)
Bayer study drug
BAY 1163877 / pan-FGFR inhibitor / rogaratinib
Study purpose:
To determine the maximum tolerated dose (MTD)
Clinical study 
phase:
I
Date:
11 DEC 2019
Study No.:
16443 
Version:
2.0
Author:
Confidential
The information provided in this document is strictly confidential and is intended solely 
for the guidance of the clinical investigation.  Reproduction or disclosure of this 
document, whether in part or in full, to parties not associated with the clinical 
investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures.
The approval of the Statistical Analysis Plan is documented in a separate Signature Document.
PPD


Statistical Analysis Plan
Protocol No.: BAY 1163877/16443
Page: 2 of 20:
Table of Contents
Title page................................................................................................................................... 1
Abbreviations............................................................................................................................ 3
1.
Introduction....................................................................................................................... 4
2.
Study Objectives................................................................................................................ 4
3.
Study Design ...................................................................................................................... 5
4.
General Statistical Considerations ................................................................................ 10
4.1
General Principles.......................................................................................................... 10
4.2
Handling of Dropouts .................................................................................................... 11
4.3
Handling of Missing Data.............................................................................................. 11
4.4
Interim Analyses and Data Monitoring ......................................................................... 11
4.5
Data Rules...................................................................................................................... 12
4.5.1 Baseline.......................................................................................................................... 12
4.5.2 Unscheduled Measurements .......................................................................................... 12
4.6
Blind Review/Validity Review...................................................................................... 12
5.
Analysis Sets .................................................................................................................... 12
5.1
Assignment of analysis sets ........................................................................................... 12
6.
Statistical Methodology .................................................................................................. 13
6.1
Population characteristics .............................................................................................. 13
6.1.1 Disposition..................................................................................................................... 13
6.1.2 Protocol deviations ........................................................................................................ 13
6.1.3 Demographics and other baseline characteristics .......................................................... 13
6.1.4 Prior and Concurrent Medication/Therapy.................................................................... 13
6.1.5 Medical History ............................................................................................................. 14
6.2
Efficacy.......................................................................................................................... 14
6.3
Pharmacokinetics/pharmacodynamics........................................................................... 15
6.3.1 Pharmacokinetics........................................................................................................... 15
6.3.2 Pharmacodynamic data.................................................................................................. 16
6.4
Safety ............................................................................................................................. 16
6.4.1 Study drug exposure ...................................................................................................... 16
6.4.2 Maximum tolerated dose ............................................................................................... 16
6.4.3 Adverse Events .............................................................................................................. 16
6.4.4 Safety Parameters .......................................................................................................... 17
6.5
Interim dose response modeling .................................................................................... 18
7.
Document history and changes in the planned statistical analysis............................. 19
8.
References ........................................................................................................................ 19


Statistical Analysis Plan
Protocol No.: BAY 1163877/16443
Page: 3 of 20:
Abbreviations
AE
Adverse event
ANOVA
Analysis of variance
AUC
Area under the curve
AUC(0-tlast)
AUC from time 0 to the last data point > LLOQ after a single dose 
AUC(0-tlast)/D
AUC(0-tlast) divided by dose
%AUC(tlast - ∞)
Percentage of AUC from the last data point > LLOQ to infinity
AUC/D
AUC divided by dose
BC
Bladder cancer
b.i.d.
Twice daily
BMI
Body mass index
BP
Blood pressure
CI
Confidence interval
Cmax
Maximum total drug concentration in plasma after a single dose
Cmax/D
Maximum drug concentration in plasma after single dose
Administration divided by dose
CR
Complete response
CRF
Case Report Form
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events Version 4.03
CV
Coefficient of variation
d
Dose level
DOR
Duration of response
DOSD
Duration of stable disease
DOT
Duration of treatment
DLT
Dose-limiting toxicity
DSMT
Drug safety monitoring team
e.g.
Exempli gratia, for example
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EOT
End of treatment
FGF
Fibroblast growth factors
FGFR
Fibroblast growth factor receptor
FU
Follow-up
GFR
Glomerular Filtration Rate
HR
Heart rate
IB
Investigator’s Brochure
i.e.
id est, that is
KM
Kaplan-Meier
LAC
Lung adenocarcinoma
LLOQ
Lower limit of quantification
log
Logarithm
LS
Least squares
MAD
Median Absolute Difference
MCMC
Markov-Chain-Monte-Carlo
MDRD
Modified Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
MR 
Magnetic resonance 
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
NCI
National Cancer Institute
NYHA
New York Heart Association (this abbreviation is usually used with roman digits to 
characterize the stage of heart failure, e.g. NYHA I)
p
Probability of observing a subject with DLTs during Cycle 1
PD
Pharmacodynamic(s)
PD
Progressive disease


Statistical Analysis Plan
Protocol No.: BAY 1163877/16443
Page: 4 of 20:
p-ERK1/2
Phospho-extracellular signal-regulated kinase 1/2 
PFS
Progression-free survival
PK
Pharmacokinetic(s)
PR
Partial response
Qd
Probability of dose being the MTD
RECIST
Response Evaluation Criteria in Solid Tumors
RMAD
Relative Median Absolute Difference
ROW
Rest of the world
RP2D
Recommended Phase II dose
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SAS
Statistical Analysis System
SCCHN
Squamous cell carcinoma of the head and neck
SD
Stable disease
SD
Standard deviation
sqNSCLC
Squamous non-small cell lung cancer
Td
(Tolerable) Probability that the DLT rate is 0.20, Pr(p <0.20|d), for a dose d
TEADR
Drug-related adverse event
TEAE
Treatment-emergent adverse event
tlast
Time to last observed concentration
tmax
Time to maximum observed concentration
TTP
Time to progression
vs
Versus, as opposed to
WHO DD
World Health Organization Drug Dictionary
1.
Introduction
Fibroblast growth factors (FGF) and their corresponding receptor family (FGFR) drive crucial 
oncogenic signaling pathways including cell proliferation, survival and migration. FGFRs are 
commonly altered in various human tumor diseases, including FGFR1 amplification in 
squamous non-small cell lung cancer (sqNSCLC) or activating mutations of FGFR3 in 
bladder cancers. These changes contribute to tumor cell growth, sustained angiogenesis, 
invasion and metastasis and resistance against other therapies. 
Rogaratinib (BAY 1163877) is an oral inhibitor of FGFR1, 2 and 3 and showed strong anti-
tumor efficacy in pre-clinical models as a single agent as well as in combination with 
cytotoxic agents in FGFR pathway addicted tumor models.
The targeted application form is oral and preclinical data suggest low clearance and low 
volume of distribution resulting in a daily dose of 300 to 800 mg.
Further details can be found in the investigator's brochure (IB) (1), which contains 
comprehensive information on the study drug. The IB is available in the Trial Master File.
Additional information elaborating on the rationale of the study and the benefit-risk 
assessment can be found in the protocol.
This Statistical Analysis Plan (SAP) is based on the Clinical Study Protocol version 7.0 
(including Amendment 7.0) (2).
2.
Study Objectives
The primary objectives of this study are:

To determine the safety and maximum tolerated dose (MTD) of BAY 1163877 in 
subjects with advanced solid organ malignancies


Statistical Analysis Plan
Protocol No.: BAY 1163877/16443
Page: 5 of 20:

To characterize the pharmacokinetics (PK) of BAY 1163877
The secondary objectives of this study are:

To evaluate biomarker status, pharmacodynamic (PD) parameters, and tumor 
response.

To assess the relative bioavailability of the tablet formulation in comparison to the 
solution formulation of BAY 1163877.
The exploratory objective of this study is:

To evaluate selected immune parameters.
3.
Study Design
This is a Phase I, first-in-human, open-label, non-randomized, multi-center, 3-part, dose 
escalation study of BAY 1163877 in sequential cohorts of subjects with refractory, locally 
advanced or metastatic solid tumors. The study will be conducted at multiple centers 
worldwide.
Study Part 1 will identify the MTD in subjects with any solid tumors (all comer) using an 
adaptive dose escalation design and expansion of cohort at MTD.
Study Part 2 will explore further the safety and PD of BAY 1163877 at the MTD identified in 
Part 1 in subjects with sqNSCLC, LAC, BC, and SCCHN to seek any evidence of preliminary 
clinical responses. Study Part 2 may start as soon as the MTD has been established in Part 1.
Study Part 3 will expand the safety database for patients on treatment with BAY1163877 at 
the MTD identified in Part 1 with sqNSCLC, LAC, and BC. In parallel, in Part 3 additional 
efficacy data will be collected and changes of selected immune parameters will be assessed.
The complete duration of the study (Part 1, Part 2, and Part 3) depends on the number of dose 
escalation steps in Part 1 and will be approximately 7 years.
Planned sample size:
Subjects will be enrolled in the pre-treatment phase of the study to recruit enough subjects 
with present high FGFR expression levels for the following study parts.
Targeted / planned enrollment:

Study Part 1 / dose escalation (all comer): The total number of subjects will depend on 
the number of cohorts necessary to identify the MTD. Relative bioavailability of the 
tablet formulation in comparison to the solution formulation will be performed in all 
subjects enrolled in one of the dose escalation cohorts; pharmacokinetic data are 
needed in a minimum of 3 subjects for relative bioavailability assessment.

Study Part 1 / MTD expansion (all comer): Additional subjects will be enrolled to 
have 20 evaluable “all comer” subjects treated at MTD.

Study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN): additional 
subjects will be enrolled to have 20 evaluable subjects with sqNSCLC or LAC and at 
least 30, up to maximum of  50 evaluable subjects with BC  and at least 8 subjects 
with SCCHN treated at MTD.


