Clinical trial NCT03172884
Conditions: Hepatic Insufficiency, Renal Insufficiency
Keywords: Renal Impairment Pharmacokinetics Hepatic impairment Envisaged indication: Treatment of cancer
Sponsor: Bayer
Start date: 2017-06-14; Completion date: 2020-05-15
Enrollment: 30 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the pharmacokinetics and safety of copanlisib in subjects with impaired hepatic or renal function in comparison to healthy subjects

Detailed description:

Arms: arm 1: Healthy subjects arm 2: Patients with Child-Pugh B (score 7-9) at the screening visit arm 3: Patients with eGFR 15-29 mL/min/1.73 m\^2 at the screening visit based on the Modification of Diet in Renal Disease (MDRD) equation arm 4: Patients with Child-Pugh C (score 10-15) at the screening visit
Interventions: intervention 1: Copanlisib (ALIQOPA, BAY80-6946)
Intervention descriptions: intervention 1: 12mg single dose, intravenous on Day 0

Protocol documents:
Prot_000.pdf: 
 
Document Type: 
Study Protocol  
Official Title: 
An open-label non-randomized, phase 1 single dose study to 
evaluate the pharmacokinetics and safety of copanlisib in subjects 
with impaired hepatic or renal function in comparison to healthy 
subjects 
NCT Number: 
NCT03172884 
Document Date: 
28 Nov 2017 
 


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Cover page of the integrated protocol
An open-label non-randomized, phase 1 single dose study to evaluate the pharmacokinetics 
and safety of copanlisib in subjects with impaired hepatic or renal function in comparison to 
healthy subjects
Phase 1 study of copanlisib in hepatic or renal impairment
This protocol version is an integration of the following documents / sections:
Original protocol, Version 1.0, dated 17 Mar 2017
Amendment 1 (described in Section 15.1)
forming integrated protocol Version 2.0, dated 28 Nov 2017


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1.
Title page
An open-label non-randomized, phase 1 single dose study to evaluate the pharmacokinetics 
and safety of copanlisib in subjects with impaired hepatic or renal function in comparison to 
healthy subjects
Phase 1 study of copanlisib in hepatic or renal impairment
Test drug:
Copanlisib / BAY 80-6946
Study purpose:
To evaluate the effect of impaired hepatic or renal function on 
copanlisib 
Clinical study phase:
1
Date:
28 Nov 2017   
Registration:
EudraCT:  2016-004561-51
Version no.:
2.0  
Sponsor’s study no.:
18041 
Sponsor:
Bayer AG, D-51368 Leverkusen, Germany
Sponsor’s medical expert:
Bayer AG
SBU Oncology, Pharmaceuticals
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) may not be displayed.  
Hence, the appearance of product names without these symbols does not imply that these names are 
not protected.
PPD
PPD


PPD
PPD


PPD
PPD


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2.
Synopsis - amended
Title
An open-label non-randomized, phase 1 single dose study to evaluate the 
pharmacokinetics and safety of copanlisib in subjects with impaired hepatic 
or renal function in comparison to healthy subjects
Short title
Phase 1 study of copanlisib in hepatic or renal impairment
Clinical study phase
1
Study objective(s)1
The primary objective of this study is to

Investigate the pharmacokinetics (PK) of copanlisib following a 
single intravenous (i.v.) dose of 12 mg copanlisib in subjects with 
moderate hepatic (Child Pugh B), severe hepatic (Child Pugh C)
or severe renal impairment compared with healthy subjects
The secondary objectives of this study is to

Evaluate the PK of M-1 metabolite

Assess the safety and tolerability of copanlisib when administered 
to subjects with moderate hepatic, severe hepatic or severe renal 
impairment
Test drug
BAY 80-6946 (Copanlisib)
Name of active ingredient
BAY 80-6946 (Copanlisib)
Dose
12 mg
Route of administration
i.v.
Duration of treatment
Single dose
Indication
Not applicable.
                                                
1 Objectives revised as subjects with severe hepatic impairment will be included into the study according to 
Amendment 1


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Diagnosis and main criteria for 
inclusion /exclusion
All subjects

Male and female subjects between 18 and 80 years of age with a 
body mass index above 18.0 and below 34.0 kg / m² and a body 
weight of above or equal 50 kg.
Healthy subjects

Healthy subjects as determined by absence of clinically significant 
deviation from normal in medical history, physical examination, 
vital signs, electrocardiograms, and clinical laboratory 
determinations.

eGFR ≥ 90 mL/min/1.73 m2 (according to Modification of Diet in 
Renal Disease [MDRD] formula).
Subjects with moderate hepatic impairment 

Subjects with confirmed liver cirrhosis by at least one of the 
following criteria: histologically by prior liver biopsy showing 
cirrhosis, liver imaging (computer tomography, and/or ultrasound 
and/or magnetic resonance imaging scans, and/or fibroscan), or 
laparoscopy.

Child-Pugh Clinical Assessment Score 7 to 9.
Subjects with severe hepatic impairment2

Subjects with confirmed liver cirrhosis by at least one of the 
following criteria: histologically by prior liver biopsy showing 
cirrhosis, liver imaging (computer tomography, and/or ultrasound 
and/or magnetic resonance imaging scans, and/or fibroscan), or 
laparoscopy.

Child-Pugh Clinical Assessment Score 10-15.
Subjects with severe renal impairment 

Subjects with severe renal impairment with an estimated 
glomerular filtration rate 15-29 mL/min/1.73 m2 according to 
MDRD formula.

Subjects with stable renal disease: no significant change in renal 
function as evidenced by serum creatinine value within ±25% 
from the last determination, obtained within at least 3 months 
before study entry and the absence of the need to start dialysis in 
the next 3 months.
Study design
Multi-center, non-randomized, open-label, single-dose, parallel group, 
study consisting of 4 groups (control group: normal hepatic and renal 
function group, Group A: moderate hepatic impairment group, Group B: 
severe renal impairment group, Group C severe hepatic impairment group)3
Methodology
Pharmacokinetics, safety, and tolerability
                                                
2 Inclusion criteria for subjects with severe hepatic impairment included as those subjects will be included into 
the study according to Amendment 1
3 Study design revised as subjects with severe hepatic impairment will be included into the study according to 
Amendment 1


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Type of control
Uncontrolled
Number of subjects4
Up to 44 evaluable male and female subjects with 8-22 evaluable subjects 
in the control group, 8 evaluable subjects each in the moderate hepatic
impairment and in the severe renal impairment investigational group, and 
6 evaluable subjects in the severe hepatic impairment investigational group.
A minimum of 30 subjects (8/group except for severe hepatic impairment: 
6) valid for PK of copanlisib (i.e., all blood samples for PK should be 
available up to 1 week [168 h]) will be required. Additional healthy 
subjects may be enrolled to achieve demographic matching between 
healthy and impaired groups until up to 22 healthy subjects valid for PK of 
copanlisib (i.e., up to 1 week [168 h]).
Primary variables
Cmax, AUC and AUC(0-168) of copanlisib in plasma
Time point/frame of 
measurement for primary 
variables
Blood samples for PK will be collected before start of infusion as well as at 
10 min and 1 h (end of infusion), 1.5, 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120 and 
168 h after start of infusion.
Plan for statistical analysis
To investigate the primary objective of this study regarding hepatic and 
renal impairment, analysis of variance appropriate for a parallel design will 
be fitted to the natural logarithmic transformation of PK parameters 
(AUC(0-168), AUC and Cmax) of copanlisib. The test/reference comparison 
ratio of geometric least-squares means and associated 90% confidence 
intervals (CIs) for each PK parameter in the moderate hepatic, severe 
hepatic5 or severe renal impairment group versus the respectively matched 
healthy subject group will be calculated by exponentiation of the natural-
log scale point estimate and the associated 90% CI.
                                                
4 Number of subjects revised as subjects with severe hepatic impairment will be included into the study 
according to Amendment 1
5 Included as subjects with severe hepatic impairment will be included into the study according to Amendment 1


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Table of contents
Cover page of the integrated protocol.................................................................................... 1
1.
Title page............................................................................................................................ 2
Signature of the sponsor’s medically responsible person..................................................... 3
Signature of coordinating investigator................................................................................... 4
2.
Synopsis - amended........................................................................................................... 5
Table of contents....................................................................................................................... 8
Table of tables......................................................................................................................... 10
Table of figures....................................................................................................................... 11
List of abbreviations – amended........................................................................................... 12
3.
Introduction - amended .................................................................................................. 17
4.
Study objectives - amended............................................................................................ 21
5.
Study design - amended.................................................................................................. 22
6.
Study population ............................................................................................................. 24
Inclusion criteria ............................................................................................................ 24
6.1
6.1.1
All subjects ................................................................................................................. 24
6.1.2
Subjects in the control group: healthy subjects .......................................................... 25
6.1.3
Subjects in Group A: moderate hepatic impairment (Child-Pugh B)......................... 25
6.1.4
Subjects in Group B: severe renal impairment........................................................... 25
6.1.5
Subjects in Group C: severe hepatic impairment - amended...................................... 26
Exclusion criteria ........................................................................................................... 26
6.2
6.2.1
All subjects - amended ............................................................................................... 26
6.2.2
Subjects in the control group: healthy subjects .......................................................... 28
6.2.3
Subjects in Group A: moderate hepatic impairment (Child-Pugh B)......................... 29
6.2.4
Subjects in Group B: severe renal impairment........................................................... 30
6.2.5
Subjects in Group C: severe hepatic impairment - amended...................................... 30
Justification of selection criteria.................................................................................... 31
6.3
Withdrawal of subjects from study................................................................................ 31
6.4
6.4.1
Withdrawal ................................................................................................................. 31
6.4.2
Replacement - amended.............................................................................................. 33
Subject identification - amended ................................................................................... 33
6.5
7.
Treatments....................................................................................................................... 33
Treatments to be administered - amended ..................................................................... 33
7.1
Identity of study treatment – amended .......................................................................... 34
7.2
Treatment assignment - amended .................................................................................. 34
7.3
Dosage and administration............................................................................................. 35
7.4
7.4.1
Selection of doses in the study - amended.................................................................. 35


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7.4.2
Selection and timing of dose for each subject............................................................ 36
Blinding ......................................................................................................................... 36
7.5
Drug logistics and accountability - amended................................................................. 36
7.6
Treatment compliance.................................................................................................... 37
7.7
8.
Non-study therapy........................................................................................................... 37
Prior and concomitant therapy....................................................................................... 37
8.1
Post-study therapy.......................................................................................................... 37
8.2
9.
Procedures and variables ............................................................................................... 37
Tabular schedule of evaluations .................................................................................... 37
9.1
Visit description............................................................................................................. 38
9.2
9.2.1
Screening visit - amended........................................................................................... 38
9.2.2
Pre-dose (Study Day -1, relative time: day -01)......................................................... 39
9.2.3
Randomization............................................................................................................ 40
9.2.4
Treatment period......................................................................................................... 40
9.2.5
Safety follow-up (relative time: day 14 (±3) and day 30 (+3)) .................................. 42
9.2.6
Special conditions during the study............................................................................ 43
Population characteristics .............................................................................................. 44
9.3
9.3.1
Demographic .............................................................................................................. 44
9.3.2
Medical history........................................................................................................... 44
9.3.3
Other baseline characteristics..................................................................................... 45
Efficacy.......................................................................................................................... 45
9.4
Pharmacokinetics / pharmacodynamics......................................................................... 45
9.5
9.5.1
Pharmacokinetics........................................................................................................ 45
9.5.2
Pharmacodynamics..................................................................................................... 47
9.5.3
Pharmacometric analysis............................................................................................ 47
Safety ............................................................................................................................. 47
9.6
9.6.1
Adverse events............................................................................................................ 47
9.6.2
Pregnancies................................................................................................................. 55
9.6.3
Safety examinations.................................................................................................... 55
Other procedures and variables...................................................................................... 57
9.7
Appropriateness of procedures / measurements ............................................................ 57
9.8
10. Statistical methods and determination of sample size ................................................. 57
General considerations................................................................................................... 57
10.1
Analysis sets .................................................................................................................. 58
10.2
Variables and planned statistical analyses - amended ................................................... 58
10.3
Determination of sample size - amended....................................................................... 60
10.4
Planned interim analyses - amended.............................................................................. 61
10.5
11. Data handling and quality assurance............................................................................ 61
Data recording................................................................................................................ 61
11.1
Monitoring ..................................................................................................................... 63
11.2
Data processing.............................................................................................................. 63
11.3
Missing data................................................................................................................... 64
11.4
Audit and inspection ...................................................................................................... 64
11.5


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Archiving ....................................................................................................................... 64
11.6
12. Premature termination of the study .............................................................................. 64
13. Ethical and legal aspects................................................................................................. 65
Investigator(s) and other study personnel...................................................................... 65
13.1
Funding and financial disclosure ................................................................................... 66
13.2
Ethical and legal conduct of the study........................................................................... 66
13.3
Subject information and consent.................................................................................... 67
13.4
Publication policy and use of data ................................................................................. 68
13.5
Compensation for health damage of subjects / insurance.............................................. 68
13.6
Confidentiality ............................................................................................................... 68
13.7
14. Reference list.................................................................................................................... 69
15. Protocol amendments...................................................................................................... 69
Amendment 1................................................................................................................. 69
15.1
15.1.1
Overview of changes to the study............................................................................... 69
15.1.2
Changes to the protocol text....................................................................................... 71
16. Appendices....................................................................................................................... 95
Study flow chart - amended........................................................................................... 95
16.1
Laboratory analyses - amended ..................................................................................... 99
16.2
Assessment of hepatic impairment - amended ............................................................ 101
16.3
Assessment of renal impairment.................................................................................. 102
16.4
Estimation of glomerular filtration rate (eGFR) using modification of diet in renal 
16.5
disease.......................................................................................................................... 102
Estimated creatinine clearance (CLcr) using Cockcroft-Gault (C-G) equation........... 102
16.6
Number connection test at screening........................................................................... 103
16.7
List of CYP3A4 inhibitors and inducers for reference. Only STRONG CYP3A4 
16.8
inhibitors and inducers are not allowed in this study................................................... 105
NYHA classification.................................................................................................... 108
16.9
Table of tables
Table 5-1: Groups - amended................................................................................................... 22
Table 7-1: Treatments administered - amended....................................................................... 33
Table 7-2: Identity of copanlisib – amended............................................................................ 34
Table 9-1: Restrictions during the study - amended ................................................................ 43
Table 9-2: Food and drink before and after dosing.................................................................. 43
Table 10-1: 90% Confidence interval for copanlisib with N=8 per group - amended............. 60
Table 10-2: 90% Confidence interval for copanlisib with N=6 per group - amended............. 61
Table 16-1: Study flow chart: Screening (all subjects) (continued) - amended....................... 96
Table 16-2: Parameters of laboratory analyses - amended .................................................... 100
Table 16-3: Child Pugh system .............................................................................................. 101
Table 16-4: Stages of chronic kidney diseasea....................................................................... 102
Table 16-5: CYP3A4 inhibitors ............................................................................................. 105


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Table 16-6: CYP3A4 inducers ............................................................................................... 107
Table 16-7: NYHA classification........................................................................................... 108
Table of figures
Figure 3-1: The distinct classes of mammalian PI3Ks.  From Nature Reviews Molecular Cell 
Biology 13, 195-203, 2012.................................................................................... 17


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List of abbreviations – amended
AUC(tlast-)
percentage of AUC from the last data point > LLOQ to infinity
AE
adverse event
AE,ur
amount excreted into urine from 0 to infinity
AE,ur(0-24)
amount excreted into urine from 0 to 24h
AKT
protein kinase B
ALT
alanine aminotransferase
anti HCV
Hepatitis C virus antibody
Anti-HCV
hepatitis C virus antibodies
AP
alkaline phosphatase
AST
aspartate aminotransferase
AUC
area under the concentration vs. time curve from zero to infinity after 
single dose
AUC(0-168)
AUC from time 0 to 168h
AUC(0-168)u
AUC of unbound drug (not protein-bound) from time 0 to 168h
AUC(0-tlast)
AUC from time 0 to the last data point > LLOQ
AUCu
area under the concentration vs. time curve of unbound drug (not 
protein-bound) from zero to infinity after single dose
BCRP
breast cancer resistance protein
BMI
body mass index: weight [kg] / (height [m])²
BPM
beats per minute
C-G
Cockcroft-Gault
CI
confidence interval
CK
creatine phosphokinase
CKD
Chronic Kidney Disease
CL
total body clearance of drug from measured matrix (volume/time) or 
(volume/time/body weight) calculated after intravenous administration
Clast
last observed concentration value above lower limit of quantitation
CLcr
creatinine clearance
CLR
renal body clearance of drug
Cmax
maximum observed drug concentration in measured matrix after single 
dose administration


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Cmax,u
maximum observed concentration of unbound drug (not protein-bound 
or free) in measured matrix after single dose administration
CR
complete response
CRF
case report form
CRO
contract research organization
CTCAE
common terminology criteria for AEs
CV
coefficient of variation
CYP
cytochrome P450
DDI
drug-drug interaction
DLBCL
diffuse large Bcell lymphoma
e.g.
exempli gratia (for example)
ECG
electrocardiogram
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
EoI
End of infusion
ePRO
electronic subject-reported outcome
E2
estradiol6
EU
European Union
EudraCT
EU data repository for clinical trials
F
absolute bioavailability of drug administered via the extravascular 
route 
FDA
Food and Drug Administration
FL
follicular lymphoma
FU
follow-up
GCP
good clinical practice
GGT
gamma glutamyl transpeptidase
GMP
good manufacturing practice
h
hour
HbA1c
glycated hemoglobin
                                                
6 Presentation revised (in protocol Version 1.0 “estradiol” was shown in the left column and “E2” in the right 
column)


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HBsAg
Hepatitis B surface antigene
HCT
hematopoietic cell transplant
HCV
hepatitis C virus
HIV
human immunodeficiency virus
i.e.
id est (that is)
i.v.
intravenous
IB
investigator’s brochure
IC50
half maximal inhibitory concentration
ICH
International Conference on Harmonization
IEC
independent ethics committee
INR
international normalized ratio (reagent-independent prothrombin ratio)
IRB
institutional review board
K/DOQI
Kidney Disease Outcomes Quality Initiative
kg
kilogram
L
liter
LDH
lactate dehydrogenase
LLOQ
lower limit of quantitation
LSLV
last subject last visit
M-1
metabolite M-1
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MDRD
modification of diet in renal disease
MedDRA
medical dictionary for regulatory activities
mg
milligram
min
minute
mL
milliliter
mmHg
millimeter of mercury
msec
millisecond
mTOR
mammalian target of rapamycin
NCI
National Cancer Institute


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NCT
number connection test
NHL
non-Hodgkin’s lymphoma
nM
nanomolar
OTC
over-the-counter
PBPK
physiologically based pharmacokinetics 
P-gp
permeability glycoprotein
pH
Pondus hydrogenii (log of the ion concentration)
PI3K
phosphatidylinositol 3-kinase
PIP3
phosphoinositol-3-phosphate
PK
pharmacokinetics
PKS
PK analysis set
popPK
population PK
PR
PR interval in ECG
PT
preferred term
QA
Quality Assurance
QC
quality control
QT
QT interval in ECG
QTcB
QT interval frequency-corrected according to Bazett’s formula
QTcF
QT interval frequency-corrected according to Fridericia’s formula
Rend
last time point for λz calculation
Rstart
first time point for λz calculation
SAE
serious adverse event
SAF
safety analysis set
SAS
Statistical Analysis System
SD
standard deviation
sec
second
SNR
screening number
SoI
Start of infusion
SUSAR
suspected unexpected serious adverse reaction
T1
tumor invades lamina propria
t1/2
half-life associated with the terminal slope


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Ta
non-invasive tumor
TEAE
treatment-emergent adverse event
Tis
carcinoma in situ
tlast
time of last observed concentration value above lower limit of 
quantitation
tmax
time to reach Cmax (in case of two identical Cmax values, the first tmax
will be used)
u
unbound (i.e. based on free / not protein bound concentration) (used as 
index for other parameters)
ULN
upper limit of norm (upper limit of normal laboratory values)
Vz
volume of distribution during terminal phase after intravascular 
administration
WBC
white blood cell (count)


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3.
Introduction - amended
Background
The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of 
rapamycin (mTOR) pathway is one of the prominent pathways that promote cellular survival 
and is constitutively activated in many types of cancer. Class I PI3K receptor is downstream 
of most cancer associated tyrosine kinase growth factor receptors. PI3K inhibitors are 
expected to be effective not only in PI3K pathway-driven tumors but also in combination with 
other chemotherapy agents. Four PI3K isoforms (PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ) are 
categorized as class I enzymes (Figure 3-1) because they can use phosphatidylinositol-4, 5-
bisphosphate as a substrate to generate phosphoinositol-3-phosphate (PIP3). Elevated PIP3 in 
cellular membranes drives several hallmarks of the cancer phenotype: cell proliferation, 
survival, metabolic reprogramming, and migration. PI3Kα and PI3Kβ are ubiquitous, while 
PI3Kγ and PI3Kδ are expressed mostly in the hematopoietic tissue.
Figure 3-1: The distinct classes of mammalian PI3Ks. 
From Nature Reviews Molecular Cell Biology 13, 195-203, 2012
Copanlisib (BAY 80-69467, approved by the Food and Drug Administration [FDA] in 
September 20178) is a novel, highly selective, -panclass- PI3K inhibitor with potent activity 
against both and isoforms, with in vitro IC50 of 0.5 nM and 0.7 nM, respectively. This 
PI3K inhibitor is being developed for the treatment of advanced and refractory malignancies 
either as a single agent or in combination with other investigational agents. Copanlisib is the 
active ingredient (free base) of BAY 84-1236, the dihydrochloride salt, which for clinical use 
is formulated as an intravenous (i.v.) drug product solution.
                                                
7 “BAY 806946” replaced by “BAY 80-6946” according to Amendment 1
8 Included according to Amendment 1


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Previous experience in humans
Safety and efficacy
Copanlisib is currently investigated in multiple trials enrolling cancer subjects. As of today, 
approximately 675 subjects with advanced cancer have been treated with copanlisib in eight
different Phase 1 studies, three Phase 2 studies and three Phase 3 studies as a single agent or 
in combination with other agents [1]. 
As a single agent, 0.8 mg/kg [Study 12871 dose escalation: 0.1, 0.2, 0.4, 0.8 and 1.2 mg/kg] 
of copanlisib is the maximum tolerated dose in nondiabetic subjects given i.v. in a 3 weeks 
on/1 week off schedule (total dose should not exceed 65 mg, in order to control copanlisib 
exposure in overweight subjects).
The dose limiting toxicity was serious left ventricular systolic dysfunction following the 
copanlisib dose of 1.2 mg/kg (~ absolute dose 93mg) The recommended (Phase 2) dose of 
monotherapy with copanlisib is 60 mg given i.v. over 1 h weekly for the first 3 weeks (on 
Days 1, 8, and 15) of a 28-day cycle, followed by a 1-week break (3 weeks on/1 week off 
schedule) based on an evaluation of pharmacokinetic and clinical data from ongoing single 
agent studies.
Clinical antitumor activity was observed in subjects of the Phase 1 monotherapy Study 12871 
and in the Phase 2 Study 16349A. In Study 12871 complete response (CR) as best overall 
response was achieved in 3 subjects (5.3%); partial response in 7 subjects (12.3%) and stable 
disease in 15 subjects (26.3%). In the Phase 2 Study 16349 (Part A) overall response rate was 
achieved in 25 subjects (32.9%).
When copanlisib was given as a single agent (Study 12871), the most common drugrelated 
adverse events of all grades that occurred in ≥20% of the 57 subjects (all cohorts) were: 
hyperglycemia (63.2%), nausea (36.8%), and hypertension (21.1%). In the phase 2 Study 
16349(Part A), transient hyperglycemia (64.5%) and hypertension (60.5%) of maximum 
common terminology criteria for adverse events (CTCAE) Grade 3 were the most frequent 
adverse events (AEs) observed following administration of copanlisib. Further AEs occurring 
with an incidence of >20% observed in this study were: fatigue (51.3%), diarrhea (42.1%), 
neutrophil count decreased (35.5%), nausea (34.2%), anemia (30.3%), and oral mucositis 
(23.7%). In the mass balance study, 6 healthy subjects received a single dose of 12 mg 
copanlisib i.v. In this study, 3 out of the 6 subjects (50%) who received treatment had at least 
one TEAE. A total of 5 gastrointestinal TEAEs (MedDRA PT: abdominal pain, nausea, 
flatulence, frequent bowel movements and diarrhea) as well as one event each of myalgia and 
oropharyngeal pain were reported. Of the 6 subjects, 2 subjects (33.3%) experienced TEAEs 
which were assessed as being related to copanlisib. These TEAEs were all of grade 1, and 
included abdominal pain and diarrhea in 1 subject and nausea in another subject. No serious 
or fatal TEAEs were reported in this study and no subject prematurely discontinued the study 
participation due to an AE. No TEAEs of specific interest were defined in this study. No 
clinically relevant changes in laboratory values, vital signs and no abnormal findings in ECG 
were found.


