Clinical trial NCT03458728
Conditions: Relapsed or Refractory Solid Tumors or Lymphoma in Children Neuroblastoma Osteosarcoma Rhabdomyosarcoma Ewing Sarcoma
Keywords: Phase I: relapsed or refractory solid tumors or lymphoma Phase II: relapsed or refractory solid tumors (neuroblastoma, osteosarcoma, rhabdomyosarcoma or Ewing sarcoma)
Sponsor: Bayer
Start date: 2018-04-30; Completion date: 2023-02-01
Enrollment: 31 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is designed to investigate whether the use of copanlisib is safe, feasible and beneficial to pediatric patients with solid solid tumors or lymphoma that are recurrent or refractory to standard therapy.

Detailed description:

Arms: arm 1: It is estimated that 2 or 3 dose cohorts may be evaluated in phase 1 of the study. Safety and MTD/RP2D dose will be evaluated in 2 age groups (\< 1 year old and ≥ 1 year old). arm 2: Recommended Phase 2 dose (RP2D) for copanlisib in pediatric patients, as defined in the Phase I part of the study, will be used. arm 3: RP2D for copanlisib in pediatric patients, as defined in the Phase I part of the study, will be used. arm 4: RP2D for copanlisib in pediatric patients, as defined in the Phase I part of the study, will be used. arm 5: RP2D for copanlisib in pediatric patients, as defined in the Phase I part of the study, will be used.
Interventions: intervention 1: Copanlisib (BAY806946)
Intervention descriptions: intervention 1: Copanlisib will be dosed on Day 1, Day 8, and Day 15 of every 28-day cycle. Phase 1: 2 or 3 dose cohorts may be evaluated in phase 1 of the study. Phase 2: RP2D for copanlisib in pediatric patients, as defined in the Phase I part of the study, will be used.

Protocol documents:
Prot_000.pdf: 
Integrated Clinical Study Protocol
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Cover page of the integrated protocol
Study title: A non-randomized, open-label, multi-center, Phase I/II study of PI3K inhibitor 
copanlisib in pediatric patients with relapsed/refractory solid tumors or lymphoma
This protocol version is an integration of the following documents / sections:
Original protocol, Version 1.0, dated 03 AUG 2017
Amendment 01. (global amendment described in Section 15.1)
forming integrated protocol Version 2.0, dated 04 APR 2019
Amendment 02. (global amendment described in Section 15.1)
forming integrated protocol Version 3.0, dated 05 MAY 2020
Amendments not included in the consecutive numbering of amendments are 
local amendments not forming part of this integrated global protocol.


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1.
Title page
A non-randomized, open-label, multi-center, Phase I/II study of PI3K inhibitor copanlisib in 
pediatric patients with relapsed/refractory solid tumors or lymphoma
Safety, tolerability, efficacy and pharmacokinetics of copanlisib in pediatric patients
Test drug:
BAY 80-6946 / Copanlisib
Study purpose:
MTD finding, safety and activity
Clinical study phase:
I/II
Date:
05 MAY 2020
Registration:
EudraCT: no. 2017-000383-15 Version no.:
3.0
Sponsor’s study no.:
BAY 80-6946 /19176
Sponsor:
Non-US: Bayer AG, D-51368 Leverkusen, Germany
US territory: Bayer HealthCare Pharmaceuticals Inc., 100 
Bayer Boulevard, P.O. Box 915, Whippany NJ 07981-0915, 
USA
Sponsor’s medical expert:
 MD
100 Bayer Boulevard, P.O. Box 915 Whippany, 
NJ 07981-0915 USA
Telephone no.: 
E-mail: 
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


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Signature of the sponsor’s medically responsible person
This document is electronically signed. The eSignature is archived in the Trial Master File 
and can be provided upon request.
The signatory agrees to the content of the final clinical study protocol as presented.
Name:
 MD,
Role: 
 
Date:
Signature:
PPD
PPD
PPD


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


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2.
Synopsis
Title
A non-randomized, open-label, multi-center, Phase I/II study of PI3K 
inhibitor copanlisib in pediatric patients with relapsed/refractory solid 
tumors or lymphoma
Short title
Safety, tolerability, efficacy and pharmacokinetics of copanlisib in pediatric 
patients
Clinical study phase
I/II
Study objective(s)
Phase I (dose escalation) part
The primary objective:

To establish the safety, maximum tolerated dose (MTD) and/or
recommended Phase 2 dose (RP2D) of copanlisib in pediatric 
patients with a relapsed/refractory solid tumor or lymphoma
The secondary objectives:

To characterize the pharmacokinetics (PK) of copanlisib 

To assess the antitumor activity of copanlisib and to identify 
specific potential tumor type(s) for further development
The exploratory objectives:

To evaluate pharmacodynamics of copanlisib

To evaluate biomarkers of efficacy, mode-of-action-related effect, 
and /or the pathomechanism of the disease
Phase II (extension) part
The primary objective:

To determine the objective response rate (ORR) of copanlisib in 
pediatric patients with relapsed/refractory neuroblastoma, 
rhabdomyosarcoma or Ewing sarcoma. 