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
Study Part 3 / MTD expansion “Safety cohort” (sqNSCLC + LAC + BC ): additional 
subjects will be enrolled to have approximately 20 subjects with sqNSCLC or LAC and 
approximately 20, subjects with BC  treated at MTD.
PK assessments will be performed in all subjects participating in study Part 1 / dose escalation 
and MTD expansion (all comer) and study Part 3/ MTD expansion “Safety cohort”. 
Additionally, PK assessments are planned in at least 12 subjects participating in study Part 2 / 
MTD expansion (sqNSCLC + LAC + BC + SCCHN) such that valid PK data are available in 
8 subjects and in approximately 8 subjects of the MTD expansion cohorts with impaired renal 
function at baseline. Food effect PK assessment is planned in approximately 8 subjects 
enrolled in the MTD expansion cohorts (study Part 1 and Part 2). Subjects participating in 
“food effect assessment” in study Part 2 may be included in the total sample size of 12 if all 
protocol requirements are met.
All subjects participating in either of the 3 MTD expansion cohorts (Part 1, Part 2, and Part 3 
despite subjects with impaired renal function) will have 2 PK samples drawn for the purpose 
of exposure-response modelling on Day 1 of Cycles 2, 3, 4, and 5 (1 blood sample just before 
the morning dose of BAY 1163877 and 1 blood sample between 0.5 and 1.5 hours post-dose). 
Subjects in Part 3 will provide one PK sample within 1 hour of biopsy collection in Cycle 2. 
The dose needs to be taken under supervision and the time recorded.
Study periods:
Figure 3–1 Schematic presentation of the treatment design
In total, the “on study” period for all subjects comprises 3 phases (see Figure 3–1):

Pre-treatment

Testing for FGFR and FGFR mutation (only for subjects recruited for Part 
1, Part 2 or Part 3 MTD expansion cohorts)


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
Screening 

Treatment

Study Part 1 / dose escalation + MTD expansion (all comer):
Individual number of 21-day Cycles with BAY 1163877 monotherapy 
(tablet or solution) until disease progression or as along as clinical benefit 
is assumed by the investigator or until unacceptable toxicity occurs.

Study Part 1 / “tablet bridging cohort” (all comer):
In one of the dose escalation cohorts, administration of a single dose of 
BAY 1163877 using the tablet formulation on Cycle 1, Day -3 followed by 
solution formulation starting Cycle 1 Day 1 as described above.

Study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN):
Individual number of 21-day Cycles with continuous BAY 1163877 
monotherapy (tablet or solution) until disease progression or as along as 
clinical benefit is assumed by the investigator or until unacceptable toxicity 
occurs.

Study Part 1 (MTD expansion cohort) and Study Part 2 (sqNSCLC + LAC 
+ BC + SCCHN) / “Food Effect Assessment”:
Approximately 8 subjects will receive single doses of BAY 1163877 on 
Cycle 1, Day -3 (after consumption of a high-fat, high-calorie breakfast) 
and on Cycle 1, Day 1 (after an overnight fast of at least 8 hours) followed 
by treatment according to the schedule described above starting on Cycle 1, 
Day 3.

Study Part 3 / MTD expansion “Safety cohort” (sqNSCLC + LAC + BC):
Individual number of 21-day Cycles with continuous BAY 1163877 
monotherapy (tablet) until disease progression or as long as clinical benefit 
is assumed by the investigator or until unacceptable toxicity occurs.
Note: Treatment with BAY 1163877 at MTD in Part 1 (expansion cohort “all comer”), Part 2 
(expansion cohort sqNSCLC + LAC + BC + SCCHN), and Part 3 (expansion cohort
“Safety cohort”, sqNSCLC + LAC + BC) can run in parallel.

Follow-up (FU)

End of Treatment (EOT) visit 0-14 days after last dose of BAY 1163877

FU visit at 30-35 days after dose of BAY 1163877
The first screening visit is scheduled within 7 days / 28 days before administration of the first 
dose of BAY 1163877. The informed consent form will be signed by the subject before or at 
the first screening visit. The screening period ends just before start of treatment.
The treatment period starts on the day of the first administration of study treatment on Cycle 
1, Day 1 or on Cycle 1, Day -3 (“tablet bridging cohort” and “food effect assessment”) and 
ends with the last day when the study medication is administered in Cycle X. The length of 
treatment period may vary from subject to subject dependent on the number of individual 
treatment cycles. A Cycle for this study is defined as 21 days. There will be no break between 
cycles.


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When a subject starts new anti-cancer therapy, he / she is no longer considered “on study”.
An EOT visit will be performed for all subjects within 0-14 days after administration of the 
last dose of BAY 1163877. The FU visit for subjects who either discontinue prematurely or 
finish dosing with BAY 1163877 will be performed 30 - 35 days after the last study drug 
treatment. There will be no long-term (survival) FU period.
Treatment: Subjects with PK assessment (all subjects of study Part 1 and 3 and at least 12 
subjects of study Part 2 and approximately 8 subjects of the MTD expansion cohorts with 
impaired renal function at baseline) will receive BAY 1163877 (tablet or solution) on a 
continuous schedule starting with single-dose administration on Cycle 1, Day 1, followed by a 
“drugfree day” (to enable single dose PK assessments except for subjects in Part 3 who will 
receive BAY 1163877 twice daily continuously with no “drug free day”). Treatment with 
BAY 1163877 will resume on Day 3 of Cycle 1 if no protocol-defined dose-limiting toxicities 
(DLTs) are reported. Starting on Cycle 1, Day 3, the study drug will be self-administered 
twice daily for the remaining 19 days of Cycle 1. For subsequent cycles, study drug will be 
administered twice daily for 21 days until disease progression or as long as clinical benefit is 
assumed by the investigator or until unacceptable toxicity occurs.
In one of the dose escalation cohorts in study Part 1 (“tablet bridging cohort”), relative 
bioavailability of the tablet formulation will be assessed by administration of a single dose of 
the tablet formulation on Cycle 1, Day -3. Starting with Cycle 1, Day 1, subjects enrolled in 
the “tablet bridging cohort” will continue with the solution formulation as described above. 
Depending on the results from the relative bioavailability assessment, subjects who initially 
start with solution formulation may be switched to tablet formulation in later cycles.
Approximately 8 subjects enrolled in the MTD expansion cohorts (study Part 1 and Part 2) 
will receive single doses of BAY 1163877 on Cycle 1, Day -3, after consumption of a high-
fat, high-calorie breakfast and on Cycle 1, Day 1, after an overnight fast of at least 8 hours 
followed by treatment according to the schedule described above starting on Cycle 1, Day 3. 
Subjects without PK assessment in study Part 2 will receive BAY 1163877 (tablet or solution) 
twice daily from Cycle 1, Day 1 ongoing.
At home, subjects will document the intake of study drug in a diary.
Subjects will continue receiving treatment until tumor progression, unacceptable toxicity, 
consent withdrawal, or subject withdrawal from the study at the discretion of the Investigator 
or his/her designated associate(s). As long as, in the judgment of the subject and the 
investigator, some benefit with evidence of tumor reduction or stable disease is being derived, 
dosing with BAY 1163877 may continue.
Determination of the MTD
An adaptive dose escalation design will be used to determine the MTD in study Part 1 / dose 
escalation (all comer). The MTD is defined as the highest dose that can be given such that not 
more than 20% of subjects experience a DLT during Cycle 1.
Without the occurrence of toxicities, dose escalation could be stopped and RP2D may be 
determined based on PK and/or PD results. The decision to continue treatment for an 
individual subjects will be made by the investigator according to the criteria specified in the 
protocol.
Each cohort will be evaluated after all subjects have completed the first 21 days of treatment 
(which will subsequently referred to as “Cycle 1”) or early discontinued.


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Safety monitoring will occur by telephone conferences with participation of the investigators 
and the sponsor on a regular basis.
At the time of dose escalation the available clinical safety information is discussed in a 
telephone conference by the involved investigators and representatives from the Sponsor 
including the Study Medical Expert as well as representatives of other clinical and if required 
further contributing functions (drug safety monitoring team – DSMT). During this telephone 
conference it will be judged if dose escalation can proceed as planned according to the 
procedure outlined below. Dose escalation for subsequent cohorts will only be considered 
after full evaluation of at least Cycle 1 safety data from the previous cohort.
The National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
Version 4.03 (CTCAE v4.03) will be used to grade toxicities / adverse events.
The dose escalation will be performed as follows:

Initially 3 subjects per dose level will be enrolled. In case 2 or more sites are 
conducting the dose escalation part, the initial enrolment of 4 subjects per dose level is 
optional.

The starting dose of BAY 1163877 is 50 mg given as a single dose on Cycle 1, Day 1, 
and twice daily (b.i.d.) from Cycle 1, Day 3 (100 mg / day).

The maximum dose escalation will be 2-fold.

Possible daily doses of BAY 1163877 starting from 100 mg in increments of 100 mg.

The possible maximum dose of BAY 1163877 is considered to be 550 mg b.i.d. 
(1100 mg / day). Higher doses might be explored after discussions between sponsor 
and investigators.

If at least 1 subject out of 3 or 1 out of 4 in a cohort has DLTs or if at least 2 subjects 
report drug-related AEs (CTCAE v4.03) of Grade ≥2, any further dose escalation, 
de-escalation or cohort expansion will be decided in consultation between all 
investigator(s), and the sponsor (within the DSMT) after consideration of all available 
safety data of the previous cohorts. Any subsequent dose will be selected in order to 
determine the MTD. 
Model-based dose-response analysis of the DLT rates will be performed during these 
interim reviews in order to guide the dose decision. The model-based dose selection 
procedure is considering data at all dose levels (not just at the last cohort). The dose 
predicted to yield 20% DLT rates will be reported from that model as a best candidate 
for the next cohort.
The final decision about the next dose will be made by the sponsor in consultation 
with all investigators (DSMT).
If the selected dose is larger than the last dose tested, then escalation will be pursued. 
If it is lower, a de-escalation step will occur.
Cohort expansion will occur when a previously tested dose is selected again for the 
next cohort of 3 subjects.
Expansions at any given dose up to a total of 9 subjects are allowed. In principle, the 
selection of a next dose level where the predicted DLT rate is close to 20% should 
insure that the next dose tested will remain safe.


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Nevertheless, the following constraint will be added in order to protect subject safety 
during the adaptive dose selection decisions:

If 2 out of 3 (or 2 out of 4), at least 4 out of 6 (or at least 5 out of 9) 
subjects experience DLTs at a given dose level, only lower doses will be 
given in all subsequent cohorts because the probability that the dose is 
above the MTD is very large (above 95.4%).