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Pharmacokinetics
Copanlisib demonstrated dose-proportional increases in Cmax and area under the plasma 
concentration vs time curve (AUC) from time zero to 25 h (AUC(0-25)) over the dose range 
of 0.1 to 1.2 mg/kg (absolute dose range: 5 to 93 mg). AUC(0-25) was chosen to assess the 
dose-linearity because plasma concentrations can be measured during that interval in all 
subjects dosed at the lower dose to the higher dose level and the exposure represents more 
than 50% of the AUC covering the 1week dosing interval. Inter-subject variability in 
copanlisib Cmax and AUC(0-25) at 0.8 mg/kg was moderate to high with a %CV of 64.4% for 
Cmax and 38.4% for AUC(0-25) (Study 12871). Copanlisib has a large volume of distribution 
of 838 L (range: 437-2150 L) and a reversible-free fraction plasma protein binding of 15.8%.
Albumin was the main binding protein. The blood-to-plasma ratio was approximately 1.7. 
The geometric mean halflife (t1/2) of the terminal phase of copanlisib elimination was 38.2 h 
(% coefficient of variation [%CV]: 42.5%, range: 16.9 - 72.7 h). The geometric mean 
population systemic clearance was 15.2 L/h (range: 7.85 - 27.9, %CV: 42.1%) (Study 12871). 
No accumulation or time-dependency in the PK of copanlisib was observed.
A population PK analysis revealed no impact of either body weight, body surface area, or 
other body size-related factors on the clearance of copanlisib which was the basis to switch to 
a fixed-dose regimen of copanlisib.
A human mass balance study in healthy subjects (Study 16353) was conducted with a single 
i.v. dose of 12 mg [14C] copanlisib in six healthy subjects. Approximately 86% of the 
administered dose was recovered, with 64% in feces and 22% in urine within a collection 
interval of 20 to 34 days. Unchanged copanlisib represented approximately 30% of the 
administered dose in feces and 15% in urine, respectively. Metabolites resulting from 
oxidation metabolism accounted for 41% of the administered dose. Metabolite M-1 
(morpholinone derivative) was the only relevant circulating metabolite in human plasma. The 
ratio M-1/total radioactivity was less than 5 % in human plasma. Conclusively, M-1 is 
considered as a minor metabolite according to ICH M3.
Copanlisib is excreted as unchanged compound and metabolites (about 50:50) in human.
Metabolism of copanlisib is mediated by cytochrome P450 CYP3A4 (> 90%) and to a minor 
extent by CYP1A1 (< 10%). Therefore, a low DDI potential due to several clearance 
pathways is anticipated. 
Further details can be found in the latest available version of the investigator's brochure 
(IB) [1], which contains comprehensive information on the study drug.
Rationale of the study
Liver infiltration in subjects with advanced malignancies including non-Hodgkin’s lymphoma 
(NHL) is common, and various degree of hepatic dysfunction may occur in the later stages of 
malignancy [2]. 
Renal failure in cancer subjects is often multifactorial including renal parenchymal invasion, 
tumor lysis syndrome, glomerular diseases, chemotherapy associated thrombocytic 
microangiopathy or hematopoietic cell transplant (HCT)-associated renal failure [3]. 


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Metabolism of copanlisib is primarily mediated by the CYP3A4 isozyme. Co-administration 
of copanlisib at 12 mg and 60 mg with the potent inhibitor of CYP3A4 itraconazole resulted 
in an increased copanlisib AUC by 1.41-fold and 1.53-fold, respectively, with no effect on the 
Cmax at both doses [1]. A human mass balance study (Study 16353) indicates the elimination of 
copanlisib is primarily via feces with 64% in feces and 22% in urine within a collection 
interval of 20 to 34 days. Based on the population PK (popPK) analysis, mild hepatic 
impairment, mild and moderate renal impairment had no significant effect on copansilib 
clearance (CL). The PK of copanlisib has not been studied in moderate and severe hepatic 
impairment and severe renal impairment. 
This study will evaluate the PK and safety of a single 12-mg dose of copanlisib in subjects 
with moderate or severe9 hepatic impairment or severe renal impairment of copanlisib and in 
age-, gender-, and weight-matched healthy controls. The results of this study will provide 
guidance for drug labeling recommendations for copanlisib in these subjects.
Benefit-risk assessment
As of today approximately 675 subjects with advanced cancer have been treated with 
copanlisib (BAY 80-694610) in eight different Phase 1 studies, three Phase 2 studies and 
three Phase 3 studies. In addition to these, a mass balance study was conducted in healthy 
subjects (Study 16353): 6 healthy male subjects were treated with a single i.v. administration 
of 12 mg [14C] copanlisib. For this class of drug, the following AEs are expected based on its 
mechanism of action: hyperglycemia, hypertension, nausea, vomiting and diarrhea.
Even if the probability that these TEAEs occur is very low after a single dose of 12 mg 
copanlisib, the monitoring and treatment of adverse events will ensure that subjects will not 
be exposed to undue risk and the inclusion and exclusion criteria will ensure that subjects who 
might be predisposed to higher risk of drug-related TEAEs are either excluded or identified 
and treated with caution.
The toxicologic and safety-pharmacologic investigations identified the need for monitoring 
cardiovascular, hepatic, renal and metabolic functions during early studies in humans. 
Practically, this will be addressed in this study through repeated physical examinations 
including check of vital signs, ECGs, monitoring of clinical chemistry laboratory including 
close monitoring of glucose especially within the next hours after the infusion. 
Because of changes in the reproductive system and adverse effects on development, including 
embryo-lethality and teratogenicity, women of childbearing potential and men must agree to 
use adequate contraception from signing of the informed consent form until at least 3 months 
after dosing. The investigator or a designated associate is requested to advise the subject how 
to achieve an adequate contraception. Adequate contraception is defined for this study as any 
medically recommended method (or combination of methods) consistent with standard of care. 
                                                
9 Included as subjects with severe hepatic impairment will be included into the study according to Amendment 1
10 “BAY 806946” replaced by “BAY 80-6946” according to Amendment 1


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An adequate contraception includes a hormonal contraception with implants or combined oral, 
transdermal, or injectable contraceptives, certain intrauterine devices, bilateral tubal ligation 
or oophorectomy, hysterectomy, or vasectomy of the partner. In addition, the use of condoms 
for subjects or their partners is required unless the woman is postmenopausal or permanently 
sterilized (hysterectomy, bilateral oophorectomy).
No direct benefit is to be expected for the study subjects since they have no malignancies 
susceptible to respond to copanlisib. However, the benefit of this trial will be to get further 
information on copanlisib in regards to PK and safety in this specific population: copanlisib is 
supposed to be used for the treatment of subjects with advanced cancer who are at high risk of 
liver and/or renal injury due to the cancer dissemination and exposure to cytotoxic systemic 
anticancer therapy. Therefore, this information will be important for the safety of the cancer 
subjects with hepatic or renal impairment treated with this drug in the future (and hence will 
provide recommendation on dose adjustment, if needed). This is also required for approval of 
the drug by the health authorities. 
4.
Study objectives - amended11
The primary objective of this study is to

Investigate the PK of copanlisib following a single i.v. dose of 12 mg copanlisib in 
subjects with moderate hepatic (Child Pugh B), severe hepatic (Child Pugh C) or 
severe renal impairment compared with healthy subjects
The secondary objective of this study is to

Evaluate the PK of M-1 metabolite

Assess the safety and tolerability of copanlisib when administered to subjects with 
moderate hepatic, severe hepatic or severe renal impairment
The exploratory objectives are to explore the relationship between PK and hepatic and renal 
function parameters:

Hepatic: Relationship between PK parameters of copanlisib AUC(0-168), AUC, Cmax, 
AUC(0-168)u, AUCu and Cmax,u and baseline hepatic function parameters (Child-Pugh 
Score, total bilirubin, prothrombin time, alpha 1-acid glycoprotein and albumin)

Renal: Relationship between PK parameters of copanlisib AUC(0-168), AUC, Cmax, 
AUC(0-168)u, AUCu and Cmax,u and eGFR (MDRD formula) and estimated creatinine 
clearance (Cockcroft-Gault formula)
                                                
11 Objectives revised as subjects with severe hepatic impairment will be included into the study according to 
Amendment 1


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5.
Study design - amended
Design overview12
This will be a multi-center, non-randomized, open-label, single-dose, parallel group, study 
consisting of 4 groups. The effect of moderate hepatic impairment (Child Pugh B), severe 
hepatic impairment (Child Pugh C) and severe renal impairment on the PK of copanlisib and 
M-1 will be investigated. In total, up to 44 evaluable male and female subjects with 
8-22 evaluable subjects in the control group, 8 evaluable subjects each in the moderate hepatic 
and severe renal impairment investigational group, and 6 evaluable subjects in the severe 
hepatic investigational group will participate in the study (Table 5-1). Each subject will be 
administered 12 mg of copanlisib (i.v. over 1 h). 
Table 5-1: Groups - amended
Group
Description
Number of evaluable subjects
Control group
Normal hepatic and renal function group 
matched to the groups of hepatic and 
renal impairment
8-22
Group A
Moderate hepatic impairment group: 
Child-Pugh B (score 7-9) at the screening 
visit
8 
Group B
Severe renal impairment group:
eGFR 15-29 mL/min/1.73 m2 at the 
screening visit based on the Modification 
of Diet in Renal Disease (MDRD) 
equation
8 
Group C
Severe hepatic impairment group: 
Child-Pugh C (score 10-15) at the 
screening visit
6
The control group (normal hepatic and renal function) should match with the groups of 
hepatic and renal impairment. Matching criteria will be age, body weight, and gender. Mean 
age and body weight between the control group and the groups with hepatic and renal 
impairment should not vary by more than ±10 years and ±10 kg. Therefore, enrollment in the 
control group will remain open until the enrollment in the moderate and severe hepatic and 
severe renal impairment groups is complete and a sufficient number of matching controls 
have been achieved for comparison. 
In all groups, the complete study is divided into several sections: screening, pre-dose, 
treatment period, end-of-treatment visit, and safety FU (telephone interview). Screening starts 
with the subject’s signature on the informed consent form and ends with the eligibility for 
pre-dose assessment.
                                                
12 Study design revised as subjects with severe hepatic impairment will be included into the study according to 
Amendment 1


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The in- / exclusion criteria will be finally checked after the results of the safety laboratory
from the morning of Day -1 are available (evening of Day -1/morning of the dosing day).13
During the treatment phase the study objectives will be followed, and the related measures 
will be performed. The subjects will be monitored for adverse events and concomitant 
medication. All post-treatment examinations will be conducted during end-of-treatment visit 
and safety FUs (for details, see Section 16.1, where the study flowcharts are presented).
Starting from approximately 24 h before until 48 h after dosing (i.e. start of infusion), the 
subjects will stay at the study site (in-house phase of 4 days). 
The total duration of the study will be approximately 7 weeks per subject. 
For time of measurements, blood samplings, and activities see study flow chart in 
Section 16.1.
Primary variables

Cmax, AUC and AUC(0-168) of copanlisib in plasma
Secondary variables:

Number of subjects with study-drug-related treatment-emergent adverse event (TEAE)
Justification of the design14
This study will investigate the PK of copanlisib and M-1 after administration of 12 mg of 
copanlisib i.v. over 1 h to subjects with moderate hepatic impairment, with severe hepatic 
impairment or subjects with severe renal impairment compared to healthy subjects. The 
choice of the trial design was made based on the following:

The PK measurements are the primary focuses of the study, therefore a non-
randomized, open-label, parallel group design with 4 groups is considered adequate.

The study will be carried out in accordance with FDA guidance [4][5]. 

Enrolling only individuals of an age range similar to the target subject population will 
provide a consistent and homogeneous study population. 
For study objectives please see Section 4.
For justification of study population, see Section 6.3.
For level of blinding, see Section 7.5.
For selection of doses, see Section 7.4.1.
For handling of missing data, see Section 11.4.
                                                
13 Time point of final check of inclusion and exclusion criteria revised according to Amendment 1 (protocol 
Version 1.0 specified in the evening prior to the administration of the study medication)
14 Justification of the design revised as subjects with severe hepatic impairment will be included into the study 
according to Amendment 1


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End of study
The end of the study according to the EU Clinical Trial Directive will be reached when the 
last visit of the last subject (LSLV) for all centers in the respective country has occurred.
As for this study, important data will be collected after last subject last visit (LSLV), the end 
of the study as a whole will be the date when the clean database is available.
Primary completion
The primary completion event for this study is LSLV. 
6.
Study population
Inclusion criteria
6.1
Subjects must fulfill all of the following criteria before receiving the study medication:
6.1.1
All subjects
1. Written informed consent obtained, dated and signed prior to any screening 
procedures
2. Male or female subjects aged 18 to 80 years at the first screening visit
3. Women must have a negative pregnancy test (in blood or urine) within 7 days prior to 
the dose of study drug or be surgically or biologically sterile or postmenopausal. 
Postmenopausal women are defined as:

Age >50 years with amenorrhea for at least 12 months or

Age ≤50 years with 6 months of spontaneous amenorrhea and follicle stimulating 
hormone level within postmenopausal range (>40 mI U/mL) or

Permanently sterilized women (hysterectomy, bilateral oophorectomy)
4. Women and men of reproductive potential must agree to use adequate contraception 
when sexually active. This applies for the time period between signing of the informed 
consent form and at least 3 months after administration of the study medication. The 
investigator or a designated associate is requested to advise the subject how to achieve 
an adequate contraception. Adequate contraception is defined for this study as any 
medically recommended method (or combination of methods) consistent with standard 
of care. An adequate contraception includes a hormonal contraception with implants 
or combined oral, transdermal, or injectable contraceptives, certain intrauterine 
devices, bilateral tubal ligation or oophorectomy, hysterectomy, or vasectomy of the 
partner. In addition, the use of condoms for subjects or their partners is required unless 
the woman is postmenopausal or permanently sterilized (hysterectomy, bilateral 
oophorectomy).
5. Men agree to refrain from sperm donation during the whole study (starting after 
informed consent) and for at least 3 months after the end of treatment with copanlisib.


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6. Body Mass Index (BMI): above 18.0 and below 34.0 kg / m² with a body weight of 
above or equal 50 kg at the first screening visit.
7. Subject must be willing to comply with dietary and fluid restriction from Day -1 to the 
end-of-treatment visit. 
8. Subjects must have venous access sufficient to allow blood sampling as required by 
the protocol.
9. Subject must be willing to undergo multiple blood draws as required by the protocol.
10. Results of alcohol tests are negative at screening and on Day -1.
6.1.2
Subjects in the control group: healthy subjects
11. Healthy subjects as determined by absence of clinically significant deviation from 
normal in medical history, physical examination, vital signs, electrocardiograms, and 
clinical laboratory determinations.
12. eGFR ≥90 mL/min/1.73 m2 (according to MDRD formula, see Section 16.5).
13. Adequate liver function as defined by:

Total bilirubin and international normalized ratio (INR) lower or equal to 1.5x 
upper limit of normal (≤ 1.5 ULN)

Alkaline phosphatase (AP) ≤1.5 ULN, alanine aminotransferase (ALT) ≤1.5 ULN, 
aspartate aminotransferase (AST) ≤1.5 ULN
6.1.3
Subjects in Group A: moderate hepatic impairment (Child-Pugh B)
14. Subjects with confirmed liver cirrhosis by at least one of the following criteria:

Histologically by prior liver biopsy showing cirrhosis.

Liver imaging (computer tomography, and/or ultrasound and/or magnetic 
resonance imaging scans, and/or fibroscan).

Laparoscopy.
15. Child-Pugh Clinical Assessment Score 7 to 9 at screening (see Section 16.3).
16. Subjects with stable liver disease: no acute decompensation (hemorrhage, 
encephalopathy, new onset ascites) in the last 2 months. 
17. Subjects with active Hepatitis B or hepatitis C virus (HCV) can be included into the 
study but only in stable condition without ongoing or indicator of immediate antiviral 
treatment. 
18. History of alcohol abuse is permissible providing that the results of alcohol test are 
negative at screening and on Day -1. 
6.1.4
Subjects in Group B: severe renal impairment
19. Subjects with severe renal impairment defined as an eGFR 15 - 29 mL/min/1.73 m2
(according to MDRD formula, see Section 16.5)


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20. Subjects with stable renal disease: no significant change in renal function as evidenced 
by serum creatinine value within ±25% from the last determination, obtained within at 
least 3 months before study entry and the absence of the need to start dialysis in the 
next 3 months.
21. Stable treatment regimen for renal impairment for at least 14 days prior to treatment 
start. Diuretics are allowed when needed.
6.1.5
Subjects in Group C: severe hepatic impairment - amended15
22. Subjects with confirmed liver cirrhosis by at least one of the following criteria:

Histologically by prior liver biopsy showing cirrhosis.

Liver imaging (computer tomography, and/or ultrasound and/or magnetic 
resonance imaging scans, and/or fibroscan).

Laparoscopy.
23. Child-Pugh Clinical Assessment Score 10 to 15 at screening (see Section 16.3). For 
subjects with hepatic encephalopathy, the condition does not, in the investigator's 
opinion, interfere with the participant's ability to provide an appropriate informed 
consent.
24. Subjects with active Hepatitis B or Hepatitis C virus (HCV) can be included into the 
study but only in stable condition without ongoing or indicator of immediate antiviral 
treatment.
25. History of alcohol abuse is permissible providing that the results of alcohol test are 
negative at screening and on Day -1.
Exclusion criteria
6.2
Subjects are to be excluded from the study if they display any of the following criteria:
6.2.1
All subjects - amended
Medical and surgical history
1. Active coronary artery disease or myocardial infarction within 6 months of study 
entry; unstable angina (angina symptoms at rest) or new-onset angina or congestive 
heart failure of grade III-IV according to New York Heart Association (NYHA) within 
3 months of study entry.
2. Immuno-compromised subjects including known history/seropositivity of human 
immunodeficiency virus (HIV).
3. Other concurrent severe and/or uncontrolled medical conditions (e.g. current diagnosis 
of type 1 or type 2 diabetes mellitus with HbA1c >8.5%) that could cause 
unacceptable safety risks or compromise compliance with protocol.
                                                
15 Inclusion criteria for subjects with severe hepatic impairment included as those subjects will be included into 
the study according to Amendment 1


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4. Previous or concurrent history of malignancies within 5 years prior to study treatment 
except for curatively treated cervical cancer in situ, non-melanoma skin cancer, 
superficial bladder cancer (Ta [non-invasive tumor], Tis [carcinoma in situ] and T1 
[tumor invades lamina propria]) as well as localized prostate cancer.
5. Known or suspected allergy or hypersensitivity to copanlisib.
6. Significant illness within 1 week prior to dosing (e.g. fever).
7. Known severe allergies (e.g. allergies to more than 3 allergens, allergies affecting the 
lower respiratory tract – allergic asthma, allergies requiring therapy with 
corticosteroids).
8. Uncontrolled hypertension despite optimal medical management (per investigator’s 
assessment). 
9. Arterial or venous thrombotic or embolic events such as cerebrovascular accident 
(including transient ischemic attacks), deep vein thrombosis or pulmonary embolism 
within 6 months before the start of study medication. 
10. Active, clinically serious infections.
11. History or concurrent condition of interstitial lung disease of any severity and/or 
severely impaired lung functions (as judged by the investigator).
12. Subjects with evidence or history of bleeding diathesis. Any hemorrhage or moderate 
bleeding event within 4 weeks of start of study medication.
Medication, drug use and special behavioral pattern
13. Administration of strong CYP3A4 inhibitors or inducers within 2 weeks prior to 
dosing until 7 days after dosing (A list of these medications can be found in 
Section 16.8 of the protocol. However, this list may not be comprehensive); the label 
of the respective co-medications should therefore be checked).
14. Use of immunosuppressive drugs.
15. Administration of medications that prolong the QT interval within 2 weeks prior to 
dosing and during the study (A list of agents that prolong the QT interval can be found 
at https://crediblemeds.org/healthcare-providers/. However, this list may not be 
comprehensive); the label of the respective co-medications should therefore be 
checked).
16. Intake of foods or beverages containing grapefruit, pomelo or Seville oranges within 
7 days before study drug administration and 7 days thereafter. The juices and products 
containing these fruits must also be avoided.
17. Regular daily consumption of more than 1 L of methylxanthine-containing beverages.
18. Unable to abstain from alcohol and methylxanthine-containing beverages or food 
(coffee, tea, cola, chocolate, “powerdrinks”) from 48 h prior to dosing of study drug 
until Day 7.
19. Subjects with known drug abuse within 1 month prior to dosing or evidence of such 
abuse as indicated by the laboratory assays conducted during the screening or baseline 
evaluations.
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Electrocardiogram (ECG)
21. Abnormal finding in the 12-lead electrocardiogram (ECG), such as QTcF (Fridericia 
correction) interval over 500 msec, or any other finding that increases the risk 
associated with study participation, as judged by the investigator.
Laboratory examination
22. Neutrophils <1500/μL16 at inclusion.
23. Positive urine drug screening at screening and Day -1.
Other exclusion criteria
24. Previous assignment to treatment during this study.
25. Close affiliation with the investigational site; e.g. a close relative of the investigator, 
dependent person (e.g. employee or student of the investigational site).
26. Criteria which in the opinion of the investigator preclude participation for scientific 
reasons, for reasons of compliance, or for reasons of the subject’s safety.
27. Inability to understand the protocol requirements, instructions and study related 
restrictions, the nature, scope, and possible consequences of the study.
28. Subject is in custody by order of an authority or a court of law. 
29. Use of investigational drugs (i.e. participation in any clinical investigation) within 
30 days prior to dosing or longer if required by local regulation, or within 5-half-lives 
of the investigational agent taken (whichever is longer).
6.2.2
Subjects in the control group: healthy subjects
Medical and surgical history
30. Incompletely cured pre-existing diseases for which it can be assumed that the 
absorption, distribution, metabolism, elimination, and effects of the study drugs will 
not be normal.
31. A history of relevant diseases of vital organs, the central nervous system, or other 
organs.
Medication, drug use and special behavioral pattern
32. Regular use of recreational drugs, e.g. carnitin products, anabolics, high dose 
vitamins. 
33. Use of any prescription drug or over-the-counter (OTC) medication within 2 weeks or 
5-half-lives prior to dosing (whichever is longer), except for acetaminophen within 
7 days before dosing. 
                                                
16 “<1000 μL” replaced by “<1500 μL” according to Amendment 1


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Physical examination
34. Clinically relevant findings in the physical examination as judged by the Investigator.
Laboratory examination
35. Positive results for hepatitis B virus surface antigen (HBsAg), hepatitis C virus 
antibodies (anti-HCV).
36. Clinically relevant deviations of the screened laboratory parameters from reference 
ranges at screening or before study drug administration according to the opinion of the 
investigator. 
6.2.3
Subjects in Group A: moderate hepatic impairment (Child-Pugh B)
Medical and surgical history
37. Symptoms or history of encephalopathy (Grade III or worse, time needed in the 
number connection test exceeds 80 sec) within 2 months prior to dosing. (For number 
connection test, please see Section 16.7).
38. Clinical evidence of severe ascites more than 6 L by ultrasound.
39. Subjects with primary and secondary biliary cirrhosis. 
40. Subjects with sclerosing cholangitis. 
41. Failure of any other major organ other than the liver; severe infection, or any clinically 
significant illness within 4 weeks prior to study drug administration. 
42. Renal failure with an eGFR <35 mL/min/1.73 m2 (according to MDRD formula, see 
Section 16.5).
Medication, drug use and special behavioral pattern
43. Subjects with a change of their chronic medication less than 4 weeks prior to study 
drug administration. 
Laboratory examination
44. INR >2.5 or prothrombin time more than 6 sec prolonged.
45. Any evidence of progressive liver disease (within the last 4 weeks) as indicated by 
liver transaminases (>4 x ULN), alkaline phosphatase (>4 x ULN), and gamma 
glutamyl transpeptidase (GGT) (>4 x ULN) (an isolated elevation of GGT above 
4 times ULN will not exclude the subject).
46. Serum albumin <20 g/L. 
47. Hemoglobin <8 g/dL. 
48. Platelet count <50 x 109/L. 
49. Clinically relevant deviations of the other screened laboratory parameters from 
reference ranges at screening or before study drug administration according to the 
opinion of the investigator. 