To determine the disease control rate (DCR) and progression free 
survival (PFS) in pediatric patients with relapsed/refractory 
osteosarcoma
Secondary objectives: 

To evaluate PFS (in indications other than osteosarcoma), overall 
survival (OS), and duration of response (DOR)

To evaluate safety 
Exploratory objectives:

To characterize population PK of copanlisib

To evaluate pharmacodynamics of copanlisib

To evaluate biomarkers of efficacy, mode-of-action-related effect, 
and/or the pathomechanism of the disease


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Test drug(s)
Copanlisib
Name of active ingredient
Copanlisib / BAY 80-6946 / phosphatidylinositol 3-kinase (PI3K) inhibitor
Dose(s)
Phase I (dose escalation)
Copanlisib will be dosed on Day 1, Day 8, and Day 15 of every 28-day 
cycle.
The starting dose for the dose-escalation phase of this study will be 60% for 
patients < 1 year old and 80% for patients ≥1 year old of the dose 
(60 mg/weekly, 3 weeks on/1 week off) in the adult population 
recommended for copanlisib development. The dose levels to be explored 
are listed in the following tables. The step size for dose escalation and de-
escalation is 20% of the adult dose. In case that a certain cohort of pediatric 
patients reaches the copanlisib plasma exposure of adult patients treated 
with the recommended dose before the pediatric MTD is defined, no higher 
dose level will be tested. It is estimated that 2 or 3 dose cohorts may be 
evaluated in this part of the study.
Copanlisib dose levels for patients < 1 year
Dose level
Copanlisib dose 
% of adult dose
mg/m2
-2
40
14
-1
60 a
21
1
80
28
2
100
35
a: Starting dose for patients < 1 year 
After patients are tested at dose level 1, the population PK (popPK) analysis will 
determine whether the exposure has reached at least 75% of adult exposure.
Copanlisib dose levels for patients ≥ 1 year
Dose level
Copanlisib dose 
% of adult dose
mg/m2
-1
60
21
1
80 a
28
2
100
35
3 b
120
42
a: Starting dose for patients ≥1 year old 
b: Dose level 3 will only be tested if the geometric mean of the copanlisib plasma 
exposure in the already tested cohorts is less than 75% of the adult plasma 
exposure of copanlisib of 60 mg. After patients are tested at dose level 2, the 
popPK analysis will determine whether the exposure has reached at least 75% of 
adult exposure.
Phase II (extension)
RP2D for copanlisib in pediatric patients, as defined in the Phase I part of
the study, will be used.


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Route of administration
Intravenous (IV) infusion 
Duration of treatment
Patients may continue treatment with copanlisib until radiological 
progressive disease, unacceptable toxicity, withdrawal of consent, death or 
other event specified by the protocol. After completion of treatment patients 
will be followed for survival for at least 2 years.
Reference drug(s)
Not applicable
Indication
Phase I: relapsed or refractory solid tumors or lymphoma
Phase II: relapsed or refractory solid tumors (neuroblastoma, osteosarcoma,
rhabdomyosarcoma or Ewing sarcoma)
Diagnosis and main criteria for 
inclusion /exclusion
Main criteria for inclusion:

Signed informed consent form by patients and/or patients’ 
parents/legal guardians and age appropriate assent form by the 
patients obtained before any study specific procedure 

Male or female patients from 6 months to ≤ 21 years old at the 
time of study enrollment

Confirmation of diagnosis:
o
Phase I: Patients must have histologic verification of a solid 
tumor or lymphoma malignancy at diagnosis, with measurable 
or evaluable disease, for which there is no standard curative 
anti-cancer treatment or treatment is no longer effective and 
must have received ≥ 1 prior line of therapy. 
o
Phase II: patients must have histologically verified tumor at 
initial diagnosis and radiologically or histologically confirmed 
status at inclusion as indicated in the following: 
neuroblastoma, osteosarcoma, rhabdomyosarcoma or Ewing 
sarcoma.
In Phase II, patients with solid tumors must have measurable 
disease (evaluable disease is acceptable for neuroblastoma 
and Ewing sarcoma). Tumor assessment will be done via 
computed tomography (CT), magnetic resonance imaging
(MRI) or positron emission tomography-computed
tomography (PET-CT). Tumor lesions situated in a 
previously irradiated area, or in an area subjected to other 
loco-regional therapy, may be considered measurable if there 
has been demonstrated progression in the lesion. Bone scans 
(if clinically indicated) should be obtained within ≤4 weeks 
prior to the start of treatment.