The dose-escalation procedure will be stopped as soon as:

the MTD has been defined with good precision (i.e. the coefficient of 
variation for the MTD is lower than or close to 40%) 
or

at any time when the selected dose level for the next cohort has already 
been given in 9 subjects.
If the dose escalation stops, the sample size for the MTD cohort will be expanded up to a total 
of 20 evaluable subjects (study Part 1 / MTD expansion cohort (all comer)).
No intra-subject dose escalation is permitted. Dose interruptions and / or dose reductions may 
be required based on individual safety and tolerability.
Variables are specified in the Clinical Study Protocol (2).
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), R release 2.4.1 or higher and BRugs release 0.3-
3 or higher. All variables will be analyzed by descriptive statistical methods. The number of 
data available, mean, standard deviation, minimum, median, and maximum will be calculated 
for metric data. Frequency tables will be generated for categorical data.
Data displays will follow the standard table catalogs for oncology standards, global standards, 
and clinical pharmacology standards, respectively.
The pharmacokinetic parameters will be evaluated statistically in accordance with pertinent 
company guidelines.
The following treatment groups will be analyzed:

Total Dose Escalation – It contains all cohorts from the escalation phase:
o
100 mg BAY 1163877 (50 mg solution BID)
o
200 mg BAY 1163877 (100 mg solution BID)
o
400 mg BAY 1163877 (200 mg tablet BID)
o
800 mg BAY 1163877 (400 mg tablet BID)
o
1200 mg BAY 1163877 (600 mg tablet BID)
o
1600 mg BAY 1163877 (800 mg tablet BID)

Expansion All Comers – Expansion phase, 1600 mg BAY 1163877 (800 mg tablet 
BID), cancer type does not fit the categories below

Expansion Bladder – Expansion phase, 1600 mg BAY 1163877 (800 mg tablet BID), 
cancer type: bladder cancer


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
Expansion Head & Neck – Expansion phase, 1600 mg BAY 1163877 (800 mg tablet 
BID), cancer type: squamous carcinoma cell head and neck

Expansion NSCLC – Expansion Phase, 1600 mg BAY 1163877 (800 mg tablet BID), 
cancer type: lung adenocarcinoma / squamous cell carcinoma
The categories of region used for subgroup analysis will be derived for each subject by using 
the variable country (location of the respective site).
4.2
Handling of Dropouts
A subject who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the subject has already been administered at least 1 dose of the study drug (BAY 
1163877).
A subject who, for any reason (e.g. failure to satisfy the selection criteria), terminates the 
study before the time point used for the definition of “dropout” (see above) is regarded a 
“screening failure”.
Subjects who discontinue due to a DLT will NOT be replaced.
Subjects who discontinue during the first cycle of therapy (Cycle 1) due to any reason other 
than a DLT and / or related toxicity, and subjects who took less than 80% of the required 
study drug (BAY 1163877) in Cycle 1 will be replaced to ensure 3 evaluable subjects per 
cohort for the determination of MTD and PK of BAY 1163877. Subjects who discontinue 
after the first cycle (Cycle 1) will not be replaced.
Subjects enrolled in Study Part 1 / MTD expansion (all comer) with insufficient paired biopsy 
samples will be replaced to ensure at least 10 subjects with paired biopsy samples for p-
ERK1/2 analysis.
4.3
Handling of Missing Data
All missing or partial data will be presented in the subject data listing as they are recorded on 
the Case Report Form (CRF). 
Missing data will not be replaced. Possible impact of missing values on the analysis will be 
discussed in the clinical study report.
4.4
Interim Analyses and Data Monitoring
Safety data will be reviewed on an ongoing basis during study Part 1 / dose escalation (all 
comer). Bayesian dose-response and / or PK / PD modeling of DLTs rates and CTCAE v4.03 
gradings may be performed after selected cohorts 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 cohort expansion during the adaptive dose escalation part. This group will 
also determine when to implement predefined stopping rules.
No interim analysis is planned during dose expansion at MTD in study Part 1 (MTD 
expansion cohort “all comer”), study Part 2 (MTD expansion cohort “sqNSCLC + LAC+ BC 
+ SCCHN”) or study Part 3 (MTD expansion cohort “Safety cohort”).


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4.5
Data Rules
4.5.1
Baseline
Unless otherwise stated, baseline is defined as the last pre-dose assessment before first study 
drug administration or as the last pre-dose assessment before the time period being analyzed.
4.5.2
Unscheduled 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 
timepoint after study drug administration are available, the planned measurement will be used 
for the calculation of descriptive statistics.
Further applicable data rules are described in section 6 “Statistical Methodology”.
4.6
Blind Review/Validity Review
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).
Safety analysis set
All subjects who received at least 1 dose of BAY 1163877 will be included in the safety 
evaluation.
MTD analysis set
All subjects who completed Cycle 1 or discontinued during Cycle 1 due to an adverse event 
or DLT in the dose escalation part will be included in the MTD evaluation.
Efficacy analysis set 
All subjects who received at least 1 dose of BAY 1163877 and who have post-baseline 
efficacy data available will be included in the efficacy evaluations.
Pharmacodynamic analysis set 
All subjects with evaluable PD data and who complete the study without major changes 
versus protocol will be included in the evaluation of PD.
Pharmacokinetic analysis set 
All subjects with valid pharmacokinetic data will be included in the evaluation of 
pharmacokinetic concentrations and parameters.


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6.
Statistical Methodology
The treatment groups to be analyzed are defined in section 4.1. 
6.1
Population characteristics
Analyses for population characteristics will be performed for the safety population on the 
treatment groups if not stated otherwise. If the pharmacokinetic population, pharmacodynmic 
population, MTD population or efficacy population differ from the safety population, 
summary statistics and frequency tables for the respective population will be provided as well.
The results will be displayed by region (Asia, ROW, and total), if reasonable. 
6.1.1
Disposition
Disposition at the end of screening will be summarized for subjects who signed the informed 
consent for FGFR testing and for all subjects who signed the main informed consent, 
respectively. All enrolled subjects population comprises subjects who signed any informed 
consent. Disposition at the end of Treatment and for the Safety follow-up will be summarized 
by treatment groups for all subjects assigned to treatment.
6.1.2
Protocol deviations
Frequency tables of protocol deviations by category and deviation coded term will be 
summarized by treatment group. 
6.1.3
Demographics and other baseline characteristics
Demographics and general baseline characteristics will be summarized by treatment group. 
Quantitative data will be summarized by arithmetic mean, SD, median, minimum and 
maximum. Frequency tables will be provided for qualitative data. Variables include sex, race, 
ethnicity, age (as reported on the eCRF), weight, height, body mass index (BMI), and NYHA 
functional class. 
Baseline cancer characteristics will be summarized by treatment group. Variables include for 
example baseline ECOG Performance Status, number of target lesions, number of non-target 
lesions, cancer type, histology, status of primary tumor, stage at initial diagnosis, grading at 
initial diagnosis, clinical status at study entry, stage at study entry, time since initial diagnosis. 
Please note that the list of the above mentioned parameters is not extensive.
In addition, demographics and baseline cancer characteristics will be summarized for all 
subjects who signed the informed consent for FGFR testing.
6.1.4
Prior and Concurrent Medication/Therapy
Prior anti-cancer therapy and surgical therapeutic procedures will be summarized by treatment 
group. The counts and percentages of patients 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 patients 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. Prior and concomitant medications 
will be coded to generic terms using the World Health Organization Drug Dictionary (WHO 


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DD) Version 2017SEP or later and summarized by treatment group. The version used in 
analyses will be presented in the clinical study report. 
6.1.5
Medical History
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 20.1 or later. The version used in analyses will be presented in the 
clinical study report. Medical history data will be summarized by system organ class, high 
level term, and preferred term by treatment group.
6.2
Efficacy
Efficacy analyses will be performed on the efficacy analysis set. 
Tumor response
Efficacy data, such as best tumor response, will be summarized using descriptive statistics 
and will be graphically displayed if appropriate.  The correlation between PD parameters and 
selected safety, efficacy, or PK parameters may be graphically displayed.  Further statistical 
analyses may be conducted.
The efficacy analysis will include descriptive analyses on response rate, progression-free
survival (PFS), time to progression (TTP), duration of response (DOR), and duration of 
treatment (DOT). 
Response as defined by RECIST v.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. 
PFS is defined as the time (days) from the date of the first dose of study drug to the date of 
the first observed disease progression (radiological or clinical) or death due to any cause, if 
death occurs before progression is documented. PFS for subjects without tumor progression at 
the time of analysis will be censored at their last date of tumor evaluation.
TTP is defined as the time from start of study treatment until first observed disease 
progression (radiological or clinical). In comparison to PFS, TTP does not consider death as 
an event.
DOR (for partial and complete response (PR/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). 
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 and TTP per treatment. In addition KM survival curves will be presented for each 
treatment group.
Best overall tumor response according to RECIST criteria will be summarized by treatment 
group and region (Asia, ROW, and total) 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.
Subgroup analysis will be performed by prior immunotherapy information (prior 
immunotherapy vs. no prior immunotherapy) .