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6.2.4
Subjects in Group B: severe renal impairment
Medical and surgical history
50. Acute renal failure at study entry. 
51. Acute nephritis at study entry.
52. Nephrotic syndrome. 
53. Acute hepatorenal syndrome. 
54. History of renal transplant. 
55. Failure of any other major organ other than the kidney. 
56. Severe infection or any clinically significant illness within 4 weeks prior to study drug 
administration.
Medication, drug use and special behavioral pattern
57. Imminent renal replacement therapy (i.e., during the trial period).
Laboratory examination
58. Positive results for HBsAg, anti-HCV.
59. Platelet count <50 x 109/L. 
60. Hemoglobin < 8 g/dL. 
61. Serum albumin < 20 g/L. 
62. Aspartate aminotransferase (AST) or ALT in conjunction with GGT ≥4 times the 
ULN (an isolated elevation of GGT above 4 times ULN will not exclude the subject). 
63. Clinically relevant deviations of the other screened laboratory parameters from 
reference ranges at screening or before study drug administration according to the 
opinion of the investigator. 
6.2.5
Subjects in Group C: severe hepatic impairment - amended17
Medical and surgical history
64. Has active encephalopathy Grade III or IV (time needed in the number connection test 
at screening or admission exceeds 80 sec) within 2 months prior to dosing. (For 
number connection test, please see Section 16.7).
65. Subjects with sclerosing cholangitis. 
66. Failure of any other major organ other than the liver; severe infection, or any clinically 
significant illness within 4 weeks prior to study drug administration. 
                                                
17 Exclusion criteria for subjects with severe hepatic impairment included as those subjects will be included into 
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67. Renal failure with an eGFR <35 mL/min/1.73 m2 (according to MDRD formula, see 
Section 16.5).
68. Clinical evidence of severe ascites more than 6 L by ultrasound.
69. Esophageal variceal bleeding within 3 months prior to dosing.
Medication, drug use and special behavioral pattern
70. Subjects with a change of their chronic medication less than 4 weeks prior to study 
drug administration.
Laboratory examination
71. Any evidence of progressive liver disease (within the last 4 weeks) as indicated by 
liver transaminases (>4 x ULN), alkaline phosphatase (>4 x ULN), and GGT (>4 x 
ULN) (an isolated elevation of GGT above 4 times ULN will not exclude the subject).
72. Serum albumin <20 g/L. 
73. Hemoglobin <8 g/dL.
74. Platelet count <50 x 109/L.
Justification of selection criteria
6.3
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.
Justification of gender selection
Male and female subjects will be included in so far as they meet all the criteria for inclusion 
and do not fulfill any of those for exclusion.  No sex-specific effects of the treatment are 
anticipated.
Withdrawal of subjects from study
6.4
6.4.1
Withdrawal
Withdrawal criteria
Subjects must be withdrawn from the study if any of the following occurs:

At their own request or at the request of their legally acceptable representative. At any 
time during the study and without giving reasons, a subject may decline to participate 
further.  The subject will not suffer any disadvantage as a result.

If, in the investigator's opinion, continuation of the study would be harmful to the 
subject's well-being

At the specific request of the sponsor and in liaison with the investigator (e.g. obvious 
non-compliance, safety concerns).


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
Violation of in- / exclusion criteria: 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.
Depending on the time point of withdrawal, a withdrawn subject is referred to as either 
“screening failure” or “dropout” as specified below:
Screening failure
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 below) is regarded a 
“screening failure”.  
For those subjects who underwent screening procedures and cannot meet eligibility within the 
28day screening period, screening procedures may be repeated within the indicated time 
window before the first dose in case the medical conditions preventing the subject’s initial 
attempt to participate have changed. Re-screening must be performed within 28 days of the 
initial screening and with approval from the sponsor.
In this case, the investigator has to ensure that the repeated general screening procedures do 
not expose the subject to an unjustifiable health risk. In addition, for general re-screening, the 
subject has to be re-consented and sign the informed consent form, even if it was not changed 
after the subject’s previous general screening.
Dropout
A subject who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the subject has already been administered the study drug.
General procedures
In all cases, the reason for withdrawal must be recorded in the CRF and in the subject's 
medical records. 
The subject may object to the generation and processing of post-withdrawal data as specified 
in Section 13.4.
Any subject removed from the trial 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) are 
provided in Section 12 (Premature termination of the study).


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6.4.2
Replacement - amended
Subjects who drop out may be replaced to obtain a minimum of 30 subjects (8/group except 
for severe hepatic impairment: 6) valid for PK of copanlisib (i.e., all blood samples for PK 
should be available up to 1 week [168 h]). Additional healthy subjects may be enrolled to 
achieve demographic matching between healthy and impaired groups in up to 22 healthy 
subjects valid for PK of copanlisib (i.e., up to 1 week [168 h]).18
Subject identification - amended
6.5
At the beginning of screening every subject is given a screening number (9 digit number 
consisting of: Digits 1 to 5 = Unique center number
Digits 6 to 9
= Current subject
number within the center).
In the morning of the dosing day before start of infusion and after assessing the pre-dose 
blood pressure and glucose values19, subjects who meet the entry criteria will be sequentially 
assigned to a unique number in ascending order (treatment number).
7.
Treatments
Treatments to be administered - amended
7.1
All eligible subjects will receive 12 mg of copanlisib i.v. over 1 h. 
The treatments to be administered during the study are displayed in Table 7-1.
Table 7-1: Treatments administered - amended20
Group
Dose of copanlisib / 
route
Frequency of 
administration
No. of evaluable subjects
Control group 
(healthy subjects)
12 mg i.v. over 1 h
Single dose on Day 1
8-22
Group A 
(moderate hepatic 
impairment group)
12 mg i.v. over 1 h
Single dose on Day 1
8
Group B (severe 
renal impairment 
group)
12 mg i.v. over 1 h
Single dose on Day 1
8
Group C (severe 
hepatic 
impairment group)
12 mg i.v. over 1 h
Single dose on Day 1
6
The cumulative dose per subject is 12 mg copanlisib.
                                                
18 Replacement strategy revised as subjects with severe hepatic impairment will be included into the study 
according to Amendment 1
19 Timepoint of treatment assignment revised according to Amendment 1 (protocol Version 1.0 specified in the 
evening of day -1 after final check of inclusion and exclusion criteria)
20 Table revised as subjects with severe hepatic impairment will be included into the study and to clarify that in 
Group B subjects with severe renal impairment will be included according to Amendment 1


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Identity of study treatment – amended
7.2
The details of the study drug are presented in Table 7-2.
Table 7-2: Identity of copanlisib – amended21
Chemical name
2amino-N[7methoxy-8(3morpholin-4ylpropoxy)-2,3dihydroimidazo [1,2-
c]quinazolin-5yl]pyrimidine-5carboxamide dihydrochloride
Substance code number
BAY 80-6946 (free base) 
Appearance
white to slightly yellowish lyophilisate
Formulation
Freeze-dried product containing 78.8 mg BAY 84-1236  (= Copanlisib 
dihydrochloride; equivalent to 68.4 mg copanlisib, free base, 
BAY 80-6946) in a 6 mL injection vial  
Composition
Copanlisib dihydrochloride, citric acid, mannitol, sodium hydroxide
Type of primary packaging
Glass vial for injections (6 mL)
Reconstitution and dilution should be performed under laminar air flow conditions and 
according to separate handling instructions.
Further details can be found in the IB, which contains comprehensive information on the 
study drug.
All study drugs will be labeled according to the requirements of local law and legislation.  
Label text will be approved according to the sponsor’s agreed procedures, and a copy of the 
labels will be made available to the study site upon request.
For all study drugs, a system of numbering in accordance with all requirements of GMP will 
be used, ensuring that each dose of study drug can be traced back to the respective bulk batch 
of the ingredients.  Lists linking all numbering levels will be maintained by the sponsor’s 
clinical supplies QA group. 
A complete record of batch numbers and expiry dates of all study treatment as well as the 
labels will be maintained in the sponsor’s study file.
Treatment assignment - amended
7.3
Before administration of the study drug (after assessing the pre-dose blood pressure and 
glucose values), subjects who meet the entry criteria will be sequentially assigned to a unique 
number in ascending order (“treatment number”). All subjects will receive the same 
treatment. 
Subjects will be assigned to the following treatment numbers:22

Subjects with moderate hepatic impairment (site 
                                                
21 “BAY 806946” replaced by “BAY 80-6946” according to Amendment 1
22 Treatment numbers revised as subjects with severe hepatic impairment will be included into the study and as a 
third study center will recruit subjects according to Amendment 1
PPD


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
Subjects with moderate hepatic impairment (site 

Subjects with severe renal impairment (site 

Subjects with severe renal impairment (site 

Subjects with severe hepatic impairment (site 

Subjects with severe hepatic impairment (site 

Subjects with severe hepatic impairment (site 

Control subjects (site 

Control subjects (site 

Control subjects (site 
Additional numbers will be used in case of replacements being needed; the replacing 
participant will receive the original subject’s treatment number 
 (site 
 or 
 (site 
or 
 (site 
Dosage and administration
7.4
Regarding the selection of dose in this study, refer to Section 7.4.1.
Regarding dose(s), route / mode of administration, formulation(s) and duration of 
treatment(s), refer to Table 7-1 and Table 7-2.
7.4.1
Selection of doses in the study - amended
Each subject will be given 12 mg of copanlisib (i.v. over 1 h). 
Rationale for copanlisib 12 mg dose 
The 12 mg dose has been chosen (not the Recommended Phase II Dose of 60 mg) to assess 
the effects of moderate hepatic, severe hepatic or severe renal impairment on copanlisib PK. 
The rationale for this is the observed dose-linear PK of copanlisib and also the favorable 
safety profile of 12 mg copanlisib dose in healthy subjects (Human mass balance 
study 16353). Therefore, the 12 mg dose can be used across all four groups in this study. The 
results from a clinical study evaluating the effect of the strong CYP3A4 inhibitor itraconazole 
(as a perpetrator) on copanlisib (as a victim) at 12 mg and 60 mg showed the effect of 
itraconazole was independent of the dose suggesting the use of 12 mg dose can be predictive 
of results at higher doses given that the PK of copanlisib is linear. 23
The popPK data for copanlisib demonstrates no statistically significant difference in 
copanlisib clearance in patients with mild hepatic impairment (total bilirubin [TB] ≤ upper 
limit of normal [ULN] and aspartate aminotransferase [AST] > ULN, or TB < 1-1.5 x ULN 
and any AST, N = 47) and patients with normal liver function (TB ≤ ULN and AST ≤ ULN, 
N = 250). 
                                                
23 Paragraph revised as subjects with severe hepatic impairment will be included into the study according to 
Amendment 1
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Further, the popPK data for copanlisib in patients with renal impairment demonstrates no 
statistically significant difference in copanlisib clearance in patients with mild (CLcr = 60-
90 mL/min, N = 112) or moderate renal impairment (CLcr = 30-60 mL/min, N = 58) and 
patients with normal renal function (CLcr ≥90 mL/min, N = 125).
Based on the above discussion, the study will be conducted in all subjects at 12 mg dose.
7.4.2
Selection and timing of dose for each subject
Each of the subjects will receive one single dose of 12 mg of copanlisib i.v. over 1 h. 
In case of a blood pressure value of ≥150/90 mmHg before the planned time point of dosing 
administration will be delayed until recovery to < 150/90 mmHg. Instructions for blood 
pressure measurements are given in Section 9.6.3.
Antihypertensive medication may be given to control arterial hypertension. Dosing can 
proceed on the scheduled day if at least 2 consecutive blood pressure values measured at 5 to 
10 min interval prior to copanlisib dosing show BP <150/90 mmHg. Otherwise, dosing must 
be delayed. Guidance for the treatment of arterial hypertension is given in Section 9.6.1.7.2.
Subject’s fasting pre-dose glucose level should be ≤125 mg/dL (non-diabetic subjects) or 
<160 mg/dL (diabetic subjects) before copanlisib infusion (see Section 3, benefit-risk 
assessment). Guidance for the treatment of transient glucose increase is given in 
Section 9.6.1.7.1.
Food and drink on the day with dosing will be standardized. For details on meals, see 
Section 9.2.6.2.
Blinding
7.5
This study will be performed in a non-blinded design, as the primary objective of this trial is 
the investigation of PK and because the PK results will neither be affected by the subjects nor 
by the investigator(s).
Drug logistics and accountability - amended
7.6
All study drugs will be stored at the contracted pharmacy 
 or at the study site 
(
 in accordance with Good Clinical 
Practice (GCP) and Good Manufacturing Practice (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’s study file; the site-relevant elements of this information will be available in the 
investigator site file.  After receipt check, the responsible site personnel will confirm receipt 
of study drug in writing.  The personnel will use the study drug only within the framework of 
this clinical study and in accordance with this protocol.  
                                                
24 Third study site included according to Amendment 1
PPD
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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.
If performing drug accountability implies a potential risk of contamination, a safety process/ 
guidance for handling returned drug will be provided.
Treatment compliance
7.7
The administration of the study medication will be done by a member of the investigator’s 
team. This person will ascertain and document that the subject receives the treatment as 
planned.
Further information about the subject’s treatment compliance can be derived from drug 
concentration measurements in plasma and urine.
8.
Non-study therapy
Prior and concomitant therapy
8.1
All prior medication used within 6 weeks before treatment will be documented (medication 
history). Copanlisib is metabolized by CYP3A4. Therefore, concomitant use of strong 
inhibitors of CYP3A4 or strong inducers of CYP3A4 is not permitted from 14 days before the 
administration of study drug until 7 days after dosing (end of blood sampling period for PK). 
Refer to Section 6.2 for medication representing exclusion criteria. A list of these medications 
can be found in Section 16.8 of the protocol.
Use of medication for concomitant therapy is not planned. Especially the use of medication 
that may have an impact on the study objectives is not permitted. This comprises any 
medication (including herbal remedies or food supplements), which could affect the 
pharmacokinetics and / or pharmacodynamics of the study drug. The subjects will be 
instructed to report any concomitant medication used to the investigator. All concomitant 
medication will be documented. 
The subjects with hepatic and renal impairment will be allowed to continue their medications 
a long as they are in line with the enrollment criteria.
Post-study therapy
8.2
Subjects will not receive post-study medication by the sponsor. Subjects with renal and 
hepatic impairment will continue their treatment for their disease as before.
9.
Procedures and variables
Tabular schedule of evaluations
9.1
See study flow chart in Section 16.1.


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Regarding protocol deviations, the processes and responsibilities defined by the sponsor will 
be followed. Respective details (e.g. identification and classification of protocol deviations)
are described separately.
Visit description
9.2
If not stated otherwise, the measures / actions listed in the following Sections 9.2.1 to 9.2.5 
will be performed by or under the supervision of an investigator.
9.2.1
Screening visit - amended
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 screening examinations.
A subject information session will be held. If the (first) screening procedures already start on 
the same day (same date) as the subject signs the informed consent form, the time of the 
subject’s signature must be recorded in the source documents.
Note: No screening procedures may be performed unless written informed consent has 
been obtained.
After

Obtaining the subject’s signature on the consent form
the below listed screening procedures will be performed and the respective results will be 
assessed within 28 days prior to treatment.

Allocation of screening number, SNR (see Section 6.5)

Demographic data collection

Weight, height, body mass index

Medical and surgical history

Questioning for special behavior (e.g. smoking history, alcohol consumption, dietary 
habits)

Participation in previous clinical studies

Current and previous medication (relevant medication history)

Adverse events before start of treatment (e.g. signs / symptoms of the subject; results 
of physical examination)

Physical examination (complete)

Vital signs: blood pressure and pulse rate after resting for at least 10 min in supine25
position and body temperature
                                                
25 Corrected to supine position according to Amendment 1 (protocol Version 1.0 specified sitting position)


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
12-lead ECG after resting for at least 10 min in a supine position

Urine drug screen and alcohol breath test (see Section 16.2 for details)

Blood and urine sample (fasting) for the laboratory examinations described in 
Section 16.2

Virology examination (i.e. HIV, hepatitis B and C virus)

For hepatic impaired subjects: Child Pugh Scoring and number connection test

For all subjects: eGFR calculation according to MDRD
Based on the information obtained from the above assessments, i.e. once all results (including 
laboratory data) are available, the subject’s eligibility will be decided upon:

Eligibility check
No subject may start study treatment unless adherence to all selection criteria as given in 
Section 6.1 and Section 6.2 is established.
In case of abnormal results caused by intercurrent diseases, short-term treatable conditions or 
other temporary health disorders (e.g. acute infection, iron deficiency, blood pressure outside 
defined range), the investigator may decide to repeat the respective screening parameter(s). 
As a rule, up to two repetitions are acceptable.
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 casting lots. In case of not being 
included in the trial the data of the additional subjects will not be listed.
9.2.2
Pre-dose (Study Day -1, relative time: day -01)
The subjects will arrive at the study site in the morning of Study Day -1 (relative time: 
day -01) (start of in-house period). 
The following measures/ actions will be carried out:

Medical history (update)

Pregnancy test in blood or urine for women with reproductive potential (including 
women whose partners are sterilized) (within 7 days prior to dosing)

Complete physical examination

Urine drug screen

Alcohol breath test;
the subjects will be instructed to continue abstaining from alcohol consumption until 
Day 7

Urine (Urinalysis) and blood samples (chemistry, hematology and coagulation) in 
fasted state for safety laboratory examinations. Results of laboratory tests will be 
checked in the afternoon /evening.

12-lead ECG after at least 10 min rest in supine position

Vital signs: Blood pressure and pulse rate after resting in supine position for at least 
10 min and body temperature


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
Open questioning for / documentation of AEs and previous/concomitant medication 
(update)

Reminder about the restrictions imposed on the subjects

Final check of applicable inclusion/ exclusion criteria

Start overnight fasting for 8 h before the procedures for the dosing start (drinking of 
water and beverages with artificial sweeteners is allowed)
9.2.3
Randomization
Not applicable. For allocation of treatment number, refer to Section 7.3.
9.2.4
Treatment period
In case more than one measure/ action to be performed coincide at a given time point, the 
following order will be adhered to: ECG, blood pressure / pulse rate, blood sample for PK at 
defined time points, blood sample for safety. 
Any meal will be served after the study-related measures / actions for a given time point have 
been completed.
Dosing and profile day (Study Day 1, relative time: day 00) - amended
9.2.4.1
The following measures / actions will be performed at the time points given in the study flow 
chart in Section 16.1.

Fasting to be continued until the capillary glucose pre-dose is performed (drinking of 
water and beverages with artificial sweeteners is allowed)

Abbreviated physical examination

After a bed rest for at least 10 min, the following baseline measurements will be 
carried out: 12-lead ECG, vital signs (blood pressure/pulse rate, body temperature), 
blood sample (fasting capillary blood glucose, PK26)

Open questioning for / documentation of AEs and previous/concomitant medication 
(update)

Low glycemic breakfast at 1.5 h prior to start of the infusion (for details, see 
Section 9.2.6.2)

BP will be measured at least 2 times with 5-10 min intervals prior to the 
administration of the study drug until 2 consecutive values are <150/90 mmHg (see 
Sections 7.4 and 9.6.3 for further details)

Study drug administration i.v. (approximately 8 a.m. for the first subject) (see
Section 7.4.2)
                                                
26 “Protein binding assessment” deleted before dosing according to Amendment 1


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
Throughout the day until 12 h p.a.:

Capillary glucose 1h after start of copanlisib infusion (end of infusion), 1, 2, 3,27
6, 8 h after start of infusion, further capillary glucose if necessary

Further capillary glucose assessment at the discretion of the investigator (based of 
previous blood glucose levels)

Vital signs (blood pressure/pulse rate, body temperature) after a least 10 min in 
supine position at 1 h after start of copanlisib infusion (end of infusion) and at 6 h 
after start of infusion

12-lead ECG after a least 10 min in supine position at 1 h after start of copanlisib 
infusion (end of infusion) and at 6 h after start of infusion

blood sampling for pharmacokinetics at 10 min after start of copanlisib infusion, 
at 1 h after start of copanlisib infusion (end of infusion) and at 1.5, 2, 2.5, 3, 5, 
and 8 h after start of infusion

blood sampling for protein binding at 1 h after start of copanlisib infusion (end of 
infusion) 

Urine sampling for pharmacokinetics (0-8 h and 8-24 h)

Documentation on meal time (whole day)

Open questioning for and documentation of AEs and update on concomitant 
medication.
Observation day (Study Day 2 and 3, relative time: day 01 and day 02)
9.2.4.2
The following measures / actions will be performed at the time points given in the study flow 
chart in Section 16.1.

Abbreviated physical examination

12-lead ECG after at least 10 min rest in supine position

Vital signs: Blood pressure and pulse rate after resting in supine position for at least 
10 min; Body temperature 

Blood and urine sample for safety laboratory examinations 

Blood sampling for PK and protein binding assessment

Further capillary glucose assessment at the discretion of the investigator (based of 
previous blood glucose levels)

Documentation of meal´s timing in case of hyperglycemia

Open questioning for and documentation of AEs and update on concomitant 
medication.
Provided there are no medical objections, the subjects are released from the ward in the 
morning of day 02 after having breakfast (48 h post-administration).
                                                
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Ambulatory visits (Study Day 4 to 6, relative time: day 03 to day 05)
9.2.4.3
The following measures / actions will be performed at the time points given in the study flow 
chart in Section 16.1.

Blood sampling for PK

Further capillary glucose assessment at the discretion of the investigator (based of 
previous blood glucose levels)

Open questioning for and documentation of AEs and update on concomitant 
medication.
Provided there are no medical objections, the subjects are released.
End-of-treatment (Study Day 8 to 11, relative time: day 07(+3))
9.2.4.4
The following measures / actions will be performed 7+3 days after administration of the study 
medication:

Complete physical examination

12-lead ECG after at least 10 min rest in supine position

Vital signs: Blood pressure and pulse rate after resting in supine position for at least 
10 min; Body temperature

Blood and urine sample for safety laboratory examinations.

Blood sampling for PK

Open questioning for and documentation of AEs and update on concomitant 
medication.
Provided there are no medical objections, the subjects are released from the study ward. 
If required in case of elevated or decreased laboratory parameters out of the normal range 
additional visits will be performed after the follow-up visit.
9.2.5
Safety follow-up (relative time: day 14 (±3) and day 30 (+3))
There will be a telephone interview 14 ± 3 and 30 + 3 days after study drug administration 
(see also study flow chart in Section 16.1). The following measures / actions will be 
performed: 

Open questioning for and documentation of AEs and update on concomitant 
medication.

Any AEs ongoing at Safety Follow-up visit 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
All SAEs (including deaths) occurring up to 30 days after the single dose should be 
reported to the sponsor per usual SAE reporting procedures.


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9.2.6
Special conditions during the study
Restrictions - amended
9.2.6.1
Restrictions to be observed by the subjects are displayed in Table 9-1 below:
Table 9-1: Restrictions during the study - amended
What?
Restriction
Smoking
not allowed during the in-house phase of the study28
Alcohol
not permitted from 48 h prior to the dosing until Day 7
Food and beverages 
containing grapefruit, 
pomelo or Seville 
oranges
not permitted within 7 days before dosing and 7 days thereafter.
Methylxanthin-
containing food and 
drinks (coffee, tea, 
cola, cacao)
not permitted from 48 h prior to dosing until Day 7
Physical activity
usual activities are permitted, strenuous exercise not allowed from 72 h 
before admission to the study site until 96 h after
study drug administration
Food and drinks
9.2.6.2
The subjects will be required to follow the alimentary restrictions listed in Table 9-1, 
otherwise they are allowed to eat and drink as usual. On the visit day of screening, the 
subjects need to come in fasting state. During their stay at the study site, the subjects will be 
served non-standardized meals considering the imposed restrictions – except for the day when 
the study medication will be administered.
Starting in the evening preceding the day with administration of the study medication, the 
subjects have to keep to the standardized food and drink presented in Table 9-2.
Table 9-2: Food and drink before and after dosing 
Time
Food and drink
Approximately 8 h until the capillary 
glucose pre-dose is performed 
(before dosing)
Fasting (drinking of water and beverages with artificial 
sweeteners is allowed)
Approximately 1.5 h before dosing
Low glycemic breakfast (eggs, cheese and/or plain yoghurt, 
vegetables, meat). The breakfast should be completed 1h 
before start of infusion
During the last hour before dosing 
and during infusion
Nothing by mouth
During the first 2 h after EoI
Water consumption ad libitum
Approx. 2 h after EoIa 
Standard lunch
                                                
28 Smoking restriction revised (protocol Version 1.0 specified that smoking is not allowed during the study)


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Table 9-2: Food and drink before and after dosing 
Time
Food and drink
Approximately 8 h until the capillary 
glucose pre-dose is performed 
(before dosing)
Fasting (drinking of water and beverages with artificial 
sweeteners is allowed)
Approximately 1.5 h before dosing
Low glycemic breakfast (eggs, cheese and/or plain yoghurt, 
vegetables, meat). The breakfast should be completed 1h 
before start of infusion
During the last hour before dosing 
and during infusion
Nothing by mouth
Whenever appropriate (no specific 
timepoint)
Standard dinner
a after the study-related measures / actions of that time point have been performed
9.2.6.2.1
Accommodation
In-house phase:
4 days 
Overnight stay:
3 nights
Ambulant visits:
5 visits (screening, Study Days 4 to 6, and end of treatment visit)
Number of periods:
1
Population characteristics
9.3
9.3.1
Demographic
For demographic assessment, the following parameters will be recorded:
Year of birth / age, sex, race / ethnicity, body weight and height.

Body weight and height, BMI
Body weight will be measured by a member of the investigator’s team under the following 
conditions:

Subject in underwear and without shoes after having emptied his / her bladder

Electronic physician (column) scale with digital display, measurement units 
0.1 kg
The subject’s height will be measured (without shoes) to calculate the BMI.
9.3.2
Medical history
Medical history findings (i.e. previous diagnoses, diseases or surgeries) meeting all criteria 
listed below will be collected as available to the investigator:

Start before signing of the informed consent 

Considered relevant for the subject’s study eligibility.
Detailed instructions on the differentiation between (i) medical history and (ii) adverse events 
can be found in Section 9.6.1.1.