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6.3
Pharmacokinetics/pharmacodynamics
6.3.1
Pharmacokinetics 
Analyses will be performed on the Pharmacokinetic analysis set. A pooled treatment group 
(all 800mg BID patients, regardless of study part or tumor type) will be included for PK 
analyses.
The concentration-times courses of all analytes will be tabulated for each cohort by treatment
group. 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), 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 by cohort using both linear and semilogarithmic scale. 
The amount and percent of drug excreted into urine will be graphically illustrated for the 
sampling interval as well as for the whole sampling period (bar-charts for the individual data 
and the arithmetic mean including standard deviation).
Pharmacokinetic characteristics (tmax, tlast, 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.
PK Dose proportionality
To investigate dose proportionality, an explorative ANOVA, including the factor cohort, will 
be performed on the log-transformed values of Cmax/D, AUC(0-tlast)/D, and AUC/D calculated 
from single (where applicable) and multiple dose PK profiles.
Bridging: tablet vs solution relative bioavailability
PK parameters of different dose levels will be analyzed together for the assessment of relative 
bioavailability.
In order to evaluate the relative bioavailability of the tablet formulation, tablet Cmax/D, 
AUC(0-tlast)/D, and AUC/D on Cycle 1, Day -3 will be compared to solution Cmax/D, AUC(0-
tlast)/D, AUC/D on Cycle 1, Day 1 for all analytes. If needed, additional PK parameters may 
be used for relative bioavailability assessment. The logarithms of these PK parameters will be 
analyzed using analysis of variance (ANOVA) including subject and formulation effects. 
Based on these analyses, point estimates (LS-means) and exploratory 90% confidence 
intervals for the ratios (tablet/solution) of Cmax/D, AUC(0- tlast)/D, and AUC/D will be 
calculated by re-transformation of the logarithmic data using the intra-individual standard 
deviation of the ANOVA.
Subjects to be included in the relative bioavailability evaluation (“tablet bridging cohort”) 
should have evaluable pharmacokinetic data on both Cycle 1, Day -3 and Cycle 1, Day 1.
Food effect


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In order to evaluate the effect of food on BAY 1163877, Cmax and AUC(0-tlast) on Cycle 1, 
Day -3 and Cmax and AUC(0-tlast) on Cycle 1, Day 1 will be compared. The logarithms of Cmax
and AUC(0-tlast) will be analyzed using ANOVA including subject and food effect. 
Based on these analyses, point estimates (LS-means) and exploratory 90% confidence 
intervals for the ratios (high-fat, high-calorie meal / fasting) of Cmax and AUC(0- tlast) will be 
calculated by re-transformation of the logarithmic data using the intra-individual standard 
deviation of the ANOVA.
The PK paramteres Cmax/D, AUC(0-tlast)/D, AUC/D, Cmax. and AUC(0-tlast) will be graphically 
illustrated using stickplots. Scatterplots of the PK parameters Cmax/D, AUC(0-tlast)/D, AUC/D 
will be created.
6.3.2
Pharmacodynamic data
Cardiovascular parameters will be described by the following summary statistics: arithmetic 
mean, standard deviation, median, minimum and maximum. These summary statistics will be 
presented by cohort for the original data as well as for the difference to baseline (defined as 
the pre-dose assessment of the day being analyzed), if applicable.
Graphical displays of individual data as well as mean values with standard deviation may be 
included for absolute values as well as change from baseline.
6.4
Safety
The analyses will be performed on the safety analysis set and results will be displayed by 
region (Asia, ROW, and total), if reasonable.
6.4.1
Study drug exposure
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 with reason will be summarized.
6.4.2
Maximum tolerated dose
Individual listings of DLTs with CTCAE v4.03 code and grade will be presented.
The incidence of subjects with DLTs during Cycle 1 will be summarized by treatment and, if
possible, modeled as a function of BAY 1163877 dose using Bayesian logistic regression.  
The moderately-informative independent priors used during the interim dose response 
analysis (see Section 6.5 for details) as well as non-informative priors will be used for this 
analysis to assess sensitivity of the estimates.  Parameter estimates and model predictions will 
be reported with 90% credibility sets.  The MTD will be computed as a derived function of 
model parameters as:
MTD = (log(0.2/0.8)-intercept)/slope.
The posterior distribution of the MTD will be summarized in tabular and graphical formats.
6.4.3
Adverse Events
Adverse events will be analyzed using the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Event (CTCAE) version 4.03. In addition a separate set of 
AE tables will be generated using MedDRA terms.


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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 treatment group CTCAE body system code and worst NCI-CTCAE 
grade. TEAEs, SAEs, drug-related TEAEs, and drug-related SAEs for events of Grade 3/4/5 
will be summarized similarly.
AEs are considered treatment emergent if they have started or worsened after the first study 
drug administration up to 30 days after the end of treatment with study drug.
Frequency tables will also be provided for the changes of CTCAE grade from pre-treatment 
and changes of worst CTCAE grade under treatment.
In addition, TEAEs, SAEs, drug-related TEAEs, and drug-related SAEs will be summarized 
by MedDRA (Version 20.1 or later) system organ class, preferred term and worst NCI-
CTCAE grade. The same will be also summarized similarly for events of Grade 3/4/5. 
Patient listings of all AEs, SAEs, AEs leading to dose reduction, AEs leading to dose 
interruption, AEs leading to discontinuation, dose limiting toxicity AEs, and deaths will be 
presented.
6.4.4
Safety Parameters
Quantitative data (vital signs, ECG, ECOG performance status) will be described by the 
following summary statistics:  arithmetic mean, standard deviation, median, minimum, and 
maximum.  These summary statistics will be presented by treatment group for the original 
data as well as for the difference to baseline. Frequency tables will be provided for qualitative 
data. Graphical displays of mean values with standard deviation will be provided.
The average of triplicate quantitative ECG parameters at all ECG time points will be used for 
all analyses.
Laboratory data outside the reference range will be listed and flagged with ‘L’ for low and 
‘H’ for high.  The incidence of laboratory data outside the reference range (low, high) will be 
summarized by treatment groupin frequency tables.
Calcium, phosphate and the product of calcium and phosphate will be described by the 
following summary statistics: arithmetic mean, standard deviation, median, minimum and 
maximum. These summary statistics will be presented by cohort for the original data as well 
as for the difference to baseline (defined as the pre-dose assessment of the day being 
analyzed).
Graphical displays of mean values with standard deviation will be included for absolute 
values as well as change from baseline.The number of subjects with at least one phosphate 
level > 5.5 mg/dL, with at least one phosphate level > 7 mg/dL and with at least one 
phosphate level > 9 mg/dL will be summarized using frequency tables.
The number of subjects with at least one value > 70 mg2/dL2 of the product phosphate and 
calcium will be summarized using frequency tables.
The incidence of laboratory toxicities will also be summarized by worst CTCAE v4.03 grade 
and by treatment group.  Frequency tables will also be provided for the changes of worst 
CTCAE v4.03 grade after start of treatment versus baseline.


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6.5
Interim dose response modeling
MTD determination takes place at the end of the dose escalation phase and is based on the 
DLT rate during Cycle 1. 
The following Bayesian dose-response analysis of the DLT rates will be performed during the 
interim reviews in order to guide the dose escalation decision.
Bayesian logistic regression
The analysis is based on a method reported by Tibaldi et al (3).
A range of doses will be tested, including possibly 100, 200, 300, 400, 500, 600, 700, 800, 
900, 1000 and 1100 mg.  Additional or alternative dose levels may be chosen.  These possible 
dose levels are labeled as d = 1, …, N, where N is the maximum number of dose levels for the 
study.  The probability, p, of observing a subject with DLTs during Cycle 1 is modeled as a 
function of dose:
d
p
p
*
slope
intercept
)
1
log(



In this trial, the MTD is defined as the predicted dose where the DLT probability is 20%:
MTD = (log(0.2/0.8)-intercept)/slope.
A Bayesian analysis will be performed, considering the following independent priors for the 
model parameters:

intercept has a normal distribution with mean equal to -3 and variance equal to 1.

slope has a positive normal distribution with mean equal to 0.0015 and variance equal 
to 0.003.
These priors were specified in the protocol. They are moderately-informative and were 
considered plausible in the context of the current dose escalation scheme and indication. 
The posterior distribution of model parameters and the MTD will be estimated with the R 
package BRugs using MCMC techniques and considering at least 10000 simulations after 
convergence of the Markov chain. 
The precision of the MTD will be monitored by calculating the relative median absolute 
difference (RMAD% = 100*mad/median). This robust estimator is a suitable statistic to 
quantify variability in asymmetric distributions. A low RMAD(MTD)% value indicates good 
precision.
In addition, the following posterior probabilities will be calculated for each dose level in the 
candidate set:

Td = (tolerable) Probability that the DLT rate is below 0.20, Pr(p <0.20| d), for a dose 
d.

Qd = Probability of dose d being the MTD. This is the probability that d is the 
maximum dose from the candidate set where p<20%. 
Guidance for selection of next dose
The posterior density of the MTD and the Qd probabilities in the candidate set are the two 
main instruments that will be reported to guide dose selection. They indicate on a continuous 


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Protocol No.: BAY 1163877/16443
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and  discrete scale respectively the desirability for a dose to become the next choice. The 
larger the value, the more likely the corresponding dose is the MTD.
We recommended to compare the desirability of various dose candidates prior to making the 
dose selection decision. Doses with a high desirability are more likely to be the MTD, so they 
are preferred. When several doses have a similarly high desirability value, they are equally 
likely to become the MTD and the choice may be driven by other factors.
To avoid over dosing, only doses at most 2-fold larger than the maximum dose tested can be 
considered as candidates for the escalation process. 
Guidance for stopping the dose escalation
Four indicators will be monitored and the dose escalation process may be terminated as soon 
as either statistic has reached a target threshold, as defined in the protocol.
1. MTD precisely estimated:  CV(MTD) calculated as the inter-quartile range over the 
median is lower than 40%.
2. Maximum possible dose is safe TN 80%.
3. Minimum dose tested (100 mg) is toxic (T1 20%).
4. Total sample size for next dose is already equal to 9.
Criteria 1. to 3. will end up in a conclusive dose escalation study. The conclusion will be 
either that 1. the MTD has been found , 2. all doses are safe or 3. they are all toxic. Criterion 
4. does not lead to any interpretation about DLTs but it is a practical constraint to limit the 
overall duration of the study.
7.
Document history and changes in the planned statistical analysis

Approval of SAP, Version 1.0, 22 Mar 2018

Approval of SAP Supplement, 11 Dec 2019
o
Added clarification regarding determination of MTD during the dose 
escalation part (section 3, section 51, section 6.5)
o
Update of treatment groups as specified in the TLF Specifications (section 4.2)
o
Deleted the statement on separate TLFs by study part (section 6)
o
Added population characteristics summaries for additional populations (section 
6.1)
o
Added definition of all enrolled subjects (section 6.1.1)
o
Deleted overall survival and duration of stable disease as they are not efficacy 
endpoints in the protocol (section 6.2)
o
Added a pooled treatment group and deleted a repetition in the PK section 
(section 6.3)
o
Wording was harmonized throughout the document (treatment groups instead 
of arms/cohorts)
8.
References
(1) Investigator’s Brochure BAY 1163877 (Rogaratinib), Version 8.0, dated 10 Oct 2017.
(2) Integrated Clinical Study Protocol No. 1163877 / 16443, Version 7.0, dated 
16 Mar 2017.


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Protocol No.: BAY 1163877/16443
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(3) Tibaldi FS, Beck BH, A. B. Implementation of a Phase 1 adaptive clinical trial in a 
treatment of type 2 diabetes. Drug Inf J. 2008;42(5):455-65.


Statistical Analysis Plan
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Page: 1 of 21
Reference Number: RD-OI-0119
Supplement Version: 8
An open label, non-randomized, Phase I dose escalation study to characterize safety, 
tolerability, pharmacokinetics and maximum tolerated dose of BAY 1163877 in subjects with 
refractory, locally advanced or metastatic solid tumors
Phase I dose escalation pan-FGFR inhibitor (Rogaratinib)
Bayer study drug
BAY 1163877 / pan-FGFR inhibitor / rogaratinib
Study purpose:
To determine the maximum tolerated dose (MTD)
Clinical study phase:
I
Date:
22 Mar 2018
Study No.:
16443
Version:
1.0
Author:
Confidential
The information provided in this document is strictly confidential and is intended solely for the 
guidance of the clinical investigation.  Reproduction or disclosure of this document, whether in 
part or in full, to parties not associated with the clinical investigation or its use for any other 
purpose without the prior written consent of the sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures.
The approval of the Statistical Analysis Plan is documented in a separate Signature Document.
PPD


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Supplement Version: 8
Table of Contents
1.
Introduction........................................................................................................................5
2.
Study Objectives.................................................................................................................5
3.
Study Design.......................................................................................................................5
4.
General Statistical Considerations .................................................................................11
4.1
General Principles...........................................................................................................11
4.2
Handling of Dropouts .....................................................................................................12
4.3
Handling of Missing Data...............................................................................................12
4.4
Interim Analyses and Data Monitoring ..........................................................................12
4.5
Data Rules.......................................................................................................................13
4.5.1 Baseline...........................................................................................................................13
4.5.2 Unscheduled Measurements...........................................................................................13
4.6
Blind Review/Validity Review.......................................................................................13
5.
Analysis Sets .....................................................................................................................13
5.1
Assignment of analysis sets............................................................................................13
6.
Statistical Methodology ...................................................................................................14
6.1
Population characteristics...............................................................................................14
6.1.1 Disposition......................................................................................................................14
6.1.2 Protocol deviations .........................................................................................................14
6.1.3 Demographics and other baseline characteristics...........................................................14
6.1.4 Prior and Concurrent Medication/Therapy.....................................................................15
6.1.5 Medical History ..............................................................................................................15
6.2
Efficacy...........................................................................................................................15
6.3
Pharmacokinetics/pharmacodynamics............................................................................16
6.3.1 Pharmacokinetics............................................................................................................16
6.3.2 Pharmacodynamic data...................................................................................................17
6.4
Safety..............................................................................................................................17
6.4.1 Study drug exposure .......................................................................................................18
6.4.2 Maximum tolerated dose ................................................................................................18
6.4.3 Adverse Events...............................................................................................................18
6.4.4 Safety Parameters ...........................................................................................................19
6.5
Interim dose response modeling.....................................................................................19
7.
Document history and changes in the planned statistical analysis..............................21
8.
References.........................................................................................................................21


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Abbreviations
AE
adverse event
ANOVA
analysis of variance
AUC
Area under the curve
AUC(0-tlast)
AUC from time 0 to the last data point > LLOQ after a single dose 
AUC(0-tlast)/D
AUC(0-tlast) divided by dose
%AUC(tlast - ∞)
percentage of AUC from the last data point > LLOQ to infinity
AUC/D
AUC divided by dose
BC
bladder cancer
b.i.d.
twice daily
BMI
Body mass index
BP
Blood pressure
CI
Confidence interval
Cmax
maximum total drug concentration in plasma after a single dose
Cmax/D
maximum drug concentration in plasma after single dose
administration divided by dose
CR
Complete response
CRF
Case Report Form
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events Version 4.03
CV
coefficient of variation
d
Dose level
DOR
Duration of response
DOSD
Duration of stable disease
DOT
Duration of treatment
DLT
dose-limiting toxicity
DSMT
Drug safety monitoring team
e.g.
exempli gratia, for example
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EOT
End of treatment
FGF
Fibroblast growth factors
FGFR
fibroblast growth factor receptor
FU
Follow-up
GFR
Glomerular Filtration Rate
HR
Heart rate
IB
Investigator’s Brochure
i.e.
id est, that is
KM
Kaplan-Meier
LAC
lung adenocarcinoma
LLOQ
lower limit of quantification
log
logarithm
LS
Least squares
MAD
Median Absolute Difference
MCMC
Markov-Chain-Monte-Carlo
MDRD
Modified Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
MR
Magnetic resonance 
MRI
Magnetic resonance imaging
MTD
maximum tolerated dose
NCI
National Cancer Institute
NYHA
New York Heart Association (this abbreviation is usually used with roman digits to 


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characterize the stage of heart failure, e.g. NYHA I)
OS
overall survival
p
probability of observing a subject with DLTs during Cycle 1
PD
Pharmacodynamic(s)
PD
Progressive disease
p-ERK1/2
phospho-extracellular signal-regulated kinase 1/2 
PFS
progression-free survival
PK
pharmacokinetic(s)
PR
Partial response
Qd
probability of dose d being the MTD
RECIST
Response Evaluation Criteria in Solid Tumors
RMAD
Relative Median Absolute Difference
ROW
Rest of the world
RP2D
recommended Phase II dose
SAE
serious adverse event
SAP
Statistical Analysis Plan
SAS
Statistical Analysis System
SCCHN
squamous cell carcinoma of the head and neck
SD
stable disease
SD
standard deviation
sqNSCLC
squamous non-small cell lung cancer
Td
(tolerable) probability that the DLT rate is 0.20, Pr(p <0.20|d), for a dose d
TEADR
drug-related adverse event
TEAE
treatment-emergent adverse event
tlast
Time to last observed concentration
tmax
Time to maximum observed concentration
TTP
time to progression
vs
versus, as opposed to
WHO DD
World Health Organization Drug Dictionary


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1.
Introduction
Fibroblast growth factors (FGF) and their corresponding receptor family (FGFR) drive crucial 
oncogenic signaling pathways including cell proliferation, survival and migration. FGFRs are 
commonly altered in various human tumor diseases, including FGFR1 amplification in squamous 
non-small cell lung cancer (sqNSCLC) or activating mutations of FGFR3 in bladder cancers. These 
changes contribute to tumor cell growth, sustained angiogenesis, invasion and metastasis and 
resistance against other therapies. 
Rogaratinib (BAY 1163877) is an oral inhibitor of FGFR1, 2 and 3 and showed strong anti-tumor 
efficacy in pre-clinical models as a single agent as well as in combination with cytotoxic agents in 
FGFR pathway addicted tumor models.
The targeted application form is oral and preclinical data suggest low clearance and low volume of 
distribution resulting in a daily dose of 300 to 800 mg.
Further details can be found in the investigator's brochure (IB)[1], which contains comprehensive 
information on the study drug. The IB is available in the Trial Master File.
Additional information elaborating on the rationale of the study and the benefit-risk assessment can 
be found in the protocol.
This Statistical Analysis Plan (SAP) is based on the Clinical Study Protocol version 7.0 (including 
Amendment 7.0)[2].
2.
Study Objectives
The primary objectives of this study are:

To determine the safety and maximum tolerated dose (MTD) of BAY 1163877 in subjects
with advanced solid organ malignancies

To characterize the pharmacokinetics (PK) of BAY 1163877
The secondary objectives of this study are:

To evaluate biomarker status, pharmacodynamic (PD) parameters, and tumor response.

To assess the relative bioavailability of the tablet formulation in comparison to the solution
formulation of BAY 1163877.
The exploratory objective of this study is:

To evaluate selected immune parameters.
3.
Study Design
This is a Phase I, first-in-human, open-label, non-randomized, multi-center, 3-part, dose escalation 
study of BAY 1163877 in sequential cohorts of subjects with refractory, locally advanced or 
metastatic solid tumors. The study will be conducted at multiple centers worldwide.
Study Part 1 will identify the MTD in subjects with any solid tumors (all comer) using an adaptive 
dose escalation design and expansion of cohort at MTD.


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Study Part 2 will explore further the safety and PD of BAY 1163877 at the MTD identified in Part 1 
in subjects with sqNSCLC, LAC, BC, and SCCHN to seek any evidence of preliminary clinical 
responses. Study Part 2 may start as soon as the MTD has been established in Part 1.
Study Part 3 will expand the safety database for patients on treatment with BAY1163877 at the 
MTD identified in Part 1 with sqNSCLC, LAC, and BC. In parallel, in Part 3 additional efficacy 
data will be collected and changes of selected immune parameters will be assessed.
The complete duration of the study (Part 1, Part 2, and Part 3) depends on the number of dose 
escalation steps in Part 1 and will be approximately 7 years.
Planned sample size:
Subjects will be enrolled in the pre-treatment phase of the study to recruit enough subjects with 
present high FGFR expression levels for the following study parts.
Targeted / planned enrollment:

Study Part 1 / dose escalation (all comer): The total number of subjects will depend on the
number of cohorts necessary to identify the MTD. Relative bioavailability of the tablet
formulation in comparison to the solution formulation will be performed in all subjects
enrolled in one of the dose escalation cohorts; pharmacokinetic data are needed in a
minimum of 3 subjects for relative bioavailability assessment.

Study Part 1 / MTD expansion (all comer): Additional subjects will be enrolled to have 20
evaluable “all comer” subjects treated at MTD.

Study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN): additional subjects will
be enrolled to have 20 evaluable subjects with sqNSCLC or LAC and at least 30, up to
maximum of  50 evaluable subjects with BC  and at least 8 subjects with SCCHN treated at
MTD.