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9.3.3
Other baseline characteristics
Information on smoking and alcohol consumption will be collected.
Efficacy
9.4
Not applicable.
Pharmacokinetics / pharmacodynamics
9.5
9.5.1
Pharmacokinetics
Drug measurements
9.5.1.1
Blood samples for pharmacokinetic analyses of copanlisib and its metabolite BAY 84-5795 
(M-1) in plasma will be collected at the time points given below and in the study flow chart, 
see Section 16.1. Urine for PK analyses of copanlisib and its metabolite M-1 will be collected 
in intervals given below and in the study flow chart (Section 16.1).
Blood samples for PK will be collected before start of infusion as well as at 10 min and 
1 h (end of infusion [EoI]), 1.5, 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120 and 168 h after start of 
infusion (SoI).
Urine samples for PK will be collected in two sampling intervals from 0-8 and >8 up to 24 h 
after start of copanlisib infusion.
For all subjects, additional blood sample for evaluation of protein binding of copanlisib will 
be collected at 1 h after SoI (at EoI) on Day 1, and at 24 h after SoI on Day 2. These samples 
will be used for determination of fraction unbound and concentrations of total plasma protein, 
albumin and alpha 1-acid glycoprotein.
Whenever possible, all efforts should be made to adhere to the planned blood sampling 
schedule for PK. However, based on practical considerations, the following time ranges are 
provided as guidance:

Pre-dose samples should be collected within 30 min before SoI.

The end-of infusion sample for copanlisib and M-1 metabolite should be collected 
within 5 min after the end of infusion (EoI) of copanlisib for adequate characterization 
of Cmax.

For planned time points ≤6 h post-dose, PK samples should be collected within 
±15 min of the planned time.

For planned time points >6 h and ≤24 h, PK samples should be collected within 
±30 min.

For planned time points >24 h, the PK sample should be taken within ±3 h.
It is of importance that the actual date and time of blood sampling are thoroughly documented 
in the electronic case report form (eCRF) because PK calculations will be based on the actual 
sampling times relative to dosing times. Deviations from the specified time points will be 
documented and taken into account when calculating the PK parameters. 


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Cumulated substantial deviations of sampling times and/or consecutive, missing PK samples 
may lead to an insufficient description of the concentration-time profile(s) of the analyte(s), 
and thus affect the quality of the PK evaluation of the respective subject(s). In this case these 
deviations should be classified as “important” and may lead to as declared “validity findings” 
to the exclusion of the respective subject(s) from the PK analysis set.
Time points for PK samples may be adapted when data from this or another study become 
available (e.g. by adding up to five blood sampling time points per subject, or moving or 
deleting sampling time points). The decision on modification of sampling time points as well 
as the rationale for this will be described in detail in the Clinical Study Report, if applicable.
Regarding handling of the samples collected, refer to Section 16.2. The bioanalytical analyses
of the samples will be performed using validated analytical methods. Quality control (QC) 
and calibration samples will be analyzed concurrently with study samples. The results of 
calibration samples and QC samples will be reported in the Bioanalytical Report which will 
be included in the Clinical Study Report for this study. Concentrations are calculated from the 
chromatographic raw data in accordance with current Bayer guidelines. 
Pharmacokinetic evaluation
9.5.1.2
Non compartmental analysis (NCA)
The PK parameters will be calculated according to the Sponsor’s current guidelines using the 
pharmacokinetic software WinNonlin (version 5.3 or higher). Based on the concentration time 
data, the following PK parameters will be calculated. 
Parameters based on unbound plasma concentrations will be calculated for copanlisib. The 
calculation of these parameters (AUC(0-24)u , AUC(0-168)u, AUCu, , and Cmax,u) will be 
performed by Data Management (see Section 11.3).
Main parameters:
Copanlisib 
Cmax, AUC(0-168) and AUC
Additional parameters:
Copanlisib 
AUC(0-24), AUC(0-tlast), t1/2, tmax, tlast, Vz, CL, 
AE,ur(0-24), CLR, Cmax,u, AUC(0-24)u, AUC(0-
168)u, and AUCu based on average value of 
unbound fraction in the 1h and 24h samples   
BAY 84-5795 (M-1)
AUC(0-168), AUC(0-tlast), AUC, t1/2, Cmax, 
tmax, tlast, AE,ur(0-24)
Other parameters:
Copanlisib and BAY 84-5795 (M-1)
number of points terminal, %AUC(tlast-∞), 
Rstart, Rend, Clast


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9.5.2
Pharmacodynamics
Not applicable.
9.5.3
Pharmacometric analysis 
In addition to the NCA analysis, all PK and /or safety data may be used for additional 
pharmacometric analyses, e.g. a population PK analysis, which describes the relationship 
between dose, time, and copanlisib concentrations, and/or evaluations of exposure- safety-
relationships for relevant safety parameters. If a popPK analysis will be conducted, the 
analysis will be described in a separate Modelling and Simulating (M&S) Analysis Plan and 
the results will be described in a separate M&S Report. Other pharmacometric analyses will 
also be reported separately. 
Safety
9.6
9.6.1
Adverse events
Definitions
9.6.1.1
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 an AE (however, the condition for which the surgery is 
required may be an AE).
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal e.g. physical examination findings, symptoms, diseases, laboratory, ECG.

Conditions that started before signing of informed consent and for which no symptoms 
or treatment are present until signing of informed consent are recorded as medical 
history (e.g. seasonal allergy without acute complaints).

Conditions that started before signing of informed consent and for which symptoms or 
treatment are present after signing of informed consent, at unchanged intensity, are 
recorded as medical history (e.g. allergic pollinosis).

Conditions that started or deteriorated after signing of informed consent will be 
documented as adverse events.  This includes intercurrent illnesses.


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Definition of serious adverse event (SAE)
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a – f):
a.
Results in death
b. Is life-threatening
The term ‘life-threatening’ in the definition refers to an event in which the 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 in-subject 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 h

The admission is pre-planned
(e.g. elective or scheduled surgery arranged prior to the start of the study; 
admission is part of the study procedures as described in Section 9.2)

The admission is not associated with an AE 
(e.g. social hospitalization for purposes of respite care).
However, it should be noted that invasive treatment during any hospitalization may 
fulfill the criterion of ‘medically important’ and as such may be reportable as an SAE 
dependent on clinical judgment.  In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedence.
d. Results in persistent or significant disability / incapacity
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions.
e.
Is a congenital anomaly / birth defect
f.
Is another serious or important medical event as judged by the investigator
Classifications for adverse event assessment
9.6.1.2
All AEs will be assessed and documented by the investigator according to the categories 
detailed below.  
9.6.1.2.1
Seriousness
For each AE, the seriousness must be determined according to the criteria given in 
Section 9.6.1.1.


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9.6.1.2.2
Intensity
The intensity of an AE is classified according to the following categories:

Mild (A type of AE that is usually transient and may require only minimal treatment 
or therapeutic intervention. The event does not generally interfere with usual activities 
of daily living)

Moderate (A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant)

Severe (A type of AE that requires intensive therapeutic intervention. The event 
interrupts usual activities of daily living, or significantly affects clinical status. The 
event possesses a significant risk of harm to the research participant and 
hospitalization may be required)
9.6.1.2.3
Causal relationship 
The assessment of the causal relationship between an AE and the administration of treatment 
is a decision to be made by the investigator, who is a qualified physician, based on all 
information available at the time of the completion of the CRF.
The assessment is based on the question whether there was a “reasonable causal relationship” 
to the study treatment in question.
Possible answers are “yes” or “no”
An assessment of “no” would include:
1. The existence of a highly likely alternative explanation, e.g. mechanical bleeding at 
surgical site.
or
2. Non-plausibility, e.g. the 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 that the AE is reasonably associated with the use of the 
study treatment.
Important factors to be considered in assessing the relationship of the AE to study treatment 
include:

The temporal sequence from drug administration:  The event should occur after the 
drug is given.  The length of time from drug exposure to event should be evaluated in 
the clinical context of the event.

Recovery on drug discontinuation (de-challenge), recurrence on drug re-introduction 
(rechallenge):  Subject’s response after de-challenge or re-challenge should be 
considered in view of the usual clinical course of the event in question.


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
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 might have caused the event in question.

Known response pattern for this class of drug: Clinical/preclinical

Exposure to physical and/or mental stresses: The exposure to stress might induce 
adverse changes in the recipient and provide a logical and better explanation for the 
event

The pharmacology and pharmacokinetics of the study treatment: 
The pharmacokinetic properties (absorption, distribution, metabolism and excretion) 
of the study treatment, coupled with the individual subject’s pharmacodynamics 
should be considered.
Causal relationship to protocol-required procedure(s)
The assessment of a possible causal relationship between the AE and protocol-required 
procedure(s) is based on the question whether there was a “reasonable causal relationship” to 
protocol-required procedure(s).
Possible answers are “yes” or “no”
9.6.1.2.4
Action taken with study treatment 
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below.

Drug withdrawn (not applicable in this study)

Drug interrupted 

Dose reduced (not applicable in this study)

Dose not changed (not applicable in this study)

Dose increased (not applicable in this study)

Not applicable 

Unknown
9.6.1.2.5
Other specific treatment(s) of adverse events

None

Remedial drug therapy

Other


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9.6.1.2.6
Outcome
The outcome of the AE is to be documented as follows: 

Recovered/resolved

Recovering/resolving

Recovered/resolved with sequelae

Not recovered/not resolved

Fatal

Unknown
Assessments and documentation of adverse events
9.6.1.3
The investigator has to record on the respective CRF pages all adverse events occurring in the 
period between the signing of the informed consent and the end of the follow-up phase; after 
the end of the follow-up phase there is no requirement to actively collect AEs including 
deaths.  
Any AEs ongoing at Safety Follow-up visit 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
All SAEs (including deaths) occurring up to 30 days after the single dose should be reported 
to the sponsor per usual SAE reporting procedures.
The type of information that should be assessed and recorded by the investigator for each AE 
is listed in Section 9.6.1.2.  
“Death” should generally not be recorded as an AE on the AE page.  Instead, “death” is the 
outcome of underlying AE(s) which should be reported. Death should be reported as a SAE 
only if the underlying event which resulted in death is unknown.  
For all SAEs the sponsor has to carry out a separate assessment for expectedness, seriousness 
and causal relationship to study drug.
Reporting of serious adverse events
9.6.1.4
The definition of SAEs is given in Section 9.6.1.1.  Each SAE must be followed up until 
resolution or stabilization by submission of updated reports to the designated recipient.
Investigator’s notification of the sponsor
All investigators will be thoroughly instructed and trained on all relevant aspects of the 
investigator’s reporting obligations for SAEs.  This information, including all relevant contact 
details, is summarized in the investigator site file.  This information will be updated as 
needed.


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The investigator must report immediately (within 24 h of the investigator’s awareness) all 
SAEs occurring during the observation period defined in Section 9.6.1.3 to the recipient 
detailed in the instructions for SAE reporting included in the Investigator File.  For this, an 
AE page in the CRF as well as the complementary pages provided in the Investigator File 
must be completed for each SAE.  
SAEs occurring after the protocol-defined observation period will be processed by the 
sponsor according to all applicable regulations.
In each case of fatal or life-threatening reaction, the investigator must seek relevant follow-up 
information and must complete a follow-up report to be faxed to the sponsor as soon as 
possible but not later than 8 calendar days after the initial report is sent.
It is not mandatory to report SAEs occurring after the protocol defined observation period 
(see Section 9.6.1.3); however, at the investigator’s discretion these may be reported if 
considered potentially relevant. In such cases, the SAEs will be processed by the sponsor 
according to all applicable regulations.
An isolated laboratory abnormality is not reportable as an SAE, unless the investigator 
assesses that the event meets standard International Conference on Harmonization (ICH) 
criteria for an SAE (see SAE definition in Section 9.6.1.1).
Notification of the IECs / IRBs
Notification of the independent ethics committee (IECs) / institutional review board (IRBs) 
about all relevant events (e.g. SAEs, suspected, unexpected, serious adverse reactions 
[SUSARs]) will be performed by the sponsor and/or by the investigator according to all 
applicable regulations.
Notification of the authorities
The processing and reporting of all relevant events (e.g. SAEs, SUSARs) to the authorities 
will be done by the sponsor according to all applicable regulations.
Sponsor’s notification of the investigational site
The sponsor will inform all investigational sites about reported relevant events (e.g. SUSARs) 
according to all applicable regulations.
Expected adverse events
9.6.1.5
For this study, the applicable reference document is the most current version of the IB of 
Copanlisib [1].
Overview listings of frequent events that have occurred so far in the clinical development are 
shown in the current IB.  If relevant new safety information is identified, the information will 
be integrated into an update of the IB and distributed to all participating sites.
The expectedness of AEs will be determined by the sponsor according to the applicable 
reference document and according to all local regulations.


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Expected conduct-related AEs
The frequent blood sampling (by single vein puncture and / or indwelling cannula) may be 
accompanied by mild pain, hematoma and in rare cases inflammation of the vessel wall or 
injury of a nerve. Awareness should be raised to the possibility of a vasovagal attack or 
syncope (marked by pallor, nausea, sweating, bradycardia, and decrease in arterial blood 
pressure which, when below critical level, results in dizziness and /or loss of consciousness) 
during the sampling procedure.
The use of adhesive electrodes (ECG leads) and / or adhesive dressings may be accompanied 
by mild and transient reddening and / or itching of the skin.
Adverse events of special safety interest
9.6.1.6
Not applicable.
Recommendations for the management of specific adverse events
9.6.1.7
9.6.1.7.1
Management of glucose increases that can occur with study treatment
Management of transient post-infusion glucose increases in non-diabetic subjects

Asymptomatic transient glucose increases
Mild to moderate asymptomatic increases of blood glucose may occur after study drug 
infusion, with larger increases potentially occurring post-prandial. Transient 
asymptomatic glucose increases that are ≤250 mg/dL do generally not require 
treatment with glucose-lowering medication. Subjects with post-dose blood glucose 
>250 mg/dL should have repeated laboratory glucose measurements to verify if the 
values are persistent or decreasing. If the repeated glucose values are decreasing, 
glucose levels may be followed without glucose-lowering medication if the subject is 
asymptomatic and if hydration status is normal as clinically assessed.

Symptomatic or persisting glucose increases
Hydration status: If the subject has symptomatic glucose increase of any grade, 
hydration status should be clinically assessed. If the clinical assessment is consistent 
with dehydration, fluids should be given as clinically appropriate (orally or IV). 
Glucose-lowering medication: Subjects with post-dose blood glucose >250 mg/dL 
should have repeated laboratory glucose measurements to verify if values are 
persistent or decreasing. If a blood glucose level of >250 mg/dL persists upon 
confirmation by repeated laboratory analysis, and/or the subject is symptomatic, 
and/or the hydration status indicates the need for hydration, glucose-lowering 
medication should be administered: Rapid or short-acting (regular) insulin may be 
given for blood glucose levels that are persisting at >250 mg/dL, or if the subject is 
symptomatic during the infusion day. “Sliding scale” short-acting or (regular) insulin 
coverage of blood glucose levels that are persisting at >250 mg/dL is recommended, 
with oral or IV hydration as clinically appropriate. Only the use of short-acting (rapid-
acting) insulin is recommended for treatment of glucose increases after the single dose 
copanlisib infusion in non-diabetic subjects. 
Meal timing is added to the glucose management log used by the investigator and to 
be continued as long as hyperglycemia induced by the copanlisib infusion persists.


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Management of transient post-infusion glucose increases in diabetic subjects
For subjects with diabetes mellitus (types 1 and 2), the regimen of oral glucose-lowering 
medication and/or insulin (short-acting, intermediate, or long-acting) may be adjusted at the 
investigator’s discretion after the single copanlisib infusion.
The management of these subjects may require, if needed the input of a diabetes specialist. 
Adjustment of the subject’s glucose-lowering regimen (whether prior use of oral 
hypoglycemic medication, insulin, or a combination of both) with special attention to post-
copanlisib infusion meal coverage should be considered for postprandial glucose increases. 
Monitoring during the study
All subjects (diabetic and non-diabetic) should be kept on ward as long as the post-dose 
glucose level is >250 mg/dL and until the glucose level decreases to <200 mg/dL non-fasting. 
All diabetic subjects as well as non-diabetic subjects who experience a glucose level of 
>250 mg/dL or require insulin administration post-infusion will have capillary glucose 
monitoring including fasting plasma glucose (morning before breakfast) and 2 further 
capillary glucose measurements approximately 2 h after intake of food. If after the required 
48 h the glucose values are not at goal (post-prandial glucose <200 mg/dL), this monitoring 
will continue until blood glucose values are at goal.
9.6.1.7.2
Treatment of arterial hypertension associated with copanlisib
Subjects with pre-existing arterial hypertension should adhere to their regular 
antihypertensive medication schedule, and take their usual doses on the day of the copanlisib 
infusion. The management of acute arterial hypertension following copanlisib will need to be 
individualized for each subject, but the experience in Phase I studies on copanlisib has 
suggested the benefit of dihydropyridine calcium channel blockers (i.e. amlodipine, 
felodipine). Topical nitrates, verapamil and diltiazem (nondihydropyridine calcium channel 
blockers) can be also considered. 
In general, antihypertensive medication should be readily available if needed. If arterial 
hypertension ≥150/90 mmHg occurs during the copanlisib infusion, antihypertensive 
treatment is suggested as indicated above. If arterial hypertension (≥160/100 mmHg) occurs 
during copanlisib IV infusion, the copanlisib IV infusion should be interrupted or slowed 
down, administration of anti-hypertensive therapy initiated and copanlisib infusion may be 
resumed when BP has returned to <150/90 mmHg.
9.6.1.7.3
Treatment of vomiting and diarrhea
Adequate hydration through appropriate fluid maintenance is essential for the treatment of 
diarrhea or vomiting. Anti-diarrhea medications may be introduced if symptoms occur. The 
recommended dose of loperamide is 4 mg at first onset, followed by 2 mg every 2 to 4 h until 
diarrhea-free for 12 h, a maximum daily dose of 16 mg is not to be exceeded. If clinically 
indicated diphenoxylate or Lomotil, which contains diphenoxylate plus atropine might also be 
used. The routine use of standard antiemetics, including 5-HT3 blockers is allowed, see 
Section 8.1 for permitted concomitant therapy.


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9.6.2
Pregnancies
A subject’s participation is to be terminated immediately if a pregnancy is supposed (i.e. in 
case her pregnancy test becomes positive).
The investigator must report to the sponsor any pregnancy occurring in a female study subject 
during her participation in this study. The outcome of the pregnancy should be followed up 
carefully, and any outcome of the mother and the child at delivery should be reported.
For a pregnancy in the partner of a male study subject, all efforts will be made to obtain 
similar information on course and outcome, subject to the partner’s consent.
For all reports, the forms provided are to be used. The investigator should submit them within 
the same timelines as an SAE.
9.6.3
Safety examinations
The following safety examinations will be performed at the time points specified in the study 
flowchart, see Section 16.1.

Physical examination
The physical examination (by means of inspection, palpation, auscultation) will be performed 
by a physician at the study site according to the schedule summarized in the flow chart in 
Section 16.1. 
Complete physical examination includes the NYHA classification (see Section 16.9) and
complete reviews of body systems.
All clinical signs and regions that can be brought into context with the underlying disease, 
with the anti-cancer treatment to be administered or with relevant accompanying diseases (if 
present) should be clinically assessed.
At the minimum, the following aspects / regions need to be assessed as well:

General appearance

Skin (paleness, jaundice, redness / rush, acneiform changes)

Hand and feet (signs of hand-foot syndrome / palmar-plantar erythrodysesthesia)

Eyes (accommodation, double images, abnormal sensitivity to light, jaundice)

Ears, nose, throat (presence of petechial bleedings, gingiva bleeding)

Head and neck

Lungs

Heart

Abdomen (pain, tenderness, peristaltic, ascites, organomegaly)

Lymph nodes

Musculoskeletal system and spine

Lower legs (petechial bleedings, ulcer, signs of thrombosis)

Neurologic findings


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Abbreviated physical examinations will be performed (by inspection, palpation, and
auscultation) by a physician at the study center according to the schedule summarized in the 
flow chart in Section 16.1.
Abbreviated physical examination includes pertinent organ systems and brief interim history 
(change of symptoms). At the minimum, the following aspects / regions need to be assessed 
as well:

Skin (paleness, jaundice, redness / rush, acneiform changes)

Hand and feet (signs of hand-foot syndrome / palmar-plantar erythrodysesthesia)

Throat (presence of petechial bleedings, gingiva bleeding)

Lungs

Abdomen (pain, tenderness, peristaltic, ascites, organomegaly)

Neurologic findings

Other clinical signs and regions might be investigated as well if clinically indicated.
Abnormal physical examination findings are recorded either as medical history or as AEs (see 
Section 9.6.1.1).

Vital Signs

Blood pressure (BP) / pulse rate (supine)
Systolic / diastolic blood pressure and pulse rate will be measured by a member of the 
investigator’s team under the following conditions:

Position: Supine (small pillow under head allowed) for at least 10 min

Measuring site: cuff to be placed on the right / left upper arm (if possible, the 
same arm will be used for all measurements in one subject) 

Method: oscillometric by automatic measurement device
Body temperature, BP, and pulse rate will be assessed according to the schedule summarized 
in the flow chart in Section 16.1. If clinically indicated, it is at the investigator’s discretion to 
perform these measurements more frequently.
BP will be measured every 5 to 10 min before the copanlisib dose until 2 consecutive values 
are <150/90 mmHg. A single BP measurement will be performed at the end of the copanlisib 
IV infusion.
For details about the management of arterial hypertension, see also Section 9.6.1.7.2
(treatment of arterial hypertension).

Body temperature
Body temperature will be measured by a member of the investigator’s team using always the 
same method according to local practice. The measured values are to be recorded in the 
electronic CRF in degree Celsius (°C).


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
Electrocardiogram
A complete standard 12-lead ECG will be recorded by a member of the investigator’s team 
under the following conditions:

Position: supine (small pillow under head allowed) for at least 15 min

Device: computerized ECG device

Automatic calculation of the following parameters: RR interval, heart rate, P-
duration, PR (PQ) interval, QRS-duration, QT (uncorrected). For data analysis by 
the sponsor, the frequency-corrected QT interval will be calculated according to 
both the formula of Fridericia (QTcF) and Bazett (QTcB) by data management.

Evaluation of ECG by a physician providing an ECG diagnosis and overall 
assessment (including clinical relevance)

Laboratory examinations
Blood and urine samples will be collected by a member of the investigator’s team, for time 
points and parameters see Section 16.1 and Section 16.2 in the appendix.
The MDRD equation will be used for the eligibility assessment in Group B (see Section 16.5). 
The creatinine clearance will be calculated from the creatinine concentration measured in 
serum according to the Cockroft-Gault formula after the study (see Section 16.6).
In the event of implausible results, the laboratory may measure additional parameters to 
assess the quality of the sample (e.g. clotted or hemolyzed) and to verify the results.  
The results from such additional analyses may neither be included in the clinical database of 
this study nor evaluated further.  If the results are relevant, the investigator will be informed 
to determine follow-up activities outside of this protocol.
Other procedures and variables
9.7
For virology and urine drug screen parameters and pregnancy test, please refer to Table 16-2.
Appropriateness of procedures / measurements
9.8
All PK and safety parameters, as well as the methods to measure them, are standard variables/ 
methods in clinical studies and/ or clinical practice. They are widely used and generally 
recognized as reliable, accurate and relevant.
10.
Statistical methods and determination of sample size
General considerations
10.1
The statistical evaluation will be performed by using the SAS software package. All data will 
be listed and trial summary tables will be provided.


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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. Whenever 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. Baseline is defined as the last pre-dose assessment before study drug 
administration.
Analysis sets
10.2
All subjects who received at least one dose of the study medication will be included in the 
safety analysis set (SAF). 
All subjects with a PK profile allowing calculation of the main PK parameters will be 
included in the PK analysis set (PKS1).
All hepatically impaired subjects and gender, age- and weight-matched healthy subjects with 
a PK profile allowing calculation of the main PK variables will be included in the PK analysis 
set for hepatic impairment assessment (PKS2).
All renally impaired subjects and gender, age- and weight-matched healthy subjects with a 
PK profile allowing calculation of the main PK variables will be included in the PK analysis 
set for renal impairment assessment (PKS3).
Variables and planned statistical analyses - amended
10.3
Primary and secondary variables are specified in Section 5.
Statistical and analytical plans

Demographic and other baseline characteristics
Analysis for population characteristics will be performed for the SAF population, unless 
otherwise specified.
Disposition at the end of screening will be summarized for all enrolled subjects. Disposition 
at the end of treatment will be summarized by group and overall for the SAF population.
Demographics will be summarized by group and overall. Quantitative data will be 
summarized by arithmetic mean, standard deviation, median, minimum and maximum. 
Frequency tables will be provided for qualitative data. Analysis of demographic data will also 
be performed for the PKS1 population if this population differs from SAF. 

Adverse events
Individual listings of AEs will be provided. The incidence of TEAEs and drug-related 
TEAEs, respectively, will be summarized by group and overall using MedDRA terms. 
Listings of deaths and SAEs will be provided.
Adverse events are considered to be treatment-emergent if they have started or worsened after 
first application of study medication up to 30 days after end of treatment with study 
medication.


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
Safety parameters
Quantitative data for safety (hematology, clinical chemistry, coagulation, urinalysis, vital 
signs, ECG) will be described by descriptive statistics (arithmetic mean, standard deviation, 
median, minimum and maximum) and will be presented by each group 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 and flagged with ‘L’ for low and‘H’ 
for high. 
Graphical displays of individual data as well as mean values with standard deviation will be 
included.