Study Part 3 / MTD expansion “Safety cohort” (sqNSCLC + LAC + BC ): additional subjects
will be enrolled to have approximately 20 subjects with sqNSCLC or LAC and approximately
20, subjects with BC  treated at MTD.
PK assessments will be performed in all subjects participating in study Part 1 / dose escalation and 
MTD expansion (all comer) and study Part 3/ MTD expansion “Safety cohort”. Additionally, PK 
assessments are planned in at least 12 subjects participating in study Part 2 / MTD expansion 
(sqNSCLC + LAC + BC + SCCHN) such that valid PK data are available in 8 subjects and in 
approximately 8 subjects of the MTD expansion cohorts with impaired renal function at baseline. 
Food effect PK assessment is planned in approximately 8 subjects enrolled in the MTD expansion 
cohorts (study Part 1 and Part 2). Subjects participating in “food effect assessment” in study Part 2 
may be included in the total sample size of 12 if all protocol requirements are met.
All subjects participating in either of the 3 MTD expansion cohorts (Part 1, Part 2, and Part 3 despite 
subjects with impaired renal function) will have 2 PK samples drawn for the purpose of exposure-
response modelling on Day 1 of Cycles 2, 3, 4, and 5 (1 blood sample just before the morning dose 
of BAY 1163877 and 1 blood sample between 0.5 and 1.5 hours post-dose). Subjects in Part 3 will 
provide one PK sample within 1 hour of biopsy collection in Cycle 2. The dose needs to be taken 
under supervision and the time recorded.


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Study periods:
Figure 3—1 Schematic presentation of the treatment design
In total, the “on study” period for all subjects comprises 3 phases (see Figure 3—1):

Pre-treatment

Testing for FGFR and FGFR mutation (only for subjects recruited for Part 1,
Part 2 or Part 3 MTD expansion cohorts)

Screening

Treatment

Study Part 1 / dose escalation + MTD expansion (all comer):
Individual number of 21-day Cycles with BAY 1163877 monotherapy (tablet or
solution) until disease progression or as along as clinical benefit is assumed by the
investigator or until unacceptable toxicity occurs.

Study Part 1 / “tablet bridging cohort” (all comer):
In one of the dose escalation cohorts, administration of a single dose of
BAY 1163877 using the tablet formulation on Cycle 1, Day -3 followed by
solution formulation starting Cycle 1 Day 1 as described above.

Study Part 2 / MTD expansion (sqNSCLC + LAC + BC + SCCHN):


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Individual number of 21-day Cycles with continuous BAY 1163877 monotherapy 
(tablet or solution) until disease progression or as along as clinical benefit is 
assumed by the investigator or until unacceptable toxicity occurs.

Study Part 1 (MTD expansion cohort) and Study Part 2 (sqNSCLC + LAC + BC
+ SCCHN) / “Food Effect Assessment”:
Approximately 8 subjects will receive single doses of BAY 1163877 on Cycle 1, 
Day -3 (after consumption of a high-fat, high-calorie breakfast) and on Cycle 1, 
Day 1 (after an overnight fast of at least 8 hours) followed by treatment according 
to the schedule described above starting on Cycle 1, Day 3.

Study Part 3 / MTD expansion “Safety cohort” (sqNSCLC + LAC + BC):
Individual number of 21-day Cycles with continuous BAY 1163877 monotherapy
(tablet) until disease progression or as long as clinical benefit is assumed by the
investigator or until unacceptable toxicity occurs.
Note: Treatment with BAY 1163877 at MTD in Part 1 (expansion cohort “all comer”), Part 2 
(expansion cohort sqNSCLC + LAC + BC + SCCHN), and Part 3 (expansion cohort
“Safety cohort”, sqNSCLC + LAC + BC) can run in parallel.

Follow-up (FU)

End of Treatment (EOT) visit 0-14 days after last dose of BAY 1163877

FU visit at 30-35 days after dose of BAY 1163877
The first screening visit is scheduled within 7 days / 28 days before administration of the first dose 
of BAY 1163877. The informed consent form will be signed by the subject before or at the first 
screening visit. The screening period ends just before start of treatment.
The treatment period starts on the day of the first administration of study treatment on Cycle 1, 
Day 1 or on Cycle 1, Day -3 (“tablet bridging cohort” and “food effect assessment”) and ends with 
the last day when the study medication is administered in Cycle X. The length of treatment period 
may vary from subject to subject dependent on the number of individual treatment cycles. A Cycle 
for this study is defined as 21 days. There will be no break between cycles.
When a subject starts new anti-cancer therapy, he / she is no longer considered “on study”.
An EOT visit will be performed for all subjects within 0-14 days after administration of the last dose 
of BAY 1163877. The FU visit for subjects who either discontinue prematurely or finish dosing with 
BAY 1163877 will be performed 30 - 35 days after the last study drug treatment. There will be no 
long-term (survival) FU period.
Treatment: Subjects with PK assessment (all subjects of study Part 1 and 3 and at least 12 subjects 
of study Part 2 and approximately 8 subjects of the MTD expansion cohorts with impaired renal 
function at baseline) will receive BAY 1163877 (tablet or solution) on a continuous schedule 
starting with single-dose administration on Cycle 1, Day 1, followed by a “drugfree day” (to enable 
single dose PK assessments except for subjects in Part 3 who will receive BAY 1163877 twice daily 
continuously with no “drug free day”). Treatment with BAY 1163877 will resume on Day 3 of 
Cycle 1 if no protocol-defined dose-limiting toxicities (DLTs) are reported. Starting on Cycle 1, 


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Day 3, the study drug will be self-administered twice daily for the remaining 19 days of Cycle 1. For 
subsequent cycles, study drug will be administered twice daily for 21 days until disease progression 
or as long as clinical benefit is assumed by the investigator or until unacceptable toxicity occurs.
In one of the dose escalation cohorts in study Part 1 (“tablet bridging cohort”), relative 
bioavailability of the tablet formulation will be assessed by administration of a single dose of the 
tablet formulation on Cycle 1, Day -3. Starting with Cycle 1, Day 1, subjects enrolled in the “tablet 
bridging cohort” will continue with the solution formulation as described above. Depending on the 
results from the relative bioavailability assessment, subjects who initially start with solution 
formulation may be switched to tablet formulation in later cycles.
Approximately 8 subjects enrolled in the MTD expansion cohorts (study Part 1 and Part 2) will 
receive single doses of BAY 1163877 on Cycle 1, Day -3, after consumption of a high-fat, high-
calorie breakfast and on Cycle 1, Day 1, after an overnight fast of at least 8 hours followed by 
treatment according to the schedule described above starting on Cycle 1, Day 3. 
Subjects without PK assessment in study Part 2 will receive BAY 1163877 (tablet or solution) twice 
daily from Cycle 1, Day 1 ongoing.
At home, subjects will document the intake of study drug in a diary.
Subjects will continue receiving treatment until tumor progression, unacceptable toxicity, consent 
withdrawal, or subject withdrawal from the study at the discretion of the Investigator or his/her 
designated associate(s). As long as, in the judgment of the subject and the investigator, some benefit 
with evidence of tumor reduction or stable disease is being derived, dosing with BAY 1163877 may 
continue.
Determination of the MTD
An adaptive dose escalation design will be used to determine the MTD in study Part 1 (all comer). 
The MTD is defined as the highest dose that can be given such that not more than 20% of subjects 
experience a DLT during Cycle 1.
Without the occurrence of toxicities, dose escalation could be stopped and RP2D may be determined 
based on PK and/or PD results. The decision to continue treatment for an individual subjects will be 
made by the investigator according to the criteria specified in the protocol.
Each cohort will be evaluated after all subjects have completed the first 21 days of treatment (which 
will subsequently referred to as “Cycle 1”) or early discontinued.
Safety monitoring will occur by telephone conferences with participation of the investigators and the 
sponsor on a regular basis.
At the time of dose escalation the available clinical safety information is discussed in a telephone 
conference by the involved investigators and representatives from the Sponsor including the Study 
Medical Expert as well as representatives of other clinical and if required further contributing 
functions (drug safety monitoring team – DSMT). During this telephone conference it will be judged 
if dose escalation can proceed as planned according to the procedure outlined below. Dose 
escalation for subsequent cohorts will only be considered after full evaluation of at least Cycle 1 
safety data from the previous cohort.


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The National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events Version 
4.03 (CTCAE v4.03) will be used to grade toxicities / adverse events.
The dose escalation will be performed as follows:

Initially 3 subjects per dose level will be enrolled. In case 2 or more sites are conducting the
dose escalation part, the initial enrolment of 4 subjects per dose level is optional.

The starting dose of BAY 1163877 is 50 mg given as a single dose on Cycle 1, Day 1, and
twice daily (b.i.d.) from Cycle 1, Day 3 (100 mg / day).

The maximum dose escalation will be 2-fold.

Possible daily doses of BAY 1163877 starting from 100 mg in increments of 100 mg.

The possible maximum dose of BAY 1163877 is considered to be 550 mg b.i.d.
(1100 mg / day). Higher doses might be explored after discussions between sponsor and
investigators.

If at least 1 subject out of 3 or 1 out of 4 in a cohort has DLTs or if at least 2 subjects report
drug-related AEs (CTCAE v4.03) of Grade ≥ 2, any further dose escalation, de-escalation or
cohort expansion will be decided in consultation between all investigator(s), and the sponsor
(within the DSMT) after consideration of all available safety data of the previous cohorts.
Any subsequent dose will be selected in order to determine the MTD.
Model-based dose-response analysis of the DLT rates will be performed during these interim
reviews in order to guide the dose decision. The model-based dose selection procedure is
considering data at all dose levels (not just at the last cohort). The dose predicted to yield
20% DLT rates will be reported from that model as a best candidate for the next cohort.
The final decision about the next dose will be made by the sponsor in consultation with all
investigators (DSMT).
If the selected dose is larger than the last dose tested, then escalation will be pursued. If it is
lower, a de-escalation step will occur.
Cohort expansion will occur when a previously tested dose is selected again for the next
cohort of 3 subjects.
Expansions at any given dose up to a total of 9 subjects are allowed. In principle, the
selection of a next dose level where the predicted DLT rate is close to 20% should insure that
the next dose tested will remain safe.
Nevertheless, the following constraint will be added in order to protect subject safety during
the adaptive dose selection decisions:

If 2 out of 3 (or 2 out of 4), at least 4 out of 6 (or at least 5 out of 9) subjects
experience DLTs at a given dose level, only lower doses will be given in all
subsequent cohorts because the probability that the dose is above the MTD is very
large (above 95.4%).