Pharmacokinetic variables
The plasma concentration vs time courses of copanlisib (and its metabolite) will be 
summarized by group. The following statistics will be calculated for each plasma sampling 
point: arithmetic mean, standard deviation (SD) 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. This rule also applies for means 
shown in figures. In tables showing mean values, where values below LLOQ are included in 
the calculation of mean values, these means will be marked.
Individual and mean concentration versus time profiles of all analytes will be plotted using 
both linear and semi-logarithmic 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.
To investigate the primary objective of this study regarding hepatic and renal impairment, 
analysis of variance appropriate for a parallel design will be fitted to the natural logarithmic 
transformation of PK parameters (AUC(0-168), AUC and Cmax) of copanlisib . 
The test/reference comparison ratio of geometric least-squares means and associated 90% 
confidence intervals (CIs) for each PK parameter in the moderate hepatic, severe hepatic29 or 
severe renal impairment group versus the matched healthy subjects group will be calculated 
by exponentiation of the natural-log scale point estimate and the associated 90% CI.
                                                
29 Included as subjects with severe hepatic impairment will be included into the study according to Amendment 1


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Determination of sample size - amended30
10.4
The study population will consist of up to 44 evaluable male and female subjects with 
8-22 evaluable subjects in the control group, 8 evaluable subjects each in the moderate 
hepatic and severe renal impairment investigational group, and 6 evaluable subjects in the 
severe hepatic impairment investigational group. The sample size of 8 subjects in each of the 
groups with impaired moderate hepatic and severe renal function and 6 subjects in the severe 
hepatic impairment group has been selected based on practical consideration and following 
the FDA guidance [4][5]. 
In copanlisib studies 12871 and 16270, the SD for log-transformed AUC(0-168) or AUC was 
estimated between 0.33 and 0.40. For the current study, we assume the SD of 0.40 for log-
transformed AUC(0-168). The PK parameter AUC(0-168) is considered appropriate for 
sample size estimation as in Study 16270 the extrapolation for calculation of AUC was only 
4.8% of AUC(0-168).  Further, based on the PK data from study 12871, the inter-subject
variability for copanlisib PK exposure was estimated to be 46.5% for AUC(0-168) and 73.3% 
for Cmax in terms of geometric coefficient of variation (CV). In study 16270, the inter-subject
variability for Cmax was 63.2% in terms of geometric mean CV.  The AUC(0-168) value has 
been considered for sample size estimation as a suitable PK parameter because of the higher 
uncertainty around of the Cmax especially for an i.v. drug. For AUC(0-168), a sample size of 
8 eligible subjects each in the control, moderate hepatic and severe renal impairment 
investigational group would provide an approximately 90% chance for the 90% confidence 
interval for the ratio of geometric least-squares means between impaired subjects and healthy 
subjects to be within a 2-fold difference, that is, within limits of 50% to 200% for AUC(0-
168). This can be shown in Table 10-1 based on different observed ratios.
Table 10-1: 90% Confidence interval for copanlisib with N=8 per group - amended
Observed Ratio
90% CI for the ratio
1
(0.685, 1.461)
1.1
(0.753, 1.607)
1.2
(0.822, 1.753)
1.3
(0.890, 1.899)
A sample size of 6 eligible subjects per each in the control and severe hepatic impairment 
investigational group would provide an approximately 90% chance for the 90% confidence 
interval for the ratio of geometric least-squares means between impaired subjects and healthy 
subjects to be within an approximately 2-fold difference, that is, within limits of 50% to 207% 
for AUC(0-168) as shown in Table 10-2 based on different observed ratios.
                                                
30 Sample size determination revised as subjects with severe hepatic impairment will be included into the study 
according to Amendment 1


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Table 10-2: 90% Confidence interval for copanlisib with N=6 per group - amended
Observed Ratio
90% CI for the ratio
1
(0.628, 1.593)
1.1
(0.691, 1.752)
1.2
(0.753, 1.911)
1.3
(0.816, 2.07)
Planned interim analyses - amended
10.5
An interim analysis will be conducted after 8 evaluable subjects with moderate hepatic 
impairment and 8 evaluable subjects with severe renal impairment with their corresponding 
matching healthy volunteers have completed the study to fulfill the first part of the post 
marketing requirement as agreed with the FDA (July 2019) based on the accelerated approval 
of copanlisib (September 14, 2017). This interim analysis will also serve as a final analysis on 
the moderate hepatic impairment and severe renal impairment groups in the final clinical 
study report. The results of the final report will include subjects with severe hepatic 
impairment as agreed with FDA (July 2021).31
11.
Data handling and quality assurance
Data recording
11.1
The data collection tool for this study will be a validated electronic data capture system called 
RAVE. Subject data necessary for analysis and reporting will be entered/ transmitted into a 
validated database or data system (SAS). 
Data required according to this protocol will be recorded by investigational site personnel via 
data entry into the internet based electronic data capture (EDC) software system RAVE, 
which has been licensed from Medidata Solutions Worldwide. RAVE has been validated by 
Medidata Solutions Worldwide for use in Bayer clinical studies. RAVE allows for the 
Integrated Clinical application of software logic to set-up data entry screens and data checks 
to ensure the completeness and accuracy of the data entered by the site personnel. The logic 
has been extensively applied to ensure data are complete and reflect the clinical data 
requirements of the study. Data queries resulting from the application of the software logic are 
resolved by the site personnel. The data are stored at a secure host facility maintained by 
Medidata Solutions Worldwide. 
All access to the RAVE system is through a password-protected security system that is part of 
the RAVE software. All internal Bayer and external investigator site personnel as well as the 
CRO personnel seeking access must go through a thorough RAVE training process before 
they are granted access to RAVE for use in Bayer's clinical studies. Training records are 
maintained. 
                                                
31 Interim analysis included according to Amendment 1


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All personnel with access to the RAVE system are supported by a Service Desk staffed with 
trained personnel to answer questions and ensure access is maintained such that data entry can 
proceed in a timely manner. 
The RAVE System contains a system-generated audit trail that captures any changes made to 
a data field, including who made the change, why the change was made and the date and time 
it was made. This information is available both at the investigator’s site and at Bayer. Data 
entries made in the RAVE EDC screens are supported by source documents maintained for all 
subjects enrolled in this study.
Source documentation
The site must implement processes to ensure availability of all required source 
documentation.  A source document checklist (not part of this protocol) will be used at the 
site to identify the source data for key data points collected and the monitor will work with the 
site to complete this.
It is the expectation of the sponsor that all data entered into the CRF has source 
documentation available at the site.
Data recorded from screening failures
At minimum, the following data should be recorded in the CRF:

Demographic information (subject number; year of birth / age; sex; if applicable race / 
ethnicity)

Date of informed consent

Relevant inclusion/exclusion criteria

Reason for premature discontinuation

Date of last visit
These data will be transferred to the respective database.
For screening failures with an SAE, the following data should be collected in the CRF in 
addition to the data specified above:

All information related to the SAE such as: 

The SAE itself

Concomitant medication

Medical history

Other information needed for SAE complementary page


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Monitoring
11.2
In accordance with applicable regulations, GCP, and sponsor’s/CRO’s procedures, monitors 
will contact the site prior to the start of the study to review with the site staff the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and sponsor’s 
requirements.  When reviewing data collection procedures, the discussion will also include 
identification and documentation of source data items.
The sponsor/designee will monitor the site activity to verify that the:

Data are authentic, accurate and complete.  
Supporting data may be requested (example: blood glucose readings to support a 
diagnosis of diabetes). 

Safety and rights of subjects are being protected

Study is conducted in accordance with the currently approved protocol 
(including study treatment being used in accordance with the protocol)

Any other study agreements, GCP, and all applicable regulatory requirements are met.
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents.
Data processing
11.3
Bioanalytical results for PK 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 Clinical Pharmacokinetics. Clinical Pharmacokinetics will calculate the PK parameters 
indicated in this protocol as described in Section 9.5.1.2 except for the parameters derived 
from unbound concentrations. The finalized evaluation will electronically be transferred to 
Data Management where all data will be included in the corresponding SAS data repository. 
Pharmacokinetic parameters for unbound copanlisib (AUCu, Cmax,u) will be calculated by Data 
Management by multiplying the pertinent parameters for copanlisib as calculated by Clinical 
Sciences with / by the individual free fraction provided by the Preclinical Pharmacokinetics 
Department. All electronic file transfer processes will follow validated procedures.
Data will be collected as described in Section 11.1. Clinical data management will be 
performed in accordance with applicable sponsor’s/CRO’s standards and data cleaning 
procedures. This is applicable for data recorded on CRF as well as for data from other sources 
(e.g. laboratory, ECG, ePRO, adjudication committees).
For data coding (e.g. AEs, medication), internationally recognized and accepted dictionaries 
will be used.
After its initial release for biometrical analysis, the clinical database is planned to be re-
opened for the inclusion of the following additional data: pharmacokinetic data.


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Missing data 
11.4
No imputation of missing data is planned. All available data will be used for statistical 
analysis.
Audit and inspection
11.5
To ensure compliance with GCP and regulatory requirements, a member of the sponsor’s (or a 
designated CRO’s) quality assurance unit may arrange to conduct an audit to assess the 
performance of the study at the study site and of the study documents originating there.  The 
investigator/institution will be informed of the audit outcome.
In addition, inspections by regulatory health authority representatives and IEC(s)/IRB(s) are 
possible.  The investigator should notify the sponsor immediately of any such inspection.
The investigator/institution agrees to allow the auditor or inspector direct access to all relevant 
documents and allocate his/her time and the time of his/her staff to the auditor/inspector to 
discuss findings and any issues.  Audits and inspections may occur at any time during or after 
completion of the study.
Archiving
11.6
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.  Where 
the archiving procedures do not meet the minimum timelines required by the sponsor, 
alternative arrangements must be made to ensure the availability of the source documents for 
the required period.
The investigator/institution notifies the sponsor if the archival arrangements change 
(e.g. relocation or transfer of ownership).
The investigator site file is not to be destroyed without the sponsor’s approval.
The contract with the investigator/institution will contain all regulations relevant for the study 
center.
12.
Premature termination of the study
The sponsor has the obligation to close this study (or, if applicable, individual segments 
thereof [e.g. treatment arms; dose steps; centers]) at any time, which may be due but not 
limited to the following reasons: 

If risk-benefit ratio becomes unacceptable owing to, for example,

Safety findings from this study (e.g. SAEs)

Results of any interim analysis

Results of parallel clinical studies

Results of parallel animal studies 
(on e.g. toxicity, teratogenicity, carcinogenicity or reproduction toxicity).


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
If the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable time 
frame.
The investigator has the right to close his/her center at any time.
For any of the above closures, the following applies:

Closures should occur only after consultation between involved parties.  Final decision 
on the closure must be in writing.

All affected institutions (e.g. IEC(s)/IRB(s); competent authority(ies); study center; 
head of study center) must be informed as applicable according to local law.

All study materials (except documentation that has to remain stored at site) must be 
returned to the sponsor.  The investigator will retain all other documents until 
notification is given by the sponsor for destruction.

In the event of a partial study closure, ongoing 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 6.4.1.
13.
Ethical and legal aspects
Investigator(s) and other study personnel
13.1
Sponsor’s Medical Expert
Name:
Title:
Address:
Bayer AG, 
SBU Oncology, Pharmaceuticals
Muellerstrasse 178
13353 Berlin, Germany
Phone:
Fax:
Coordinating Investigator for the Study
Name:
Title:
Address:
 Germany
Phone:
Fax:
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.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Whenever the term ‘investigator’ is noted in the protocol text, it may refer to either the 
principal investigator at the site, or an appropriately qualified, trained and delegated 
individual of the investigational site.
The coordinating investigator must sign the protocol signature page and must receive all 
required external approvals (e.g. health authority, ethics committee, sponsor) before subject 
recruitment may start at the respective center.  Likewise, all amendments to the protocol must 
be signed by the coordinating investigator and must have received all required external 
approvals before coming into effect at the respective center.
A complete list of all participating centers and their investigators, as well as all required 
signature documents, will be maintained in the sponsor’s study file.
Funding and financial disclosure
13.2
Funding
This study will be funded by its sponsor.
Financial disclosure 
Each investigator (including principal and/or any sub investigators) who is directly involved 
in the treatment or evaluation of research subjects has to provide a financial disclosure 
according to all applicable legal requirements.  All relevant documentation will be filed in the 
trial master file.
Ethical and legal conduct of the study
13.3
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 
GCP guidelines and the guiding principles detailed in the Declaration of Helsinki.  The study 
will also be carried out in keeping with applicable local law(s) and regulation(s).
Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating 
centers/countries before start of the study, according to GCP, local laws, regulations and 
organizations.  When necessary, an extension, amendment or renewal of the IEC/IRB 
approval must be obtained and also forwarded to the sponsor.  The responsible unit (e.g. 
IEC/IRB, head of the study center/medical institution) must supply to the sponsor, upon 
request, a list of the IEC/IRB members involved in the vote and a statement to confirm that 
the IEC/IRB is organized and operates according to GCP and applicable laws and regulations.
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol.  
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties.  However, the investigator or the sponsor may 
implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) 
to the trial subjects without prior IEC/IRB/sponsor approval/favorable opinion.  


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As soon as possible, the implemented deviation or change, the reasons for it and if appropriate 
the proposed protocol amendment should be submitted to the IEC/IRB/head of medical 
institution/sponsor.  Any deviations from the protocol must be explained and documented by 
the investigator.
Details on discontinuation of the entire study or parts thereof can be found in Section 12.
Subject information and consent
13.4
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 
subject information and informed consent 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 (i.e. before any 
examinations and procedures associated with the selection for the study are performed or any 
study-specific data is recorded on study-specific forms).
The investigator will also mention that written approval of the IRB/IEC has been obtained.
Each subject will be informed about the following aspects of premature withdrawal:

Each subject has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision.  

The subject’s consent covers end-of-study examinations as specified in the visit 
description described in Section 9.2 to be conducted after withdrawal of consent.  

The subject’s data that have been collected until the time of withdrawal will be 
retained and statistically analyzed in accordance with the statistical analysis plan. 

Subject-specific data on the basis of material obtained before withdrawal may be 
generated after withdrawal (e.g. image reading, analysis of biological specimen such 
as blood, urine or tissues); these data would also be retained and statistically analyzed 
in accordance with the statistical analysis plan.  The subject has the right to object to 
the generation and processing of this post-withdrawal data. The subject’s oral 
objection may be documented in the subject’s source data.
Each subject will have ample time and opportunity to ask questions.
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 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 investigator site file 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.


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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.
Publication policy and use of data
13.5
The sponsor has made the information regarding the study protocol publicly available on the 
internet at www.clinicaltrials.gov. 
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the sponsor who may utilize them in various ways, such as for 
submission to government regulatory authorities or disclosure to other investigators.
Regarding public disclosure of study results, the sponsor will fulfill its obligations according 
to all applicable laws and regulations.  The sponsor is interested in the publication of the 
results of every study it performs.  
The sponsor recognizes the right of the investigator to publish the results upon completion of 
the study.  However, the investigator, whilst free to utilize study data derived from his/her 
center for scientific purposes, must obtain written consent of the sponsor on the intended 
publication manuscript before its submission.  To this end, the investigator must send a draft 
of the publication manuscript to the sponsor within a time period specified in the contract.  
The sponsor will review the manuscript promptly and will discuss its content with the 
investigator to reach a mutually agreeable final manuscript.
Compensation for health damage of subjects / insurance
13.6
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.
Confidentiality
13.7
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 CRF, 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.  As part of 
the informed consent process, 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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14.
Reference list 
[1]
Investigator’s Brochure: BAY 80-6946 (Copanlisib), current version.
[2]
Walz-Mattmueller R, Horny HP, Ruck P, Kaiserling E. Incidence and pattern of liver 
involvement in haematological malignancies. Pathol Res Pract. 1998;194(11):781–789.
[3]
Humphreys BD, Soiffer RJ, Magee CC. Renal failure associated with cancer and its 
treatment: an update. J Am Soc Nephrol. 2005 Jan;16(1):151-61. Epub 2004 Dec 1.
[4]
Guidance for Industry: Pharmacokinetics in patients with impaired hepatic function: 
study design, data analysis, and impact on dosing and labeling. Food and Drug 
Administration. May 2003.
[5]
Draft Guidance for Industry: Pharmacokinetics in patients with impaired renal function: 
study design, data analysis, and impact on dosing and labeling. Food and Drug 
Administration. March 2010.
[6]
National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Chronic Kidney 
Disease: Evaluation, Classification and Stratification. Am J Kidney Dis 39:S1-S266, 
2002 (suppl 1).
15.
Protocol amendments
Amendment 1
15.1
Amendment 1 (substantial) is dated 28 Nov 2017.
15.1.1
Overview of changes to the study
This amendment is issued as a result of the FDA’s comment in the e-mail from 03 Aug 2017.

Modification 1 (Enrollment of subjects with severe hepatic impairment): As copanlisib 
is mainly metabolized and excreted by the liver subjects with severe hepatic 
impairment (Child-Pugh C) will additionally be enrolled in this study. A total of 
6 evaluable subjects with severe hepatic impairment will be included in Group C. An 
interim analysis will be conducted after 8 evaluable subjects with moderate hepatic 
impairment and 8 evaluable subjects with severe renal impairment with their 
corresponding matching healthy volunteers have completed the study to fulfill the post 
marketing requirement as agreed upon with the FDA after the accelerated approval of 
copanlisib in September 2017. The subject number ranges were revised (Sections 2 
[synopsis], 3, 4, 5, 6.1.5, 6.2.5, 6.4.2, 7.1, 7.3, 7.4.1, 10.3, 10.4, 10.5, and 16.3).
In addition, this amendment covers the following modifications:

Modification 2 (Inclusion of a third study center). A third study center was included
The subject number ranges were revised (Section 7.3, 7.6, 
and 16.2).

Modification 3 (Revision of abbreviation list): The presentation of the abbreviation E2 
for estradiol was revised in the abbreviation list (list of abbreviations).
PPD


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
Modification 4 (Revision of Table 7-1): In the first column of Table 7-1 “severe” was 
included to Group B for clarification (Section 7.1).

Modification 5 (Correction of position for vital sign measurements): The position for 
vital sign measurements at screening was corrected in Section 9.2.1 from “sitting” to 
“supine”. Vital signs will be determined in supine position as described in 
Section 9.6.3 and the flow chart (Section 9.2.1).

Modification 6 (Addition of follicle stimulating hormone to the table of laboratory 
parameters): Follicle stimulating hormone was added to the table of laboratory 
parameters as this parameter will be determined in postmenopausal women ≤50 years 
of age as described in inclusion criterion no. 3 (Section 16.2).

Modification 7 (Correction of position of footnote “b” in the flow chart): Footnote “b” 
(before any study specific tests or procedures are done) applies to “informed consent” 
and not to “blood pressure” and “pulse rate”. The flow chart was corrected 
accordingly (Section 16.1).

Modification 8 (Deletion of protein binding assessment at pre-dose): The protein 
binding assessment was deleted at pre-dose in the visit description. The assessment 
will not be performed at pre-dose as described in Section 9.5.1.1 and the flow chart 
(Section 9.2.4.1).

Modification 9 (Deletion of assessment of capillary glucose at 4 h): The assessment of 
capillary glucose was deleted at 4 h after start of infusion in the visit description. The 
assessment will not be performed at 4 h as described in the flow chart 
(Section 9.2.4.1).

Modification 10 (Revision of smoking restriction): It was clarified that smoking will 
not be allowed during the in-house phase of the study (Section 9.2.6.1).

Modification 11 (Correction of fasting period after dosing): In the flow chart the 
fasting period was corrected from 1 h to 2 h after end of infusion. The fasting period 
will last 2 h as described in Table 9-2 and footnote “i” of the flow chart (Section 16.1).

Modification 12 (Revision of time points for final check of inclusion and exclusion 
criteria and treatment assignment): Final assessment of inclusion and exclusion criteria 
will take place after the results of the safety laboratory from the morning of Day -1 are 
available (evening of Day -1/morning of the dosing day). Treatment assignment will 
take place in the morning of the dosing day before start of infusion and after assessing 
the pre-dose blood pressure and glucose values. The protocol was corrected 
accordingly (Sections 5, 6.5, and 16.1).

Modification 13 (Correction of time period in title of the flow chart): The title of the 
flow chart was corrected from “-00d16h – 07d00h” to “-01d00h – 05d00h” 
(Section 16.1).

Modification 14 (Approval of BAY 80-6946 by FDA). BAY 80-6946 was approved 
by the FDA in September 2017. This information was included (Section 3).


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
Modification 15 (Change of exclusion criterion regarding neutrophils): In order to be 
consistent with other copanlisib studies, the upper limit of neutrophils was increased 
in the exclusion criterion. Subjects will not be included into the study in case of 
neutrophils <1500/μL instead of <1000/μL at inclusion (Section 6.2.1).

Modification 16 (Harmonization of name of study drug). The name of the study drug 
was harmonized (BAY 80-6946 instead of BAY 806946). The name of the study drug 
should have 7 digits (Section 3 and 7.2).
15.1.2
Changes to the protocol text
In this section on changes to the protocol text, all protocol sections affected by the respective 
amendment are detailed; the sequence of the sections follows the structure of the most recent 
previous protocol version. As applicable, changes to the protocol text are highlighted as 
follows:

Addition of a whole new portion
Brief identification of the new portion

Removal of a whole portion
Complete display of the removed portion, 
formatted as crossed out

Editing of an existing portion
Comparative presentation of “old text” versus 
“new text”, with “old text” referring to the most 
recent previous protocol version. Deletions are 
crossed out in the “old text”. Additions are 
underlined in the “new text”.

Tables / figures
The term “amended” is added to the caption.

Terminological changes
Brief specification of the terminological change
Correction of typos or omissions is not highlighted.
Section 2 Synopsis
15.1.2.1
This section was changed as a result of Modification 1.


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Old table
[…]
Study objective(s)
The primary objective of this study is to

Investigate the pharmacokinetics (PK) of copanlisib following a 
single intravenous (i.v.) dose of 12 mg copanlisib in subjects with 
moderate hepatic (Child Pugh B) or severe renal impairment 
compared with healthy subjects
The secondary objective of this study is to

Evaluate the PK of M-1 metabolite

Assess the safety and tolerability of copanlisib when administered 
to subjects with moderate hepatic or severe renal impairment
[…]
Diagnosis and main criteria for 
inclusion /exclusion
[…]
Subjects with moderate hepatic impairment 

Subjects with confirmed liver cirrhosis by at least one of the 
following criteria: histologically by prior liver biopsy showing 
cirrhosis, liver imaging (computer tomography, and/or ultrasound 
and/or magnetic resonance imaging scans, and/or fibroscan), or 
laparoscopy.

Child-Pugh Clinical Assessment Score 7 to 9.
Subjects with severe renal impairment 

Subjects with severe renal impairment with an estimated 
glomerular filtration rate 15-29 mL/min/1.73 m2 according to
MDRD formula.

Subjects with stable renal disease: no significant change in renal 
function as evidenced by serum creatinine value within ±25% 
from the last determination, obtained within at least 3 months 
before study entry and the absence of the need to start dialysis in 
the next 3 months.
Study design
Multi-center, non-randomized, open-label, single-dose, parallel group, 
study consisting of 3 groups (control group: normal hepatic and renal 
function group, Group A: moderate hepatic impairment group, Group B: 
severe renal impairment group
[…]
Number of subjects
Up to 32 evaluable male and female subjects with 8-16 evaluable subjects 
in the control group and 8 evaluable subjects in each investigational group 
(hepatic and renal impairment)
A minimum of 24 subjects (8/group) valid for PK of copanlisib (i.e., all 
blood samples for PK should be available up to 1 week [168 h]) will be 
required. Additional healthy subjects may be enrolled to achieve 
demographic matching between healthy and impaired groups until up to 
16 healthy subjects valid for PK of copanlisib (i.e., up to 1 week [168 h]).
[…]


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Plan for statistical analysis
To investigate the primary objective of this study regarding hepatic and 
renal impairment, analysis of variance appropriate for a parallel design will 
be fitted to the natural logarithmic transformation of PK parameters 
(AUC(0-168), AUC and Cmax) of copanlisib. The test/reference comparison 
ratio of geometric least-squares means and associated 90% confidence 
intervals (CIs) for each PK parameter in the moderate hepatic or severe 
renal impairment group versus the respectively matched healthy subject 
group will be calculated by exponentiation of the natural-log scale point 
estimate and the associated 90% CI.
New table
[…]
Study objective(s)
The primary objective of this study is to

Investigate the pharmacokinetics (PK) of copanlisib following a 
single intravenous (i.v.) dose of 12 mg copanlisib in subjects with 
moderate hepatic (Child Pugh B), severe hepatic (Child Pugh C)
or severe renal impairment compared with healthy subjects
The secondary objectives of this study is to

Evaluate the PK of M-1 metabolite

Assess the safety and tolerability of copanlisib when administered 
to subjects with moderate hepatic, severe hepatic or severe renal 
impairment
[…]


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Diagnosis and main criteria for 
inclusion /exclusion
[…]
Subjects with moderate hepatic impairment 

Subjects with confirmed liver cirrhosis by at least one of the 
following criteria: histologically by prior liver biopsy showing 
cirrhosis, liver imaging (computer tomography, and/or ultrasound 
and/or magnetic resonance imaging scans, and/or fibroscan), or 
laparoscopy.

Child-Pugh Clinical Assessment Score 7 to 9.
Subjects with severe hepatic impairment

Subjects with confirmed liver cirrhosis by at least one of the 
following criteria: histologically by prior liver biopsy showing 
cirrhosis, liver imaging (computer tomography, and/or ultrasound 
and/or magnetic resonance imaging scans, and/or fibroscan), or 
laparoscopy.

Child-Pugh Clinical Assessment Score 10-15.
Subjects with severe renal impairment 

Subjects with severe renal impairment with an estimated 
glomerular filtration rate 15-29 mL/min/1.73 m2 according to 
MDRD formula.

Subjects with stable renal disease: no significant change in renal 
function as evidenced by serum creatinine value within ±25% 
from the last determination, obtained within at least 3 months 
before study entry and the absence of the need to start dialysis in 
the next 3 months.
Study design
Multi-center, non-randomized, open-label, single-dose, parallel group, 
study consisting of 4 groups (control group: normal hepatic and renal 
function group, Group A: moderate hepatic impairment group, Group B: 
severe renal impairment group, Group C severe hepatic impairment group)
[…]
Number of subjects
Up to 44 evaluable male and female subjects with 8-22 evaluable subjects 
in the control group, 8 evaluable subjects each in the moderate hepatic
impairment and in the severe renal impairment investigational group, and 
6 evaluable subjects in the severe hepatic impairment investigational group.
A minimum of 30 subjects (8/group except for severe hepatic impairment: 
6) valid for PK of copanlisib (i.e., all blood samples for PK should be 
available up to 1 week [168 h]) will be required. Additional healthy 
subjects may be enrolled to achieve demographic matching between 
healthy and impaired groups until up to 22 healthy subjects valid for PK of 
copanlisib (i.e., up to 1 week [168 h]).
[…]


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Plan for statistical analysis
To investigate the primary objective of this study regarding hepatic and 
renal impairment, analysis of variance appropriate for a parallel design will 
be fitted to the natural logarithmic transformation of PK parameters 
(AUC(0-168), AUC and Cmax) of copanlisib. The test/reference comparison 
ratio of geometric least-squares means and associated 90% confidence 
intervals (CIs) for each PK parameter in the moderate hepatic, severe 
hepatic or severe renal impairment group versus the respectively matched 
healthy subject group will be calculated by exponentiation of the natural-
log scale point estimate and the associated 90% CI.
List of abbreviations
15.1.2.2
This section was changed as a result of Modification 3.
Old table
[…]
ePRO
electronic subject-reported outcome
Estradiol
E2
EU
European Union
[…]
New table
[…]
ePRO
electronic subject-reported outcome
E2
estradiol
EU
European Union
[…]
Section 3 Introduction
15.1.2.3
This section was changed as a result of Modification 1, 14, and 16.
Old text
Background
[…]
Copanlisib (BAY 806946) is a novel, highly selective, -panclass- PI3K inhibitor with potent 
activity against both and isoforms, with in vitro IC50 of 0.5 nM and 0.7 nM, respectively.
[…]


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Rationale of the study
[…]
This study will evaluate the PK and safety of a single 12-mg dose of copanlisib in subjects 
with moderate hepatic impairment or severe renal impairment of copanlisib and in age-, 
gender-, and weight-matched healthy controls. The results of this study will provide guidance 
for drug labeling recommendations for copanlisib in these subjects.
Benefit-risk assessment
As of today approximately 675 subjects with advanced cancer have been treated with 
copanlisib (BAY 806946) in eight different Phase 1 studies, three Phase 2 studies and 
three Phase 3 studies. 
[…]
New text
Background
[…]
Copanlisib (BAY 80-6946, approved by the Food and Drug Administration [FDA] in 
September 2017) is a novel, highly selective, -panclass- PI3K inhibitor with potent activity 
against both and isoforms, with in vitro IC50 of 0.5 nM and 0.7 nM, respectively.
[…]
Rationale of the study
[…]
This study will evaluate the PK and safety of a single 12-mg dose of copanlisib in subjects 
with moderate or severe hepatic impairment or severe renal impairment of copanlisib and in 
age-, gender-, and weight-matched healthy controls. The results of this study will provide 
guidance for drug labeling recommendations for copanlisib in these subjects.
Benefit-risk assessment
As of today approximately 675 subjects with advanced cancer have been treated with 
copanlisib (BAY 80-6946) in eight different Phase 1 studies, three Phase 2 studies and 
three Phase 3 studies. 
[…]
Section 4 Study objectives
15.1.2.4
This section was changed as a result of Modification 1.


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Old text
The primary objective of this study is to

Investigate the PK of copanlisib following a single i.v. dose of 12 mg copanlisib in 
subjects with moderate hepatic (Child Pugh B) or severe renal impairment compared 
with healthy subjects
The secondary objective of this study is to

Evaluate the PK of M-1 metabolite

Assess the safety and tolerability of copanlisib when administered to subjects with 
moderate hepatic or severe renal impairment
[…]
New text
The primary objective of this study is to

Investigate the PK of copanlisib following a single i.v. dose of 12 mg copanlisib in 
subjects with moderate hepatic (Child Pugh B), severe hepatic (Child Pugh C) or 
severe renal impairment compared with healthy subjects
The secondary objective of this study is to

Evaluate the PK of M-1 metabolite

Assess the safety and tolerability of copanlisib when administered to subjects with 
moderate hepatic, severe hepatic or severe renal impairment
[…]
Section 5 Study design
15.1.2.5
This section was changed as a result of Modification 1 and 12.
Old text
Design overview
This will be a multi-center, non-randomized, open-label, single-dose, parallel group, study 
consisting of 3 groups. The effect of moderate hepatic impairment (Child Pugh B) and severe 
renal impairment on the PK of copanlisib and M-1 will be investigated. In total, up to 
32 evaluable male and female subjects with 8-16 evaluable subjects in the control group and
8 evaluable subjects in each investigational group (hepatic and renal impairment) will 
participate in the study (Table 5-1). Each subject will be administered 12 mg of copanlisib (i.v. 
over 1 h). 


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Table 5-1: Groups
Group
Description
Number of evaluable subjects
Control group
Normal hepatic and renal function group 
matched to the groups of hepatic and 
renal impairment
8-16
Group A
Moderate hepatic impairment group: 
Child-Pugh B (score 7-9) at the screening 
visit
8 
Group B
Severe renal impairment group:
eGFR 15-29 mL/min/1.73 m2 at the 
screening visit based on the Modification 
of Diet in Renal Disease (MDRD) 
equation
8 
The control group (normal hepatic and renal function) should match with the groups of 
hepatic and renal impairment. Matching criteria will be age, body weight, and gender. Mean 
age and body weight between the control group and the groups with hepatic and renal 
impairment should not vary by more than ±10 years and ±10 kg. Therefore, enrollment in the 
control group will remain open until the enrollment in the moderate hepatic and severe renal 
impairment groups is complete and a sufficient number of matching controls have been 
achieved for comparison. 
[…]
At pre-dose, which in this study is the evening prior to the administration of the study 
medication, the in- / exclusion criteria will be finally checked. During the treatment phase the 
study objectives will be followed, and the related measures will be performed.
[…]
Justification of the design
This study will investigate the PK of copanlisib and M-1 after administration of 12 mg of 
copanlisib i.v. over 1 h to subjects with moderate hepatic impairment or subjects with severe 
renal impairment compared to healthy subjects. The choice of the trial design was made based 
on the following:

The PK measurements are the primary focuses of the study, therefore a non-
randomized, open-label, parallel group design with 3 groups is considered adequate.
[…]
New text
Design overview
This will be a multi-center, non-randomized, open-label, single-dose, parallel group, study 
consisting of 4 groups. The effect of moderate hepatic impairment (Child Pugh B), severe 


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hepatic impairment (Child Pugh C) and severe renal impairment on the PK of copanlisib and 
M-1 will be investigated. In total, up to 44 evaluable male and female subjects with 
8-22 evaluable subjects in the control group, 8 evaluable subjects each in the moderate hepatic 
and severe renal impairment investigational group, and 6 evaluable subjects in the severe 
hepatic investigational group will participate in the study (Table 5-1). Each subject will be 
administered 12 mg of copanlisib (i.v. over 1 h). 
Table 5-1: Groups 
Group
Description
Number of evaluable subjects
Control group
Normal hepatic and renal function group 
matched to the groups of hepatic and 
renal impairment
8-22
Group A
Moderate hepatic impairment group: 
Child-Pugh B (score 7-9) at the screening 
visit
8 
Group B
Severe renal impairment group:
eGFR 15-29 mL/min/1.73 m2 at the 
screening visit based on the Modification 
of Diet in Renal Disease (MDRD) 
equation
8 
Group C
Severe hepatic impairment group: 
Child-Pugh C (score 10-15) at the 
screening visit
6
The control group (normal hepatic and renal function) should match with the groups of 
hepatic and renal impairment. Matching criteria will be age, body weight, and gender. Mean 
age and body weight between the control group and the groups with hepatic and renal 
impairment should not vary by more than ±10 years and ±10 kg. Therefore, enrollment in the 
control group will remain open until the enrollment in the moderate and severe hepatic and 
severe renal impairment groups is complete and a sufficient number of matching controls 
have been achieved for comparison.
[…]
The in- / exclusion criteria will be finally checked after the results of the safety laboratory
from the morning of Day -1 are available (evening of Day -1/morning of the dosing day).
During the treatment phase the study objectives will be followed, and the related measures 
will be performed. 
[…]
Justification of the design
This study will investigate the PK of copanlisib and M-1 after administration of 12 mg of 
copanlisib i.v. over 1 h to subjects with moderate hepatic impairment, with severe hepatic 
impairment or subjects with severe renal impairment compared to healthy subjects. 


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The choice of the trial design was made based on the following:

The PK measurements are the primary focuses of the study, therefore a non-
randomized, open-label, parallel group design with 4 groups is considered adequate.
[…]
Section 6.1.5 Subjects in Group C: severe hepatic impairment
15.1.2.6
This section was added as a result of Modification 1.
New section
Section 6.1.5: Subjects in Group C: severe hepatic impairment
22. Subjects with confirmed liver cirrhosis by at least one of the following criteria:

Histologically by prior liver biopsy showing cirrhosis.

Liver imaging (computer tomography, and/or ultrasound and/or magnetic 
resonance imaging scans, and/or fibroscan).

Laparoscopy.
23. Child-Pugh Clinical Assessment Score 10 to 15 at screening (see Section 16.3). For 
subjects with hepatic encephalopathy, the condition does not, in the investigator's 
opinion, interfere with the participant's ability to provide an appropriate informed 
consent.
24. Subjects with active Hepatitis B or Hepatitis C virus (HCV) can be included into the 
study but only in stable condition without ongoing or indicator of immediate antiviral 
treatment.
25. History of alcohol abuse is permissible providing that the results of alcohol test are 
negative at screening and on Day -1.
Section 6.2.1: All subjects
15.1.2.7
This section was changed as a result of Modification 15.
Old text
[…]
Laboratory examination
22. Neutrophils <1000/μL at inclusion.
23. Positive urine drug screening at screening and Day -1.
[…]
New text
[…]
Laboratory examination
22. Neutrophils <1500/μL at inclusion.
23. Positive urine drug screening at screening and Day -1.
[…]


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Section 6.2.5 Subject in Group C: severe hepatic impairment
15.1.2.8
This section was added as a result of Modification 1.
New section
Section 6.2.5: Subject in Group C: severe hepatic impairment
Medical and surgical history
64. Has active encephalopathy Grade III or IV, (time needed in the number connection 
test at screening or admission exceeds 80 sec) within 2 months prior to dosing. (For 
number connection test, please see Section 16.7).
65. Subjects with sclerosing cholangitis. 
66. Failure of any other major organ other than the liver; severe infection, or any clinically 
significant illness within 4 weeks prior to study drug administration. 
67. Renal failure with an eGFR <35 mL/min/1.73 m2 (according to MDRD formula, see 
Section 16.5).
68. Clinical evidence of severe ascites more than 6 L by ultrasound.
69. Esophageal variceal bleeding within 3 months prior to dosing.
Medication, drug use and special behavioral pattern
70. Subjects with a change of their chronic medication less than 4 weeks prior to study 
drug administration.
Laboratory examination
71. Any evidence of progressive liver disease (within the last 4 weeks) as indicated by 
liver transaminases (>4 x ULN), alkaline phosphatase (>4 x ULN), and GGT (>4 x 
ULN) (an isolated elevation of GGT above 4 times ULN will not exclude the subject).
72. Serum albumin <20 g/L. 
73. Hemoglobin <8 g/dL.
74. Platelet count <50 x 109/L.
Section 6.4.2 Replacement
15.1.2.9
This section was changed as a result of Modification 1.
Old text
Subjects who drop out may be replaced to obtain a minimum of 24 subjects (8/group) valid 
for PK of copanlisib (i.e., all blood samples for PK should be available up to 1 week [168 h]). 
Additional healthy subjects may be enrolled to achieve demographic matching between 
healthy and impaired groups in up to 16 healthy subjects valid for PK of copanlisib (i.e., up to 
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New text
Subjects who drop out may be replaced to obtain a minimum of 30 subjects (8/group except 
for severe hepatic impairment: 6) valid for PK of copanlisib (i.e., all blood samples for PK 
should be available up to 1 week [168 h]). Additional healthy subjects may be enrolled to 
achieve demographic matching between healthy and impaired groups in up to 22 healthy 
subjects valid for PK of copanlisib (i.e., up to 1 week [168 h]).
Section 6.5 Subject identification
15.1.2.10
This section was changed as a result of Modification 12.
Old text
[…]
In the evening of day -01 after final check of inclusion and exclusion criteria, subjects who 
meet the entry criteria will be sequentially assigned to a unique number in ascending order 
(treatment number).
New text
[…]
In the morning of the dosing day before start of infusion and after assessing the pre-dose 
blood pressure and glucose values, subjects who meet the entry criteria will be sequentially 
assigned to a unique number in ascending order (treatment number).
Section 7.1 Treatments to be administered
15.1.2.11
This section was changed as a result of Modification 1 and 4.
Old table
Table 7-1: Treatments administered
Group
Dose of copanlisib / 
route
Frequency of 
administration
No. of evaluable 
subjects
Control group 
(healthy subjects)
12 mg i.v. over 1 h
Single dose on Day 1
8-16
Group A 
(moderate 
hepatic 
impairment 
group)
12 mg i.v. over 1 h
Single dose on Day 1
8
Group B (renal 
impairment 
group)
12 mg i.v. over 1 h
Single dose on Day 1
8


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New table
Table 7-1: Treatments administered 
Group
Dose of copanlisib / 
route
Frequency of 
administration
No. of evaluable 
subjects
Control group 
(healthy subjects)
12 mg i.v. over 1 h
Single dose on Day 1
8-22
Group A 
(moderate 
hepatic 
impairment 
group)
12 mg i.v. over 1 h
Single dose on Day 1
8
Group B (severe
renal impairment 
group)
12 mg i.v. over 1 h
Single dose on Day 1
8
Group C (severe 
hepatic 
impairment 
group)
12 mg i.v. over 1 h
Single dose on Day 1
6
Section 7.2 Identiy of study drugs
15.1.2.12
This section was changed as a result of Modification 16.
Old table
Table 7-2: Identity of copanlisib
Chemical name
2amino-N[7methoxy-8(3morpholin-4ylpropoxy)-2,3dihydroimidazo [1,2-
c]quinazolin-5yl]pyrimidine-5carboxamide dihydrochloride
Substance code number
BAY 806946 (free base) 
Appearance
white to slightly yellowish lyophilisate
Formulation
Freeze-dried product containing 78.8 mg BAY 84-1236  (= Copanlisib 
dihydrochloride; equivalent to 68.4 mg copanlisib, free base, 
BAY 806946) in a 6 mL injection vial  
Composition
Copanlisib dihydrochloride, citric acid, mannitol, sodium hydroxide
Type of primary packaging
Glass vial for injections (6 mL)


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New table
Table 7-2: Identity of copanlisib
Chemical name
2amino-N[7methoxy-8(3morpholin-4ylpropoxy)-2,3dihydroimidazo [1,2-
c]quinazolin-5yl]pyrimidine-5carboxamide dihydrochloride
Substance code number
BAY 80-6946 (free base) 
Appearance
white to slightly yellowish lyophilisate
Formulation
Freeze-dried product containing 78.8 mg BAY 84-1236  (= Copanlisib 
dihydrochloride; equivalent to 68.4 mg copanlisib, free base, 
BAY 80-6946) in a 6 mL injection vial  
Composition
Copanlisib dihydrochloride, citric acid, mannitol, sodium hydroxide
Type of primary packaging
Glass vial for injections (6 mL)
Section 7.3 Treatment assignment
15.1.2.13
This section was changed as a result of Modification 1 and 2.
Old text
[…]
Subjects will be assigned to the following treatment numbers:

Subjects with moderate hepatic impairment (site 

Subjects with moderate hepatic impairment (site 

Subjects with severe renal impairment (site 

Subjects with severe renal impairment (site 

Control subjects (site 

Control subjects (site 
Additional numbers will be used in case of replacements being needed; the replacing 
participant will receive the original subject’s treatment number 
 (site 
 or + 
 (site 
New text
[…]
Subjects will be assigned to the following treatment numbers:

Subjects with moderate hepatic impairment (site 

Subjects with moderate hepatic impairment (site 

Subjects with severe renal impairment (site 

Subjects with severe renal impairment (site 

Subjects with severe hepatic impairment (site 

Subjects with severe hepatic impairment (site 

Subjects with severe hepatic impairment (site 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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
Control subjects (site 

Control subjects (site 

Control subjects (site 
Additional numbers will be used in case of replacements being needed; the replacing 
participant will receive the original subject’s treatment number 
 (site 
 or 
 (site 
 
or 
 (site 
Section 7.4.1 Selection of doses in the study
15.1.2.14
This section was changed as a result of Modification 1.
Old text
Each subject will be given 12 mg of copanlisib (i.v. over 1 h). 
Rationale for copanlisib 12 mg dose 
The 12 mg dose has been chosen (not the Recommended Phase II Dose of 60 mg) to assess 
the effects of moderate hepatic or severe renal impairment on copanlisib PK. The rationale for 
this is the observed dose-linear PK of copanlisib and also the favorable safety profile of 
12 mg copanlisib dose in healthy subjects (Human mass balance study 16353). Therefore, the 
12 mg dose can be used across all three groups in this study. 
[…]
New text
Each subject will be given 12 mg of copanlisib (i.v. over 1 h). 
Rationale for copanlisib 12 mg dose 
The 12 mg dose has been chosen (not the Recommended Phase II Dose of 60 mg) to assess 
the effects of moderate hepatic, severe hepatic or severe renal impairment on copanlisib PK. 
The rationale for this is the observed dose-linear PK of copanlisib and also the favorable 
safety profile of 12 mg copanlisib dose in healthy subjects (Human mass balance 
study 16353). Therefore, the 12 mg dose can be used across all four groups in this study. 
[…]
Section 7.6 Drug logistics and accountability
15.1.2.15
This section was changed as a result of Modification 2.
Old text
All study drugs will be stored at the contracted pharmacy 
 or at the study site 
 in accordance with Good Clinical Practice (GCP) and Good 
Manufacturing Practice (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.
[…]
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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New text
All study drugs will be stored at the contracted pharmacy 
 or at the study site 
 in accordance with Good Clinical 
Practice (GCP) and Good Manufacturing Practice (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.
[…]
Section 9.2.1 Screening visit
15.1.2.16
This section was changed as a result of Modification 5.
Old text

[…]

Physical examination (complete)

Vital signs: blood pressure and pulse rate after resting for at least 10 min in sitting 
position and body temperature

12-lead ECG after resting for at least 10 min in a supine position

[…]
New text

[…]

Physical examination (complete)

Vital signs: blood pressure and pulse rate after resting for at least 10 min in supine 
position and body temperature

12-lead ECG after resting for at least 10 min in a supine position

[…]
Section 9.2.4.1 Dosing and profile day (Study Day 1, relative time: 
15.1.2.17
day 00)
This section was changed as a result of Modification 8 and 9.
Old text

[…]

Abbreviated physical examination

After a bed rest for at least 10 min, the following baseline measurements will be 
carried out: 12-lead ECG, vital signs (blood pressure/pulse rate, body temperature), 
blood sample (fasting capillary blood glucose, PK, protein binding assessment)

Open questioning for / documentation of AEs and previous/concomitant medication 
(update)
PPD
PPD


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
[…]

Throughout the day until 12 h p.a.:

Capillary glucose 1h after start of copanlisib infusion (end of infusion), 1, 2, 3, 4,
6, 8 h after start of infusion, further capillary glucose if necessary

Further capillary glucose assessment at the discretion of the investigator (based of 
previous blood glucose levels)

[…]
New text

[…]

Abbreviated physical examination

After a bed rest for at least 10 min, the following baseline measurements will be 
carried out: 12-lead ECG, vital signs (blood pressure/pulse rate, body temperature), 
blood sample (fasting capillary blood glucose, PK)

Open questioning for / documentation of AEs and previous/concomitant medication 
(update)

[…]

Throughout the day until 12 h p.a.:

Capillary glucose 1h after start of copanlisib infusion (end of infusion), 1, 2, 3, 6, 
8 h after start of infusion, further capillary glucose if necessary

Further capillary glucose assessment at the discretion of the investigator (based of 
previous blood glucose levels)

[…]
Section 9.2.6.1 Restrictions
15.1.2.18
This section was changed as a result of Modification 10.
Old table
Table 9-1: Restrictions during the study
What?
Restriction
Smoking
not allowed during the study
Alcohol
not permitted from 48 h prior to the dosing until Day 7
[…]


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New table
Table 9-1: Restrictions during the study
What?
Restriction
Smoking
not allowed during the in-house phase of the study
Alcohol
not permitted from 48 h prior to the dosing until Day 7
[…]
Section 10.3 Variables and planned statistical analyses
15.1.2.19
This section was changed as a result of Modification 1.
Old text
[…]

Pharmacokinetic variables
[…]
To investigate the primary objective of this study regarding hepatic and renal impairment, 
analysis of variance appropriate for a parallel design will be fitted to the natural logarithmic 
transformation of PK parameters (AUC(0-168), AUC and Cmax) of copanlisib . The 
test/reference comparison ratio of geometric least-squares means and associated 90% 
confidence intervals (CIs) for each PK parameter in the moderate hepatic or severe renal 
impairment group versus the matched healthy subjects group will be calculated by 
exponentiation of the natural-log scale point estimate and the associated 90% CI.
New text
[…]

Pharmacokinetic variables
[…]
To investigate the primary objective of this study regarding hepatic and renal impairment, 
analysis of variance appropriate for a parallel design will be fitted to the natural logarithmic 
transformation of PK parameters (AUC(0-168), AUC and Cmax) of copanlisib . The 
test/reference comparison ratio of geometric least-squares means and associated 90% 
confidence intervals (CIs) for each PK parameter in the moderate hepatic, severe hepatic or 
severe renal impairment group versus the matched healthy subjects group will be calculated 
by exponentiation of the natural-log scale point estimate and the associated 90% CI.


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Section 10.4 Determination of sample size
15.1.2.20
This section was changed as a result of Modification 1.
Old text/table
The study population will consist of up to 32 evaluable male and female subjects with 
8-16 evaluable subjects in the control group and 8 evaluable subjects in each investigational 
group (hepatic and renal impairment). The sample size of 8 subjects in each of the groups 
with impaired hepatic and renal function has been selected based on practical consideration 
and following the FDA guidance [4][5].
[…]
For AUC(0-168), a sample size of 8 eligible subjects per each group would provide an 
approximately 90% chance for the 90% confidence interval for the ratio of geometric least-
squares means between impaired subjects and healthy subjects to be within a 2-fold 
difference, that is, within limits of 50% to 200% for AUC(0-168). This can be shown in the 
table below based on different observed ratios.
Table 10-1: 90% Confidence interval for copanlisib
Observed Ratio
90% CI for the ratio
1
(0.685, 1.461)
1.1
(0.753, 1.607)
1.2
(0.822, 1.753)
1.3
(0.890, 1.899)
New text/tables
The study population will consist of up to 44 evaluable male and female subjects with 
8-22 evaluable subjects in the control group, 8 evaluable subjects each in the moderate 
hepatic and severe renal impairment investigational group, and 6 evaluable subjects in the 
severe hepatic impairment investigational group. The sample size of 8 subjects in each of the 
groups with impaired moderate hepatic and severe renal function and 6 subjects in the severe 
hepatic impairment group has been selected based on practical consideration and following 
the FDA guidance [4][5]. 
[…]
For AUC(0-168), a sample size of 8 eligible subjects each in the control, moderate hepatic 
and severe renal impairment investigational group would provide an approximately 90% 
chance for the 90% confidence interval for the ratio of geometric least-squares means 
between impaired subjects and healthy subjects to be within a 2-fold difference, that is, within 
limits of 50% to 200% for AUC(0-168). This can be shown in Table 10-1 based on different 
observed ratios.