The dose-escalation procedure will be stopped as soon as:


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
the MTD has been defined with good precision (i.e. the coefficient of
variation for the MTD is lower than or close to 40%)
or

at any time when the selected dose level for the next cohort has already been
given in 9 subjects.
If the dose escalation stops, the sample size for the MTD cohort will be expanded up to a total of 20 
evaluable subjects (study Part 1 / MTD expansion cohort (all comer)).
No intra-subject dose escalation is permitted. Dose interruptions and / or dose reductions may be 
required based on individual safety and tolerability.
Variables are specified in the Clinical Study Protocol[2].
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), R release 2.4.1 or higher and BRugs release 0.3-3 or higher. 
All variables will be analyzed by descriptive statistical methods. The number of data available, 
mean, standard deviation, minimum, median, and maximum will be calculated for metric data. 
Frequency tables will be generated for categorical data.
Data displays will follow the standard table catalogs for oncology standards, global standards, and 
clinical pharmacology standards, respectively.
The pharmacokinetic parameters will be evaluated statistically in accordance with pertinent 
company guidelines.
The following treatment groups will be analyzed.
In the following “XX mg” stands for the assigned dose.
Study Part 1: Dose escalation

XX mg sol.

For regular dose escalation cohorts

XX mg sol./tab. (and potentially XX mg tab./sol.)

For dose escalation cohorts related to bioavailability

Total Dose Escalation
Study Part 1, Part 2 and Part 3 MTD Dose Expansion

Exp.1 All Comers – XX mg tab.

Exp.2 sqNSCLC – XX mg tab.


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
Exp.2 LAC – XX mg tab.

Exp.2 BC – XX mg tab.

Exp.2 SCCHN – XX mg tab.

Exp.3 sqNSCLC – XX mg tab.

Exp.3 LAC – XX mg tab.

Exp.3 BC – XX mg tab.
The categories of region used for subgroup analysis will be derived for each subject by using the 
variable country (location of the respective site).
4.2
Handling of Dropouts
A subject who discontinues study participation prematurely for any reason is defined as a “dropout” 
if the subject has already been administered at least 1 dose of the study drug (BAY 1163877).
A subject who, for any reason (e.g. failure to satisfy the selection criteria), terminates the study 
before the time point used for the definition of “dropout” (see above) is regarded a “screening 
failure”.
Subjects who discontinue due to a DLT will NOT be replaced.
Subjects who discontinue during the first cycle of therapy (Cycle 1) due to any reason other than a 
DLT and / or related toxicity, and subjects who took less than 80% of the required study drug 
(BAY 1163877) in Cycle 1 will be replaced to ensure 3 evaluable subjects per cohort for the 
determination of MTD and PK of BAY 1163877. Subjects who discontinue after the first cycle 
(Cycle 1) will not be replaced.
Subjects enrolled in Study Part 1 / MTD expansion (all comer) with insufficient paired biopsy 
samples will be replaced to ensure at least 10 subjects with paired biopsy samples for p-ERK1/2 
analysis.
4.3
Handling of Missing Data
All missing or partial data will be presented in the subject data listing as they are recorded on the 
Case Report Form (CRF). 
Missing data will not be replaced. Possible impact of missing values on the analysis will be 
discussed in the clinical study report.
4.4
Interim Analyses and Data Monitoring
Safety data will be reviewed on an ongoing basis during study Part 1 / dose escalation (all comer). 
Bayesian dose-response and / or PK / PD modeling of DLTs rates and CTCAE v4.03 gradings may 
be performed after selected cohorts in order to generate additional relevant information for the 
adaptive dose selection decisions. The sponsor together with all investigators will review all 
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during the adaptive dose escalation part. This group will also determine when to implement 
predefined stopping rules.
No interim analysis is planned during dose expansion at MTD in study Part 1 (MTD expansion 
cohort “all comer”), study Part 2 (MTD expansion cohort “sqNSCLC + LAC+ BC + SCCHN”) or 
study Part 3 (MTD expansion cohort “Safety cohort”).
4.5
Data Rules
4.5.1
Baseline
Unless otherwise stated, baseline is defined as the last pre-dose assessment before first study drug 
administration or as the last pre-dose assessment before the time period being analyzed.
4.5.2
Unscheduled 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 timepoint after study drug 
administration are available, the planned measurement will be used for the calculation of descriptive 
statistics.
Further applicable data rules are described in section 6 “Statistical Methodology”.
4.6
Blind Review/Validity Review
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).
Safety analysis set
All subjects who received at least 1 dose of BAY 1163877 will be included in the safety evaluation.
MTD analysis set
All subjects who completed Cycle 1 or discontinued during Cycle 1 due to an adverse event or DLT 
will be included in the MTD evaluation.
Efficacy analysis set 


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All subjects who received at least 1 dose of BAY 1163877 and who have post-baseline efficacy data 
available will be included in the efficacy evaluations.
Pharmacodynamic analysis set 
All subjects with evaluable PD data and who complete the study without major changes versus 
protocol will be included in the evaluation of PD.
Pharmacokinetic analysis set 
All subjects with valid pharmacokinetic data will be included in the evaluation of pharmacokinetic 
concentrations and parameters.
6.
Statistical Methodology
The treatment groups to be analyzed are defined in section 4.1. The tables, listings, and figures will 
be separately displayed for the different parts of the study (i.e. Part 1 dose escalation, Part 1 MTD 
expansion cohort “all comer”, Part 2 MTD expansion cohort “sqNSCLC + LAC+ BC + SCCHN”, 
and Part 3 MTD expansion cohort “Safety cohort”).  
6.1
Population characteristics
Analyses for population characteristics will be performed for the safety population on the treatment 
groups if not stated otherwise. The results will be displayed by region (Asia, ROW, and total), if 
reasonable. 
6.1.1
Disposition
Disposition at the end of screening will be summarized for subjects who signed the informed 
consent for FGFR testing and for all subjects who signed the main informed consent, respectively. 
Disposition at the end of Treatment and for the Safety follow-up will be summarized by treatment 
groups for all subjects assigned to treatment and the safety analysis set, respectively. 
6.1.2
Protocol deviations
Frequency tables of protocol deviations by category and deviation coded term will be summarized 
by treatment group. 
6.1.3
Demographics and other baseline characteristics
Demographics and general baseline characteristics will be summarized by treatment group. 
Quantitative data will be summarized by arithmetic mean, SD, median, minimum and maximum. 
Frequency tables will be provided for qualitative data. Variables include sex, race, ethnicity, age (as 
reported on the eCRF), weight, height, body mass index (BMI), and NYHA functional class. 
Baseline cancer characteristics will be summarized by treatment group. Variables include for 
example baseline ECOG Performance Status, number of target lesions, number of non-target 
lesions, cancer type, histology, status of primary tumor, stage at initial diagnosis, grading at initial 
diagnosis, clinical status at study entry, stage at study entry, time since initial diagnosis. Please note 
that the list of the above mentioned parameters is not extensive.


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In addition, demographics and baseline cancer characteristics will be summarized for all subjects 
who signed the informed consent for FGFR testing.
6.1.4
Prior and Concurrent Medication/Therapy
Prior anti-cancer therapy and surgical therapeutic procedures will be summarized by treatment 
group. The counts and percentages of patients 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 patients 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. Prior 
and concomitant medications will be coded to generic terms using the World Health Organization 
Drug Dictionary (WHO DD) Version 2017SEP or later and summarized by treatment group. The 
version used in analyses will be presented in the clinical study report. 
6.1.5
Medical History
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 20.1 or later. The version used in analyses will be presented in the clinical study 
report. Medical history data will be summarized by system organ class, high level term, and 
preferred term by treatment group.
6.2
Efficacy
Tumor response
Efficacy data, such as best tumor response, will be summarized using descriptive statistics and will 
be graphically displayed if appropriate.  The correlation between PD parameters and selected safety, 
efficacy, or PK parameters may be graphically displayed.  Further statistical analyses may be 
conducted.
The efficacy analysis will include descriptive analyses on response rate, progression-free survival 
(PFS), time to progression (TTP), overall survival (OS), duration of response (DOR), duration of 
stable disease (DOSD), and duration of treatment (DOT). 
Response as defined by RECIST v.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. 
OS is defined as the time (days) from the date of first dose of study drug to death due to any cause.  
Subjects alive at the time of analysis will be censored at the last contact date.  OS for subjects 
without any contact after first dose of study drug will be censored at 1 day.
PFS is defined as the time (days) from the date of the first dose of study drug to the date of the first 
observed disease progression (radiological or clinical) or death due to any cause, if death occurs 
before progression is documented. PFS for subjects without tumor progression at the time of 
analysis will be censored at their last date of tumor evaluation.
TTP is defined as the time from start of study treatment until first observed disease progression 
(radiological or clinical). In comparison to PFS, TTP does not consider death as an event.


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DOR (for partial and complete response (PR/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). 
DOSD is defined as the time (days) from start of study treatment to date that disease progression or 
death (if death occurs before progression) is first documented.
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 and 
TTP per treatment. In addition KM survival curves will be presented for each treatment group.
Best overall tumor response according to RECIST criteria will be summarized by treatment group 
and region (Asia, ROW, and total) 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.
Subgroup analysis will be performed by prior immunotherapy information (prior immunotherapy vs. 
no prior immunotherapy) .
6.3
Pharmacokinetics/pharmacodynamics
6.3.1
Pharmacokinetics 
The concentration-times courses of all analytes will be tabulated for each cohort by treatment. 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 
by cohort using both linear and semilogarithmic scale. 
The amount and percent of drug excreted into urine will be graphically illustrated for the sampling 
interval as well as for the whole sampling period (bar-charts for the individual data and the 
arithmetic mean including standard deviation).
Pharmacokinetic characteristics (tmax, tlast, 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.
PK Dose proportionality
To investigate dose proportionality, an explorative ANOVA, including the factor cohort, will be 
performed on the log-transformed values of Cmax/D, AUC(0-tlast)/D, and AUC/D calculated from 
single (where applicable) and multiple dose PK profiles.