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Table 10-1: 90% Confidence interval for copanlisib with N=8 per group 
Observed Ratio
90% CI for the ratio
1
(0.685, 1.461)
1.1
(0.753, 1.607)
1.2
(0.822, 1.753)
1.3
(0.890, 1.899)
A sample size of 6 eligible subjects per each in the control and severe hepatic impairment 
investigational group would provide an approximately 90% chance for the 90% confidence 
interval for the ratio of geometric least-squares means between impaired subjects and healthy 
subjects to be within an approximately 2-fold difference, that is, within limits of 50% to 207% 
for AUC(0-168) as shown in Table 10-2 based on different observed ratios.
Table 10-2: 90% Confidence interval for copanlisib with N=6 per group 
Observed Ratio
90% CI for the ratio
1
(0.628, 1.593)
1.1
(0.691, 1.752)
1.2
(0.753, 1.911)
1.3
(0.816, 2.07)
Section 10.5 Planned interim analyses
15.1.2.21
This section was changed as a result of Modification 1.
Old text
A formal interim analysis is not planned. However; all data will be reviewed during the study 
on an ongoing basis for potential deviations from expected safety and pharmacokinetics 
results.
New text
An interim analysis will be conducted after 8 evaluable subjects with moderate hepatic 
impairment and 8 evaluable subjects with severe renal impairment with their corresponding 
matching healthy volunteers have completed the study to fulfill the first part of the post 
marketing requirement as agreed with the FDA (July 2019) based on the accelerated approval 
of copanlisib (September 14, 2017). This interim analysis will also serve as a final analysis on 
the moderate hepatic impairment and severe renal impairment groups in the final clinical 
study report. The results of the final report will include subjects with severe hepatic 
impairment as agreed with FDA (July 2021).
Section 16.1 Study flow chart
15.1.2.22
This section was changed as a result of Modification 7, 11, 12, and 13.


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Old table
Table 16-1: Study flow chart: Screening (all subjects) (continued)
Screeninga 
Study Day
-28 to -2
Relative time
day
- 28 to -02
Informed consent (date of written informed consent)
X
[…]
Blood pressure b,c, pulse rate b,c, body temperature
X
[…]
[…]
b
Before any study specific tests or procedures are done
[…]
New table
Table 16-1: Study flow chart: Screening (all subjects) (continued)
Screeninga 
Study Day
-28 to -2
Relative time
day
- 28 to -02
Informed consent (date of written informed consent)b
X
[…]
Blood pressure c, pulse rate c, body temperature
X
[…]
[…]
b
Before any study specific tests or procedures are done
[…]


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Old table
Table 16-1: Study flow chart (continued): -00d16h – 07d00h (all subjects) (continued)
Study period
Treatment Period
Study Day
-1
1
2
3
4
5
6
Relative time
day
hour
minute
-01
-00
-00
00
00
00
00
00
00
00
00
00
00
00
00
01
02
03
04
05
00
01
00
00
00
01
01
02
02
03
05
06
08
10
12
00
00
00
00
00
00
30
30
00
10
00
30
00
30
00
00
00
00
00
00
00
00
00
00
00
Approximate 24-hour clock time 
1st subject
08:00
06:30 07:30 08:00 08:10 09:00 09:30 10:00 10:30 11:00 13:00 14:00 16:00 18:00 20:00 08:00 08:00 08:00 08:00 08:00
In-house
X














X
Ambulatory follow-up visits
X
X
X
Final check of inclusion/exclusion 
criteria
X
[…]
Fastingi
X




X
[…]
X
[…]


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New table
Table 16-1: Study flow chart (continued): -01d00h – 05d00h (all subjects) (continued)
Study period
Treatment Period
Study Day
-1
1
2
3
4
5
6
Relative time
day
hour
minute
-01
-00
-00
00
00
00
00
00
00
00
00
00
00
00
00
01
02
03
04
05
00
01
00
00
00
01
01
02
02
03
05
06
08
10
12
00
00
00
00
00
00
30
30
00
10
00
30
00
30
00
00
00
00
00
00
00
00
00
00
00
Approximate 24-hour clock time 
1st subject
08:00
06:30 07:30 08:00 08:10 09:00 09:30 10:00 10:30 11:00 13:00 14:00 16:00 18:00 20:00 08:00 08:00 08:00 08:00 08:00
In-house
X














X
Ambulatory follow-up visits
X
X
X
Final check of inclusion/exclusion 
criteria
Xl
[…]
Fastingi
X






X
[…]
X
[…]
l
Final check of inclusion and exclusion criteria takes place after availability of the safety laboratory results (evening of Day -1 or morning of 
Day 1)


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Section 16.2 Laboratory analyses
15.1.2.23
This section was changed as a result of Modification 2 and 6.
Old table
Table 16-2: Parameters of laboratory analyses
[…]
Urinalysis - dipstick:
Hemoglobin/erythrocytes, pH, protein, glucose, bilirubin, urobilinogen, 
ketone, nitrite, leukocytes (semi-quantitatively/dipstick) 
 None (to be 
performed at the study 
site) 
 Local 
laboratory
[…]
Pregnancy test in blood or urine
beta-hCG (within 7 days prior to dosing), in women with reproductive 
potential including women whose partners are sterilized)
Blood: Local laboratory
Urine: None (to be 
performed at the study 
site)
Urine drug screen:
Methadone, cocaine, amphetamines and methamphetamine/ecstacy, 
cannabinoids, barbiturates, benzodiazepines, tricyclic antidepressants, 
phencyclidin, morphine/opiates
None (to be performed at 
the study site)
[…]
New table
Table 16-2: Parameters of laboratory analyses
[…]
Urinalysis - dipstick:
Hemoglobin/erythrocytes, pH, protein, glucose, bilirubin, urobilinogen, 
ketone, nitrite, leukocytes (semi-quantitatively/dipstick) 
 None (to be 
performed at the study 
site) 
 Local 
laboratory
 local 
laboratory
[…]
Pregnancy test in blood or urine
beta-hCG (within 7 days prior to dosing), in women with reproductive 
potential including women whose partners are sterilized)
Blood: Local laboratory
Urine: None (to be 
performed at the study 
site)
Follicle stimulating hormone in blood
In postmenopausal women ≤50 years of age
Local laboratory
Urine drug screen:
Methadone, cocaine, amphetamines and methamphetamine/ecstacy, 
cannabinoids, barbiturates, benzodiazepines, tricyclic antidepressants, 
phencyclidin, morphine/opiates
None (to be performed at 
the study site)
[…]
PPD
PPD
PPD
PPD
PPD


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Section 16.3 Assessment of hepatic impairment
15.1.2.24
This section was added as a result of Modification 1.
Old text
In Group A, subjects with moderate hepatic impairment will be included (Child-Pugh B: 
score 7-9).
[…]
New text
In Group A, subjects with moderate hepatic impairment will be included (Child-Pugh B: 
score 7-9) and in Group C, subjects with severe hepatic impairment will be included (Child-
Pugh C: score 10-15).
[…]
16.
Appendices
Study flow chart - amended
16.1
The reference point (relative time: day 00 : hour 00 : minute 00) for the time matrix to be used 
for data evaluation will be the administration of copanlisib. All measures / actions to be 
performed before this reference point will be assigned to negative time points, all 
subsequent measures / actions will have positive time points. Table 16-1 in the following 
provides a flow chart presenting the time points for the study related measures / actions. 


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Table 16-1: Study flow chart: Screening (all subjects) (continued) - amended
Screeninga 
Study Day
-28 to -2
Relative time
day
- 28 to -02
Informed consent (date of written informed consent)b32
X
Allocation of screening number
X
Demographic data collection
X
Height, weight, body mass index
X
Medical and surgical history 
X
Smoking history, alcohol / diet
X
Participation in previous clinical studies
X
Current and previous medication
X
Complete physical examination
X
Blood pressure c, pulse rate c, body temperature
X
12-lead electrocardiogram c
X
Blood sampling
-  Safety (clinical chemistry, hematology, coagulation) d
X
-  HbA1C
X
-  Virology: HIV, HBs-Ag, Anti HCV-AB
X
Urine sampling
- Safety (dipstick sediment) d
X
-  Drug screen
X
Alcohol breath test
X
Child Pugh Scoring (for hepatic impaired subjects)
X
Number connection test (for hepatic impaired subjects)
X
eGFR calculation e
X
Adverse events
X
Eligibility check 
X
anti HCV-AB=hepatitis C virus antibodies, eGFR=estimated glomerular filtration rate, HbA1c=glycated 
hemoglobin, HBs-AG=Hepatitis B surface antigen, HIV=human immunodeficiency virus
X
To be done at the time point indicated
a
Within 28 days prior to treatment
b
Before any study specific tests or procedures are done
c
After at least 10 min rest in supine position
d
In fasted state
e
For all subject calculation according to MDRD
                                                
32 Footnote “b” shifted from blood pressure and pulse rate to informed consent according to Amendment 1


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Table 16-1: Study flow chart (continued): -01d00h – 05d00h33 (all subjects) (continued) - amended
Study period
Treatment Period
Study Day
-1
1
2
3
4
5
6
Relative time
day
hour
minute
-01
-00
-00
00
00
00
00
00
00
00
00
00
00
00
00
01
02
03
04
05
00
01
00
00
00
01
01
02
02
03
05
06
08
10
12
00
00
00
00
00
00
30
30
00
10
00
30
00
30
00
00
00
00
00
00
00
00
00
00
00
Approximate 24-hour clock time 
1st subject
08:00
06:30 07:30 08:00 08:10 09:00 09:30 10:00 10:30 11:00 13:00 14:00 16:00 18:00 20:00 08:00 08:00 08:00 08:00 08:00
In-house
X














X
Ambulatory follow-up visits
X
X
X
Final check of inclusion/exclusion 
criteria
Xl
Medical History
Xa
Pregnancy test in blood or urine
Xf
Complete physical examination
X
Abbreviated physical examination
X
X
X
Urine drug screen, alcohol breath 
test
X
Fastingi
X





X34
Low glycemic breakfasti
X
Study drug administrationi
X

X
Blood sampling
- PK assessment of copanlisib 
and M-1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
- Protein binding/ fraction  
unbound (fu) calculation
X
X
- Safetyd (clinical chemistry, 
hematology, coagulation)
X
X
X
Urine sampling
- PK of copanlisib and M-1
X








X


X
                                                
33 Time period revised in title according to Amendment 1
34 Fasting period prolonged until 2 h after end of infusion according to Amendment 1 (protocol Version 1.0 stated fasting lasts until 1 h after end of infusion)


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Table 16-1: Study flow chart (continued): -01d00h – 05d00h33 (all subjects) (continued) - amended
Study period
Treatment Period
Study Day
-1
1
2
3
4
5
6
Relative time
day
hour
minute
-01
-00
-00
00
00
00
00
00
00
00
00
00
00
00
00
01
02
03
04
05
00
01
00
00
00
01
01
02
02
03
05
06
08
10
12
00
00
00
00
00
00
30
30
00
10
00
30
00
30
00
00
00
00
00
00
00
00
00
00
00
Approximate 24-hour clock time 
1st subject
08:00
06:30 07:30 08:00 08:10 09:00 09:30 10:00 10:30 11:00 13:00 14:00 16:00 18:00 20:00 08:00 08:00 08:00 08:00 08:00
- Safetyd (dipstick sediment)
X
X
X
12-lead electrocardiogram c
X
X
X
X
X
X
Vital signs (body temperature, 
blood pressure/pulse rate)c
X
X
X
X
X
X
Capillary glucose
Xk
X
X
X
X
X
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Documentation of meal time
X











X
Xj
Xj
Adverse events
X


















Previous/Concomitant 
medications
X


















Discharge from ward
X
EoI=end of infusion, PK=pharmacokinetics
X
To be done at the time point indicated

To be done continuously, starting from the time point indicated
a
Medical History: update only
c
After at least 10 min rest in supine position
d
In fasted state
f
Within 7 days prior to dosing in women with reproductive potential (including women whose partners are sterilized
g
Not mandatory, depends on result of prior capillary glucose results
h
End-of-treatment: within 7 + 3 days after administration
i
Subjects will receive a low glycemic breakfast at 1.5 h prior to start of the infusion. The breakfast should be completed 1 h prior to start of the infusion. 
Subjects should remain fasted until 2 h after the end of infusion. During the fasting period after the infusion water may be consumed.
j
Only in case of hyperglycemia
k
Prior to glycemic breakfast
l
Final check of inclusion and exclusion criteria takes place after availability of the safety laboratory results (evening of Day -1 or morning of Day 1).35
                                                
35 Footnote added according to Amendment 1


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Table 16-1: Study flow chart (continued): End-of-treatment and safety follow-up (all 
subjects)
End-of 
treatment
Telephone interview 
Study Day
8 (+3)
15 (±3)
31 (+3)
Relative 
time
day
7 (+3)
14 (±3)
30 (+3)
Ambulatory follow-up visits
X
Complete physical examination
X
Vital signs
X
12-lead ECG
X
Blood sampling
- safety (clinical chemistry, hematology, 
coagulation)
X
- PK assessment of copanlisib and M-1
X
Urine sampling
- Safetyd (dipstick sediment)
X
Adverse events
X
Xa
Xa
Concomitant medication 
X
X
X
a
Any AEs ongoing at Safety Follow-up visit 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. All SAEs (including deaths) occurring up to 30 days after the single dose 
should be reported to the sponsor per usual SAE reporting procedures.
d
In fasted state
Laboratory analyses - amended
16.2
Detailed information about the volume, collection, processing, storage and shipment of the 
samples will be provided separately (e.g. sample handling sheets and / or laboratory manual). 
The amount of blood planned to be withdrawn during the course of this study will be below 
500 mL. The approximate volume will be given in the Subject Information Sheet and Consent 
Form. The calculation sheet of the total amount of blood to be withdrawn per subject will be 
stored in the study files.
Table 16-2 provides information on the parameters to be analyzed, and indicates the 
laboratories to be used.
Samples relevant for the subject’s safety evaluation will be immediately analyzed, and the 
respective results will be made promptly available to the investigator. Samples collected for 
non-safety purposes may be stored under pre-defined conditions until final analysis.
Sampling in the morning for the laboratory examinations will be done on a fasting state of the 
subjects, i.e. an overnight fast of ≥10 h has to be adhered to: nothing to eat or drink except for 
water. During the treatment period, refer to Section 9.2.6.1 and Section 9.2.6.2 for alimentary 
restrictions imposed.


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Table 16-2: Parameters of laboratory analyses - amended
Parameters (by group)
Sample destination
Hematology:
Leukocytes, erythrocytes, hemoglobin, hematocrit, MCV, MCH, MCHC, 
platelets, WBC with differential to include absolute neutrophil, lymphocyte, 
monocyte, basophil and eosinophil counts.
Local laboratory
Coagulation:
Prothrombin time (Quick), reagent-independent prothrombin ratio (INR, 
international normalized ratio), activated partial thromboplastin time
Local laboratory
Clinical chemistry:
AST, ALT, AP, GGT, LDH, CK, total amylase, lipase, plasma glucose 
(fasted), cholesterol (total), triglycerides, creatinine, urea, uric acid, total 
bilirubin, total protein, albumin, sodium, potassium, calcium (total/corrected 
calcium or ionized calcium), chloride, magnesium, inorganic phosphate
Local laboratory
Glucose metabolism: HbA1c
Local laboratory
Virology:
Hepatitis B surface antigen, hepatitis C virus antibodies, human 
immunodeficiency virus antibodies 1/2 (at screening)
Local laboratory
Urinalysis - dipstick:
Hemoglobin/erythrocytes, pH, protein, glucose, bilirubin, urobilinogen, 
ketone, nitrite, leukocytes (semi-quantitatively/dipstick) 
 None (to be 
performed at the study 
site) 
 Local 
laboratory
 local 
laboratory36
Urinalysis - sediment:
Urine sediment only if dipstick indicates abnormalities
Local laboratory 
Pregnancy test in blood or urine
beta-hCG (within 7 days prior to dosing), in women with reproductive 
potential including women whose partners are sterilized)
Blood: Local laboratory
Urine: None (to be 
performed at the study 
site)
Follicle stimulating hormone in blood
In postmenopausal women ≤50 years of age37
Local laboratory
Urine drug screen:
Methadone, cocaine, amphetamines and methamphetamine/ecstacy, 
cannabinoids, barbiturates, benzodiazepines, tricyclic antidepressants, 
phencyclidin, morphine/opiates
None (to be performed at 
the study site)
Alcohol breath test
None (to be performed at 
the study site)
Bioanalysis:
Copanlisib and its metabolite M1 in plasma (including assessment of 
protein binding)
Bioanalytical laboratories
                                                
36 Included according to Amendment 1
37 Included according to Amendment 1
PPD
PPD
PPD


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Assessment of hepatic impairment - amended
16.3
Child Pugh system
In Group A, subjects with moderate hepatic impairment will be included (Child-Pugh B: 
score 7-9) and in Group C, subjects with severe hepatic impairment will be included (Child-
Pugh C: score 10-15).38
Hepatic impairment will be assessed using the classification of Child Pugh (Table 16-3): 
5 factors will be scored from 1 point to 3 points. The Child Pugh score is calculated by adding 
the scores of the 5 factors and can range from 5 to 15.
Table 16-3: Child Pugh system
Points scored for observed findings
1
2
3
Encephalopathy grade*
None
1 or 2
3 or 4
Ascites
absent
slight
moderate
Serum bilirubin (mg/dL)
<2
2 to 3
>3
Serum albumin (g/dL)
>3.5
2.8 to 3.5
<2.8
Prothrombin time (sec prolonged)
<4
4 to 6
>6
*
Grade 0: normal consciousness, personality, neurological examination, electroencephalogram
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves
Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta activity
Assessment as A or mild if 5 or 6 points; B or moderate if 7 to 9 points; and C or severe if 10 to 
15 points.
Assessment of hepatic encephalopathy
The exclusion of a possible hepatic encephalopathy will be performed using a trailmaking 
test, the number connection test (NCT) (see Section 16.7). This test measures cognitive motor 
abilities. In the NCT, subjects have to connect numbers printed on paper consecutively from 
1 to 25, as quickly as possible. Errors are not enumerated, but subjects are instructed to return 
to the preceding correct number and then carry on. The test score is the time the subject needs 
to perform the test, including the time needed to correct the errors. A low score indicates a 
good performance.
If the time needed exceeds 80 sec, subjects will be excluded from the study. If the subject 
needs <30 sec, hepatic encephalopathy can be excluded. An example of the NCT will be 
given in the clinical study report.
In addition, an experienced physician will assess hepatic encephalopathy by performing a 
standard neurological examination, which includes handwriting and common amnestic 
testing.
                                                
38 Included as subjects with severe hepatic impairment will be included into the study according to Amendment 1


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Assessment of renal impairment
16.4
Stages of renal impairment are based on Kidney Disease Outcomes Quality Initiative 
(K/DOQI) Clinical Practice Guidelines for Chronic Kidney Disease (CKD) from the National 
Kidney Foundation in 2002; GFR: glomerular filtration rate [6] (Table 16-4).
Table 16-4: Stages of chronic kidney diseasea
Stage
Descriptionb 
eGFRb (mL/min/1.73m2) 
1 
Kidney damage with normal or increased GFR
≥90 
2 
Kidney damage with mild decrease in GFR
60-89 
3 
Moderate decrease in GFR
30-59 
4 
Severe decrease in GFR
15-29 
5 
Kidney failure
<15 (or dialysis)
a = Chronic kidney disease is defined as either kidney damage or GFR <60 mL/min/1.73 m2 for 
≥3 months. Kidney damage is defined as pathologic abnormalities or markers of damage, 
including abnormalities in blood or urine tests or imaging studies.
b = eGFR: estimate of GFR based on an MDRD equation
Estimation of glomerular filtration rate (eGFR) using modification of 
16.5
diet in renal disease
In accordance with established nephrology practice and guidelines, renal function at baseline 
and throughout the study will be assessed by means of the eGFR, calculated using the 
abbreviated MDRD Study equation.
This equation of 4 variables (serum creatinine level, age, sex, and ethnicity) is recommended 
by the National Kidney Foundation for use in individuals 18 years or older. The formula is as 
follows:
GFR (mL/min/1.73 m2) = k × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African 
American),
where 
k=175 if serum creatinine was measured by methods calibrated to an IDMS reference method.
For the purpose of the study, it is recommended to use the Bayer-verified calculator 
(preferred) or online MDRD GFR calculator at http://mdrd.com/
Estimated creatinine clearance (CLcr) using Cockcroft-Gault (C-G) 
16.6
equation
The CLcr expressed as mL/min, is yielded by Cockcroft- Gault Equation, relating serum 
creatinine with age (in years) and body weight (in kg).
CLcr is estimated from a spot serum creatinine determination. The C-G Equation assumes that 
women have a 15% lower CLcr compared to men.


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Number connection test at screening
16.7
In subjects with hepatic impairment only
Time to complete: _____ sec.
Investigator’s signature: _____________________


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List of CYP3A4 inhibitors and inducers for reference. Only STRONG 
16.8
CYP3A4 inhibitors and inducers are not allowed in this study
Table 16-5: CYP3A4 inhibitors
Substance name
Inhibitor strength
Amiodarone
Weak
Amlodipine
Weak
Amprenavir
Moderate
Aprepitant
Moderate
Atazanavir
Moderate
Azithromycine
Weak
Berberine
Weak
Boceprevir1
Strong
Bicalutamide
Weak
Casopitant
Moderate
Chloramphenicol
Moderate
Chlorzoxazone
Weak
Ciclosporine/Cyclosporine
Weak
Cilostazol
Weak
Cimetidine
Weak
Clarithromycin1
Strong
Citrus and grape fruit juice
Depends on dose 
Cobicistat1
Strong
Conivaptan1
Strong
Crizotinib
Moderate
Darunavir
Moderate
Dasatinib
Weak
Delavirdine
Moderate
Diltiazem
Moderate
Dronedarone
Moderate
Erythromycin
Moderate
Everolimus
Weak
Fluconazole
Moderate
Fluoxetine
Moderate
Fluvoxamine
Weak
Fosamprenavir
Moderate
Fosaprepitant
Weak
Ginkgo biloba
Weak
Idealisib1
Strong
Imatinib
Moderate
Indinavir1
Strong
Isoniazid
Weak
Itraconazole1
Strong
Ivacaftor
Weak
Ketoconazole1
Strong
Lapatinib
Weak
Lomitapide
Weak


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Table 16 5: CYP3A4 inhibitors (continued)
Substance name
Inhibitor strength
Lopinavir1
Strong
Mibefradil1
Strong
Miconazole1
Strong
Mifepristone
Moderate
Nefazodone1
Strong
Nelfinavir1
Strong
Nilotinib
Weak
Pazopanib
Weak
Posaconazole1
Strong
Quinupristin/dalfopristin
Moderate
Propiverine
Weak
Ranitidine
Weak
Ranolazine
Moderate
Ritonavir1
Strong
Roxithromycin
Weak
Saquinavir1
Strong
Schisanda sphenantera
Moderate
Sitaxentan
Weak
Tabimorelin
Weak
Tacrolimus
Weak
Telaprevir1
Strong
Telithromycin
Strong
Ticagrelor
Weak
Tipranavir1
Strong
Tofisopam
Moderate
Tolvaptan
Weak
Valproic acid (valproate)
Moderate
Verapamil
Moderate
Voriconazole1
Strong
1
Only strong CYP3A4 inhibitors will be forbidden.


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Table 16-6: CYP3A4 inducers 
Substance name
Inducer strength
Phenobarbital1
Strong
Armodafinil
Weak
Avasimibe1
Strong
Bexarotene
Weak
Bosentan
Moderate
Carbamazepine1
Strong
Clobazam
Weak
Dexamethasone
Weak
Enzalutamide
Potent
Efavirenz
Moderate
Etravirine
Moderate
Genistein
Weak
Hypericum1
Strong
Lersivirine
Weak
Lopinavir
Moderate
Lumacaftor1
Strong
Mephenytoin
Moderate
Methylphenobarbital
Potent
Mitotane
Potent
Modafinil
Moderate
Nafcillin
Moderate
Nevirapine
Weak
Oxcarbazepine
Weak
Phenytoin1
Strong
Pleconaril
Weak
Quercetin
Weak
Rifabutin
Moderate
Rifampicin1
Strong
Rifamycin1
Strong
Rufinamide
Weak
Semagacestat
Moderate
Sulfinopyrazone
Weak
Thioridazine
Moderate
Vemurafenib
Weak
1
Only strong CYP3A4 inducers will be forbidden.


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NYHA classification
16.9
Table 16-7: NYHA classification
Class
Functional Capacity: How a patient with cardiac disease feels 
during physical activity
I
No limitation of physical activity. Ordinary physical activity does not 
cause undue fatigue, palpitation, dyspnea (shortness of breath).
II
Slight limitation of physical activity. Comfortable at rest. Ordinary 
physical activity results in fatigue, palpitation, dyspnea (shortness of 
breath).
III
Marked limitation of physical activity. Comfortable at rest. Less than 
ordinary activity causes fatigue, palpitation, or dyspnea.
IV
Unable to carry on any physical activity without discomfort. Symptoms 
of heart failure at rest. If any physical activity is undertaken, 
discomfort increases.
Class
Objective assessment
A
No objective evidence of cardiovascular disease. No symptoms and 
no limitation in ordinary physical activity.
B
Objective evidence of minimal cardiovascular disease. Mild symptoms 
and slight limitation during ordinary activity. Comfortable at rest.
C
Objective evidence of moderately severe cardiovascular disease. 
Marked limitation in activity due to symptoms, even during less-than-
ordinary activity. Comfortable only at rest.
D
Objective evidence of severe cardiovascular disease. Severe 
limitations. Experiences symptoms even while at rest.
Source: Adapted from Dolgin M, Association NYH, Fox AC, Gorlin R, Levin RI, New York Heart 
Association. Criteria Committee. Nomenclature and criteria for diagnosis of diseases of the heart and 
great vessels. 9th ed. Boston, MA: Lippincott Williams and Wilkins; March 1, 1994. 
Original source: Criteria Committee, New York Heart Association , Inc. Diseases of the Heart and 
Blood Vessels. Nomenclature and Criteria for diagnosis, 6th edition Boston, Little, Brown and 
Co. 1964, p 114.