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Bridging: tablet vs solution relative bioavailability
PK parameters of different dose levels will be analyzed together for the assessment of relative 
bioavailability.
In order to evaluate the relative bioavailability of the tablet formulation, tablet Cmax/D, 
AUC(0-tlast)/D, and AUC/D on Cycle 1, Day -3 will be compared to solution Cmax/D, AUC(0-tlast)/D, 
AUC/D on Cycle 1, Day 1 for all analytes. If needed, additional PK parameters may be used for 
relative bioavailability assessment. The logarithms of these PK parameters will be analyzed using 
analysis of variance (ANOVA) including subject and formulation effects. 
Based on these analyses, point estimates (LS-means) and exploratory 90% confidence intervals for 
the ratios (tablet/solution) of Cmax/D, AUC(0- tlast)/D, and AUC/D will be calculated by 
re-transformation of the logarithmic data using the intra-individual standard deviation of the 
ANOVA.
Subjects to be included in the relative bioavailability evaluation (“tablet bridging cohort”) should 
have evaluable pharmacokinetic data on both Cycle 1, Day -3 and Cycle 1, Day 1.
Food effect
In order to evaluate the effect of food on BAY 1163877, Cmax and AUC(0-tlast) on Cycle 1, Day -3 
and Cmax and AUC(0-tlast) on Cycle 1, Day 1 will be compared. The logarithms of Cmax and 
AUC(0-tlast) will be analyzed using ANOVA including subject and food effect. 
Based on these analyses, point estimates (LS-means) and exploratory 90% confidence intervals for 
the ratios (high-fat, high-calorie meal / fasting) of Cmax and AUC(0- tlast) will be calculated by 
re-transformation of the logarithmic data using the intra-individual standard deviation of the 
ANOVA.
The PK paramteres Cmax/D, AUC(0-tlast)/D, AUC/D, Cmax. and AUC(0-tlast) will be graphically 
illustrated using stickplots. Scatterplots of the PK parameters Cmax/D, AUC(0-tlast)/D, AUC/D will 
be created.
6.3.2
Pharmacodynamic data
Cardiovascular parameters will be described by the following summary statistics: arithmetic mean, 
standard deviation, median, minimum and maximum. These summary statistics will be presented by 
cohort for the original data as well as for the difference to baseline (defined as the pre-dose 
assessment of the day being analyzed).
Graphical displays of individual data as well as mean values with standard deviation will be 
included for absolute values as well as change from baseline.
6.4
Safety
The results will be displayed by region (Asia, ROW, and total), if reasonable.


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6.4.1
Study drug exposure
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 
with reason will be summarized.
6.4.2
Maximum tolerated dose
Individual listings and treatment summaries of DLTs with CTCAE v4.03 code and grade will be 
presented.
The incidence of subjects with DLTs during Cycle 1 will be summarized by treatment and, as 
possible, modeled as a function of BAY 1163877 dose using Bayesian logistic regression.  The 
moderately-informative independent priors used during the interim dose response analysis (see 
Section 6.5 for details) as well as non-informative priors will be used for this analysis to assess 
sensitivity of the estimates.  Parameter estimates and model predictions will be reported with 90% 
credibility sets.  The MTD will be computed as a derived function of model parameters as:
MTD = (log(0.2/0.8)-intercept)/slope.
The posterior distribution of the MTD will be summarized in tabular and graphical formats.
6.4.3
Adverse Events
Adverse events will be analyzed using the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Event (CTCAE) version 4.03. In addition a separate set of AE tables will be 
generated using MedDRA terms.
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 treatment arm, cohort, CTCAE body system code and worst NCI-CTCAE grade. 
TEAEs, SAEs, drug-related TEAEs, and drug-related SAEs for events of Grade 3/4/5 will be 
summarized similarly. 
AEs are considered treatment emergent if they have started or worsened after the first study drug 
administration up to 30 days after the end of treatment with study drug.
Frequency tables will also be provided for the changes of CTCAE grade from pre-treatment and 
changes of worst CTCAE grade under treatment.
In addition, TEAEs, SAEs, drug-related TEAEs, and drug-related SAEs will be summarized by 
MedDRA (Version 20.1 or later) system organ class, preferred term and worst NCI-CTCAE grade. 
The same will be also summarized similarly for events of Grade 3/4/5. 
Patient listings of all AEs, SAEs, AEs leading to dose reduction, AEs leading to dose interruption, 
AEs leading to discontinuation, dose limiting toxicity AEs, and deaths will be presented.


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6.4.4
Safety Parameters
Quantitative data (vital signs, ECG, ECOG performance status) will be described by the following 
summary statistics:  arithmetic mean, standard deviation, median, minimum, and maximum.  These 
summary statistics will be presented by treatment arm and cohort for the original data as well as for 
the difference to baseline. Frequency tables will be provided for qualitative data. Graphical displays 
of mean values with standard deviation will be provided.
The average of triplicate quantitative ECG parameters at all ECG time points will be used for all 
analyses.
Laboratory data outside the reference range will be listed and flagged with ‘L’ for low and ‘H’ for 
high.  The incidence of laboratory data outside the reference range (low, high) will be summarized 
by treatment arm and cohort in frequency tables.
Calcium, phosphate and the product of calcium and phosphate will be described by the following 
summary statistics: arithmetic mean, standard deviation, median, minimum and maximum. These 
summary statistics will be presented by cohort for the original data as well as for the difference to 
baseline (defined as the pre-dose assessment of the day being analyzed).
Graphical displays of mean values with standard deviation will be included for absolute values as 
well as change from baseline.The number of subjects with at least one phosphate level > 5.5 mg/dL, 
with at least one phosphate level > 7 mg/dL and with at least one phosphate level > 9 mg/dL will be 
summarized using frequency tables.
The number of subjects with at least one value > 70 mg2/dL2  of the product phosphate and calcium 
will be summarized using frequency tables.
The incidence of laboratory toxicities will also be summarized by worst CTCAE v4.03 grade and by 
treatment group and cohort.  Frequency tables will also be provided for the changes of worst 
CTCAE v4.03 grade after start of treatment versus baseline.
6.5
Interim dose response modeling
The following Bayesian dose-response analysis of the DLT rates will be performed during the 
interim reviews in order to guide the dose escalation decision.
Bayesian logistic regression
The analysis is based on a method reported by Tibaldi et al.[3]
A range of doses will be tested, including possibly 100, 200, 300, 400, 500, 600, 700, 800, 900, 
1000 and 1100 mg.  Additional or alternative dose levels may be chosen.  These possible dose levels 
are labeled as d = 1, …, N, where N is the maximum number of dose levels for the study.  The 
probability, p, of observing a subject with DLTs during Cycle 1 is modeled as a function of dose:
d
p
p
*
slope
intercept
)
1
log(



In this trial, the MTD is defined as the predicted dose where the DLT probability is 20%:
MTD = (log(0.2/0.8)-intercept)/slope.


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A Bayesian analysis will be performed, considering the following independent priors for the model 
parameters:

intercept has a normal distribution with mean equal to -3 and variance equal to 1.

slope has a positive normal distribution with mean equal to 0.0015 and variance equal to
0.003.
These priors were specified in the protocol. They are moderately-informative and were considered 
plausible in the context of the current dose escalation scheme and indication. 
The posterior distribution of model parameters and the MTD will be estimated with the R package 
BRugs using MCMC techniques and considering at least 10000 simulations after convergence of the 
Markov chain. 
The precision of the MTD will be monitored by calculating the relative median absolute difference 
(RMAD% = 100*mad/median). This robust estimator is a suitable statistic to quantify variability in 
asymmetric distributions. A low RMAD(MTD)% value indicates good precision.
In addition, the following posterior probabilities will be calculated for each dose level in the 
candidate set:

Td = (tolerable) Probability that the DLT rate is below 0.20, Pr(p <0.20| d), for a dose d.

Qd = Probability of dose d being the MTD. This is the probability that d is the maximum
dose from the candidate set where p<20%.
Guidance for selection of next dose
The posterior density of the MTD and the Qd probabilities in the candidate set are the two main 
instruments that will be reported to guide dose selection. They indicate on a continuous and  discrete 
scale respectively the desirability for a dose to become the next choice. The larger the value, the 
more likely the corresponding dose is the MTD.
We recommended to compare the desirability of various dose candidates prior to making the dose 
selection decision. Doses with a high desirability are more likely to be the MTD, so they are 
preferred. When several doses have a similarly high desirability value, they are equally likely to 
become the MTD and the choice may be driven by other factors.
To avoid over dosing, only doses at most 2-fold larger than the maximum dose tested can be 
considered as candidates for the escalation process. 
Guidance for stopping the dose escalation
Four indicators will be monitored and the dose escalation process may be terminated as soon as 
either statistic has reached a target threshold, as defined in the protocol.
1. MTD precisely estimated:  CV(MTD) calculated as the inter-quartile range over the median
is lower than 40%.
2. Maximum possible dose is safe TN 80%.
3. Minimum dose tested (100 mg) is toxic (T1 20%).


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4. Total sample size for next dose is already equal to 9.
Criteria 1. to 3. will end up in a conclusive dose escalation study. The conclusion will be either that 
1. the MTD has been found , 2. all doses are safe or 3. they are all toxic. Criterion 4. does not lead to
any interpretation about DLTs but it is a practical constraint to limit the overall duration of the
study.
7.
Document history and changes in the planned statistical analysis

Approval of SAP, Version 1.0, 22 Mar 2018
8.
References
[1] Investigator’s Brochure BAY 1163877 (Rogaratinib), Version 8.0, dated
10 Oct 2017.
[2] Integrated Clinical Study Protocol No. 1163877 / 16443, Version 7.0, dated
16 Mar 2017.
[3] Tibaldi FS, Beck BH, A. B. Implementation of a Phase 1 adaptive clinical trial in a
treatment of type 2 diabetes. Drug Inf J. 2008;42(5):455-65.