SAP_001.pdf: 
 
Document Type: 
Statistical Analysis Plan  
Official Title: 
An open-label non-randomized, phase 1 single dose study to 
evaluate the pharmacokinetics and safety of copanlisib in subjects 
with impaired hepatic or renal function in comparison to healthy 
subjects 
NCT Number: 
NCT03172884 
Document Date: 
25 JUL 2018 
 
 
 


Statistical Analysis Plan
Protocol No.: BAY 80-6946 / 18041
Page: 1 of 15
Title Page
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.
An open-label non-randomized, phase 1 single dose study to evaluate the 
pharmacokinetics and safety of copanlisib in subjects with impaired hepatic 
or renal function in comparison to healthy subjects
Short title
Phase 1 study of copanlisib in hepatic or renal impairment
Bayer study drug
Copanlisib / BAY 80-6946
Study purpose:
To evaluate the effect of impaired hepatic or renal function on 
copanlisib
Clinical study 
phase:
I
Date:
25  JUL 2018
Study No.:
18041
Version:
3.0
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.
PPD


Statistical Analysis Plan
Protocol No.: BAY 80-6946 / 18041
Page: 2 of 15
Table of Contents
Title Page ...................................................................................................................................1
Table of Contents ......................................................................................................................2
Abbreviations ............................................................................................................................3
1.
Introduction........................................................................................................................5
2.
Study Objectives.................................................................................................................5
3.
Study Design.......................................................................................................................6
4.
General Statistical Considerations ...................................................................................8
4.1
General Principles.............................................................................................................8
4.2
Handling of Dropouts .......................................................................................................8
4.3
Handling of Missing Data.................................................................................................9
4.4
Interim Analyses and Data Monitoring ............................................................................9
4.5
Data Rules.........................................................................................................................9
5.
Analysis Sets .......................................................................................................................9
5.1
Assignment of Analysis Sets ............................................................................................9
6.
Statistical Methodology ...................................................................................................10
6.1
Population Characteristics ..............................................................................................10
6.1.1
Disposition ..................................................................................................................10
6.1.2
Demographic and Other Baseline Characteristics.......................................................10
6.1.3
Medical History...........................................................................................................10
6.1.4
Prior and Concomitant Medication .............................................................................10
6.2
Efficacy...........................................................................................................................10
6.3
Pharmacokinetics/Pharmacodynamics ...........................................................................10
6.3.1
Pharmacokinetics ........................................................................................................10
6.3.2
Pharmacodynamics......................................................................................................12
6.4
Safety..............................................................................................................................12
6.4.1
Adverse Avents ...........................................................................................................12
6.4.2
Other Safety Parameters..............................................................................................13
7.
Determination of Sample Size.........................................................................................13
8.
Document history and changes in the planned statistical analysis..............................14
9.
References.........................................................................................................................15


Statistical Analysis Plan
Protocol No.: BAY 80-6946 / 18041
Page: 3 of 15
Abbreviations
%AUC(tlast-
percentage of AUC from the last data point > LLOQ to infinity
AE
adverse event
AE,ur
amount excreted into urine from 0 to infinity
AE,ur(x-y)
amount excreted into urine from x to y
ANOVA
analysis of variance
AUC
area under the concentration vs. time curve from zero to infinity after single (first) dose
AUC(t1-t2)
AUC from time t1 to t2, e.g. AUC(4-8), AUC(0-24)
AUC(t1-t2)u
AUC of unbound drug (not protein-bound) from time t1 to t2
AUCu
area under the concentration vs. time curve of unbound drug (not protein-bound) from 
zero to infinity after single dose
CI
Confidence Interval
Clast
last observed concentration value above lower limit of quantitation
CLIPS
Clinical Pharmacology Standard
CLR
copansilib clearance
CLcr
Clearance Creatinine
Cmax
maximum observed drug concentration in measured matrix after single dose 
administration
Cmax,u
maximum observed concentration of unbound drug (not protein-bound or free) in 
measured matrix after single dose administration
CV
coefficient of variation
DDI
drug-drug interaction
e.g.
exempli gratia (for example)
ECG
electrocardiogram
eGFR
estimated glomerular filtration rate
FDA
Food and Drug Administration
HCT
hematopoietic cell transplant
i.e.
id est (that is)
i.v.
intravenous
LLOQ
lower limit of quantification
LS-Means
least squares means
MDRD
Modified Diet of Renal Disease
MedDRA
medical dictionary for regulatory activities
mg
milligram
mL
milliliter
NHL
non-Hodgkin’s lymphoma
PK
pharmacokinetic(s)
PKS1
PK analysis set
PKS2
PK analysis set for hepatic impairment assessment
PKS3
PK analysis set for renal impairment assessment
PopPK
population PK
Rend
last time point for λz calculation
Rstart
last time point for λz calculation
SAE
serious adverse event
SAF
safety analysis set
SAP
Statistical Analysis Plan
SAS
Statistical Analysis System
SD
standard deviation
TEAE
treatment-emergent adverse event


Statistical Analysis Plan
Protocol No.: BAY 80-6946 / 18041
Page: 4 of 15
t1/2
Half-life associated with the terminal slope
tlast
time of last observed concentration value above lower limit of quantitation
tmax
time to reach maximum drug concentration (in case of two identical Cmax values, the first 
tmax will be used)
Vz
volume of distribution during terminal phase after intravascular
WHO-DD
WHO Drug Dictionary


Statistical Analysis Plan
Protocol No.: BAY 80-6946 / 18041
Page: 5 of 15
1. 
Introduction
Copanlisib (BAY 80-6946), approved by the Food and Drug Administration [FDA] in September 
2017), is a novel, highly selective, pan-class PI3K inhibitor with potent activity against both α and β 
isoforms, with in vitro IC50 of 0.5 nM and 0.7 nM, respectively. This PI3K inhibitor is being 
developed for the treatment of advanced and refractory malignancies either as a single agent or in 
combination with other investigational agents. Copanlisib is the active ingredient (free base) of 
BAY 84-1236, the dihydrochloride salt, which for clinical use is formulated as an intravenous (i.v.) 
drug product solution.
Copanlisib is excreted as unchanged compound and metabolites (about 50:50) in human. 
Metabolism of copanlisib is mediated by cytochrome P450 CYP3A4 (> 90%) and to a minor extent 
by CYP1A1 (< 10%). Therefore, a low DDI potential due to several clearance pathways is 
anticipated.
Liver infiltration in subjects with advanced malignancies including non-Hodgkin’s lymphoma 
(NHL) is common, and various degree of hepatic dysfunction may occur in the later stages of 
malignancy.
Renal failure in cancer subjects is often multifactorial including renal parenchymal invasion, tumor 
lysis syndrome, glomerular diseases, chemotherapy associated thrombocytic microangiopathy or 
hematopoietic cell transplant (HCT)-associated renal failure.
Metabolism of copanlisib is primarily mediated by the CYP3A4 isozyme. Co-administration of 
copanlisib at 12 mg and 60 mg with the potent inhibitor of CYP3A4 itraconazole resulted in an 
increased copanlisib AUC by 1.41-fold and 1.53-fold, respectively, with no effect on the Cmax at 
both doses. A human mass balance study (Study 16353) indicates the elimination of copanlisib is 
primarily via feces with 64% in feces and 22% in urine within a collection interval of 20 to 34 days. 
Based on the population PK (popPK) analysis, mild hepatic impairment, mild and moderate renal 
impairment had no significant effect on copansilib clearance (CL). The PK of copanlisib has not 
been studied in moderate and severe hepatic impairment and severe renal impairment. 
This study will evaluate the PK and safety of a single 12-mg dose of copanlisib in subjects with 
moderate or severe hepatic impairment or severe renal impairment of copanlisib and in age-, gender-
, and weight-matched healthy controls. The results of this study will provide guidance for drug 
labeling recommendations for copanlisib in these subjects.
This Statistical Analysis Plan (SAP) is based on the final Clinical Study Protocol BAY 80-6946 / 
18041 Version 2.0, dated 28 Nov 2017 [1].
2. 
Study Objectives
The primary objective is to 

Investigate the PK of copanlisib following a single i.v. dose of 12 mg copanlisib in subjects
with moderate hepatic (Child Pugh B), severe hepatic (Child Pugh C) or severe renal
impairment compared with healthy subjects


Statistical Analysis Plan
Protocol No.: BAY 80-6946 / 18041
Page: 6 of 15
The secondary objectives are to

Evaluate the PK of M-1 metabolite 

Assess the safety and tolerability of copanlisib when administered to subjects with moderate 
hepatic, severe hepatic or severe renal impairment 
The exploratory objectives are to explore the relationship between PK and hepatic and renal 
function parameters:

Hepatic: Relationship between PK parameters of copanlisib AUC(0-168), AUC, Cmax, 
AUC(0-168)u, AUCu and Cmax,u and baseline hepatic function parameters (Child-Pugh Score, 
total bilirubin, prothrombin time, alpha 1-acid glycoprotein and albumin) 

Renal: Relationship between PK parameters of copanlisib AUC(0-168), AUC, Cmax, AUC(0-
168)u, AUCu and Cmax,u and eGFR (MDRD formula) and estimated creatinine clearance 
(Cockcroft-Gault formula)
3.
Study Design
This will be a multi-center, non-randomized, open-label, single-dose, parallel group, study 
consisting of 4 groups. The effect of moderate hepatic impairment (Child Pugh B), severe hepatic 
impairment (Child Pugh C) and severe renal impairment on the PK of copanlisib and M-1 will be 
investigated. In total, up to 44 evaluable male and female subjects with 8-22 evaluable subjects in 
the control group, 8 evaluable subjects each in the moderate hepatic and severe renal impairment 
investigational group, and 6 evaluable subjects in the severe hepatic investigational group will 
participate in the study (Table 3–1). Each subject will be administered 12 mg of copanlisib (i.v. over 
1 h).


Statistical Analysis Plan
Protocol No.: BAY 80-6946 / 18041
Page: 7 of 15
Table 3–1: Groups
Group
Description
Number of evaluable 
subjects
Control group
Normal hepatic and renal function 
group matched to the groups of 
hepatic and renal impairment
8-22
Group A
Moderate hepatic impairment group: 
Child-Pugh B (score 7-9) at the 
screening visit
8
Group B
Severe renal impairment group:
eGFR 15-29 mL/min/1.73 m2 at the 
screening visit based on the 
Modification of Diet in Renal 
Disease (MDRD) equation
8
Group C
Severe hepatic impairment group: 
Child-Pugh C (score 10-15) at the 
screening visit
6
The control group (normal hepatic and renal function) should match with the groups of hepatic and 
renal impairment. Matching criteria will be age, body weight, and gender. Mean age and body 
weight between the control group and the groups with hepatic and renal impairment should not vary 
by more than ±10 years and ±10 kg. Therefore, enrollment in the control group will remain open 
until the enrollment in the moderate and severe hepatic and severe renal impairment groups is 
complete and a sufficient number of matching controls have been achieved for comparison.


Statistical Analysis Plan
Protocol No.: BAY 80-6946 / 18041
Page: 8 of 15
Primary variables:

Cmax, AUC and AUC(0-168) of copanlisib in plasma
Secondary variables: 

Number of subjects with study drug-related treatment-emergent AE (TEAE)
Additional pharmacokinetic parameters: 
Copanlisib 
AUC(0-24), AUC(0-tlast), t1/2, tmax, tlast, Vz, CL, AE,ur(0-24), 
CLR, Cmax,u, AUC(0-24)u, AUC(0-168)u, and AUCu based 
on average value of unbound fraction in the 1h and 24h 
samples 
BAY 84-5795 (M-1) 
AUC(0-168), AUC(0-tlast), AUC, t1/2, Cmax, tmax, tlast, 
AE,ur(0-24) 
Other pharmacokinetic parameters:
Copanlisib and BAY 84-5795 (M-1) 
number of points terminal, %AUC(tlast-∞), Rstart, Rend, Clast 
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). 
Clinical Pharmacology Standard (CLIPS), Version 1.2 [2] will be used.
All data will be listed and study summary tables as well as graphical illustrations will be provided 
where appropriate. Whenever appropriate, summary statistics will be provided by group for the 
original data as well as for the change versus baseline. Frequency tables will be generated for 
categorical data.
This is an exploratory study; any confirmatory statistical analysis is not intended.
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 treated.
Subjects who drop out may be replaced to obtain a minimum of 30 subjects (8/group except for 
severe hepatic impairment: 6) valid for PK of copanlisib (i.e., all blood samples for PK should be 
available up to 1 week [168 h]). Additional healthy subjects may be enrolled to achieve 
demographic matching between healthy and impaired groups in up to 22 healthy subjects valid for 
PK of copanlisib (i.e., up to 1 week [168 h]).  
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” is regarded a “screening failure”.  


Statistical Analysis Plan
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4.3
Handling of Missing Data
Missing data will not be replaced. Analyses will be performed considering all valid data observed 
for the respective analysis sets. 
All missing or partial data will be presented in the subject data listing as they are recorded.
4.4
Interim Analyses and Data Monitoring
An interim analysis will be conducted after 8 evaluable subjects with moderate hepatic impairment 
and 8 evaluable subjects with severe renal impairment with their corresponding matching healthy 
volunteers have completed the study to fulfill the first part of the postmarketing requirement as 
agreed with the FDA (July 2019) based on the accelerated approval of copanlisib (September 14, 
2017). This interim analysis will also serve as a final analysis on the moderate hepatic impairment 
and severe renal impairment groups in the final clinical study report. The results of the final report 
will include subjects with severe hepatic impairment as agreed with FDA (July 2021).
4.5
Data Rules
Unless otherwise specified, the baseline assessment will be the last valid value prior to first 
treatment.  
Repeated Measurements: If control measurements for a planned time point during screening epoch 
are available, the last non-missing valid value will be used for the calculation of descriptive 
statistics. If control measurements for a planned time point after the screening epoch are available, 
the first non-missing valid value (i.e. of the planned measurement) will be used for the calculation of 
descriptive statistics.
Data at unscheduled visit will be listed only. 
5.
Analysis Sets
5.1
Assignment of Analysis Sets
Final decisions regarding the assignment of subjects to analysis sets will be made during the validity 
review meeting and documented in the final list of important deviations, validity findings and 
assignment to analysis sets.
All subjects who signed informed consent will be included in the All Enrolled Subjects evaluations. 
All subjects who completed the screening period and entered the treatment period will be included 
in the All Subjects Assigned to Treatment evaluations. In addition, the following analysis sets will 
be used in this study:

All subjects who received one dose of the study medication will be included in the safety 
analysis set (SAF).

All subjects with a PK profile allowing calculation of the main PK parameters will be 
included in the PK analysis set (PKS1).


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
All hepatically impaired subjects and gender, age- and weight-matched healthy subjects with 
a PK profile allowing calculation of the main PK variables will be included in the PK 
analysis set for hepatic impairment assessment (PKS2).

All renally impaired subjects and gender, age- and weight-matched healthy subjects with a 
PK profile allowing calculation of the main PK variables will be included in the PK analysis 
set for renal impairment assessment (PKS3).
6.
Statistical Methodology
6.1
Population Characteristics
Analysis for population characteristics will be performed for the SAF-population, unless otherwise 
specified.
6.1.1
Disposition
Disposition at the end of screening will be summarized for all enrolled subjects. Disposition at the 
end of treatment and for follow-up will be summarized for total and each group for the SAF-
population.
6.1.2
Demographic and Other Baseline Characteristics
Demography will be summarized using descriptive statistics (arithmetic mean, standard deviation, 
median, minimum and maximum for quantitative variables) or frequency tables in case of qualitative 
data. Analysis of demographic data will also be performed for the PKS1, PKS2 and PKS3 
population if these populations differ from SAF.
6.1.3
Medical History
Medical history findings will be summarized using Medical Dictionary for Regulatory Activities 
(MedDRA, version 20.1 or higher) terms. 
6.1.4
Prior and Concomitant Medication
The number of subjects that used prior or concomitant medication will be analyzed using frequency 
tables based on classified data. The classification will be done according to the WHO-DD
version2017SEP.
6.2
Efficacy
Not applicable.
6.3
Pharmacokinetics/Pharmacodynamics
6.3.1
Pharmacokinetics
The PK analysis will be done by analyte separately, which includes analytes of copanlisib and its 
metabolite BAY 84-5795 (M-1). The plasma concentration-time profiles of each analyte will be 
summarized by group, where the groups include the age- and weight-matched healthy subject group
and severe renal,a moderate hepatic and severe hepatic impaired patients. The following statistics 


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will be calculated for each of the sampling points: arithmetic mean, standard deviation and 
coefficient of variation (CV), geometric mean, geometric standard deviation (retransformed 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 versus 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 group using both linear and semilogarithmic scale. 
Pharmacokinetic characteristics (tmax and tlast and parameters listed in the protocol as ‘other 
parameters’ excluded) will be summarized by group using the statistics mentioned above. tmax and 
tlast will be described utilizing minimum, maximum and median as well as frequency counts. Other 
parameters will be listed only.
Box-Whisker plots for Cmax, AUC, AUC(0-168), Cmax,u, AUC(0-168)u, and AUCu will be presented 
by group.

Renal Impairment
To investigate the primary objective of this study regarding renal impairment, an explorative 
analysis of variance (ANOVA) including group as factor will be performed on the log-transformed 
values of PK parameters Cmax, AUC, AUC(0-168). The factor group will have two levels (matched 
healthy subjects and severe renal impaired subjects). Point estimates (LS-Means) as well as 90% 
confidence intervals (CIs) of the ratio

severe renal impaired group/ matched healthy volunteer group
will be calculated by retransformation of the logarithmic results given by the ANOVA. 
A corresponding SAS code base is outlined below:
PROC GLM data=dataset;
CLASS group
MODEL log_PK = group;
LSMEANS group / pdiff cl alpha=0.1;
RUN;
Plots of the relationship between PK parameters of copanlisib and M-1 metabolite AUC(0-168), 
AUC, Cmax, AUC(0-168)u, AUCu and Cmax,u, respectively and eGFR (MDRD formula) and estimated 
creatinine clearance (Cockcroft-Gault formula) at screening. 
Based on patient’s age, weight and serum creatinine information collected at the visit, estimated 
creatinine clearance will be calculated as following: 
for male, CLcr (mL/minute)={((l40–age (years)) x weight (kg))/(72xSerum 
creatinine(mg/dL))};


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for female, CLcr (mL/minute)={((l40–age (years)) x weight (kg))/(72xSerum creatinine
(mg/dL))}x 0.85.
The corresponding Spearman's rank correlation coefficients including the associated 95% 
confidence intervals will be calculated to explore any monotone relationship between the PK 
variables and eGFR at screening. 
A linear regression analysis of PK variables versus eGFR at screening will be presented.

Hepatic Impairment
To investigate the primary objective of this study regarding hepatic impairment, an explorative 
analysis of variance (ANOVA) including group as factor will be performed on the log-transformed 
values of PK parameters Cmax, AUC, AUC(0-168). The factor group will have two levels (matched 
healthy subjects and moderate hepatic impaired subjects; or healthy subjects and severe hepatic
impaired subjects). Point estimates (LS-Means) as well as 90% confidence intervals of the ratio

Severe hepatic impaired group/ matched healthy volunteer group

Moderate hepatic impaired group/ matched healthy volunteer group
will be calculated by retransformation of the logarithmic results given by the ANOVA. 
A corresponding SAS code base is outlined above.
Plots of the relationship between PK parameters of copanlisib and M-1 metabolite AUC(0-168), 
AUC, Cmax, AUC(0-168)u, AUCu and Cmax,u, respectively and baseline hepatic function parameters 
(Child-Pugh Score, total bilirubin, prothrombin time, alpha 1-acid glycoprotein and albumin). The 
corresponding Spearman's rank correlation coefficients including the associated 95% confidence 
intervals will be calculated to explore any monotone relationship between the PK variables and 
baseline hepatic function parameters. 
A linear regression analysis of PK variables versus baseline hepatic function parameters will be 
presented.
A confirmatory statistical analysis is not intended in this study.
6.3.2
Pharmacodynamics
Not applicable.
6.4
Safety
6.4.1
Adverse Avents
Individual listings of adverse events (AEs) will be provided. The incidence of TEAEs and drug-
related TEAEs as well as TEAEs with treatment number and worst severity, respectively, will be 
summarized by group using MedDRA terms (version 20.1 or higher). Listings of deaths, SAEs and 
AEs leading to discontinuation (death and serious AEs excluded) will be provided.
Adverse events are considered to be treatment-emergent if they have started or worsened after first 
application of study medication up to 30 days after end of treatment with study medication.


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6.4.2
Other Safety Parameters
Quantitative data for safety (e.g. hematology, coagulation, clinical chemistry, urinalysis, vital signs, 
ECG) will be described by descriptive statistics (arithmetic mean, standard deviation, median, 
minimum and maximum) and will be presented by each group 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 and flagged with ‘L’ for low and ‘H’ for 
high. Additional tables with all abnormal values will be presented. 
Graphical displays of individual data as well as mean values with standard deviation will be 
included.
7. 
Determination of Sample Size
The study population will consist of up to 44 evaluable male and female subjects with 8-22 
evaluable subjects in the control group, 8 evaluable subjects each in the moderate hepatic and severe 
renal impairment investigational group, and 6 evaluable subjects in the severe hepatic impairment 
investigational group. The sample size of 8 subjects in each of the groups with impaired moderate 
hepatic and severe renal function and 6 subjects in the severe hepatic impairement group has been 
selected based on practical consideration and following the FDA guidance [3] [4]. In copanlisib 
studies 12871 and 16270, the standard deviation (SD) for log-transformed AUC(0-168) or AUC was 
estimated between 0.33 and 0.40. For the current study, we assume the SD of 0.40 for log-
transformed AUC(0-168). The PK parameter AUC(0-168) is considered appropriate for sample size 
estimation as in Study 16270 the extrapolation for calculation of AUC was only 4.8% of AUC(0-
168). Further, based on the PK data from study 12871, the inter-subject variability for copanlisib PK 
exposure was estimated to be 46.5% for AUC(0-168) and 73.3% for Cmax in terms of geometric 
coefficient of variation. In study 16270, the inter-subject variability for Cmax was 63.2% in terms of 
geometric mean CV. The AUC(0-168) value has been considered for sample size estimation as a 
suitable PK parameter because of the higher uncertainty around of the Cmax especially for an i.v. 
drug. For AUC(0-168), a sample size of 8 eligible subjects each in the control, moderate hepatic and 
severe renal impairment investigational group would provide an approximately 90% chance for the 
90% confidence interval for the ratio of geometric least-squares means between impaired subjects 
and healthy subjects to be within a 2-fold difference, that is, within limits of 50% to 200% for 
AUC(0-168). This can be shown in Table 7–1 based on different observed ratios.


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Table 7–1: 90% Confidence interval for copanlisib with N=8 per group
Observed Ratio
90% CI for the ratio
1
(0.685, 1.461)
1.1
(0.753, 1.607)
1.2
(0.822, 1.753)
1.3
(0.890, 1.899)
A sample size of 6 eligible subjects per each in the control and severe hepatic impairment 
investigational group would provide an approximately 90% chance for the 90% confidence interval 
for the ratio of geometric least-squares means between impaired subjects and healthy subjects to be 
within an approximately 2-fold difference, that is, within limits of 50% to 207% for AUC(0-168) as 
shown in Table 7–2 based on different observed ratios.
Table 7–2: 90% Confidence interval for copanlisib with N=6 per group
Observed Ratio
90% CI for the ratio
1
(0.628, 1.593)
1.1
(0.691, 1.752)
1.2
(0.753, 1.911)
1.3
(0.816, 2.07)
8.
Document history and changes in the planned statistical analysis

Approval of SAP v1.0 (25 Jul 2017)

Final SAP v2.0 updated on 07 MAY 2018 according to the protocol amendment 1 forming
integrated protocol Version 2.0, dated 28 Nov 2017

Final SAP v3.0 updated on 25 JUL 2018 by adding the clearance creatinine calculation


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9.
References
[1] d. 1. M. 2. Clinical Study Protocol BAY 80-6946 / 18041 Version 1.0.
[2] V. 1. d. 1. D. 2. Clinical Pharmacology Standards (CLIPS).
[3] d. a. a. i. o. d. a. l. M. 2. Guidance for Industry: Pharmacokinetics in patients with impaired 
hepatic function: study design.
[4] d. a. a. i. o. d. a. l. M. 2. Guidance for Industry: Pharmacokinetics in patients with impaired renal 
function: study design.