Performance level: Lansky ≥ 50% for patients ≤ 16 years of age 
and Karnofsky ≥ 50% for patients > 16 years of age.

Adequate bone marrow, renal and liver function.
Main criteria for exclusion:

Active or uncontrolled infection (NCI-CTCAE Grade ≥ 2).

History or concurrent condition of interstitial lung disease of any 
severity and/or severely impaired lung function (as judged by the 


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investigator).

Diabetes mellitus.

Uncontrolled arterial hypertension despite optimal medical 
management (per institutional guidelines).

Patients with central nervous system (CNS) malignancies.
Study design
Study 19176 (Children’s Oncology Group [COG] study number 
ADVL1721) is a multicenter, open-label, non-randomized Phase I/II study 
of copanlisib consisting of a Phase I dose escalating part in pediatric 
patients with a relapsed/refractory solid tumor or lymphoma followed by a 
Phase II part with Simon 2-stage design to establish efficacy signal of 
copanlisib in pediatric patients with relapsed/refractory neuroblastoma, 
osteosarcoma, rhabdomyosarcoma or Ewing sarcoma.
The study (applicable to Phase I and Phase II parts) is composed of the 
following periods: 

Screening

Treatment

Active follow-up 

Long-term follow-up
Phase I part
Dose escalation phase: to establish copanlisib single agent MTD and/or
RP2D, PK, pharmacodynamics and safety/tolerability in the pediatric 
population; a Rolling-6 study design will be utilized.
MTD extension phase: up to 6 patients to confirm safety at MTD.
The MTD of copanlisib for patients < 1 year old will be established and 
analyzed separately from the patients ≥1 year old and the results will be 
provided in a descriptive statistical analysis. 
If in the Phase I part of the study the MTD will not be established in 
patients < 1 year old, the MTD determination in patients < 1 year old will 
continue in parallel with the Phase II part and will be stopped when the 
Phase II part has been closed. Patients < 1 year old may not be enrolled in
the Phase II part of the study until the MTD and RP2D for that age group 
has been established.
If in the Phase I part a certain cohort of pediatric patients reaches the 
copanlisib plasma exposure of adult patients treated with the recommended 
dose before the pediatric MTD is defined, no higher dose level will be 
tested.
Phase I dose:
The starting dose for the dose-escalation phase of this study will be 60% for 
patients < 1 year old and 80% for patients ≥1 year old of the dose 
(60 mg/weekly, 3 weeks on/1 week off) in the adult population 
recommended for copanlisib development.
Decision about dose escalation or reduction for subsequent cohorts will be 
determined based on dose-limiting toxicity (DLT) evaluation according to 
the Rolling-6 design.


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Phase II part
Separate Simon 2-stage design in up to 4 arms to establish efficacy signals 
in: 1) neuroblastoma; 2) osteosarcoma; 3) rhabdomyosarcoma; 4) Ewing 
sarcoma treated at the RP2D.
Phase II dose: The RP2D in mg/m2 will be based on findings in the Phase I 
portion of this study.
Methodology
Standard tumor measurement procedures will be used. Solid tumors will be 
evaluated based on RECIST v1.1. For neuroblastoma patients with 
MIBG-avid disease, the SIOPEN or Curie score will be used and for 
lymphoma patients, the modified Lugano Classification 2014 will be used. 
Tumor assessments will be performed at screening (within 28 days prior to 
start of treatment), during treatment period: every 8 weeks (± 7 days) until 
radiological tumor progression, at the end of treatment (EOT) (not needed if 
the patient discontinued due to PD which has been radiologically confirmed 
within the 4 weeks preceding EOT) and during active FU period: every 
12 weeks (± 14 days) until radiological tumor progression or start of new 
anti-cancer therapy, whichever occurs first. 
Safety evaluations will be done at screening, on the first day of study drug 
administration (Cycle 1 Day 1), at each clinic visit during the treatment, at 
EOT visit and at the SFU visit. The National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 will 
be used to grade toxicities/AEs.
Sparse blood samples for pharmacokinetic (PK) analysis will be collected in 
all patients to characterize the PK of copanlisib.
Blood samples for pharmacodynamic and biomarker analyses will be 
collected from all patients (except ≤1 year old) at screening and at selected 
time points during treatment. In addition, tumor archival tissue (when 
available) and fresh paired tumor biopsy (when feasible) will be collected. 
Patients will remain on therapy with copanlisib until tumor progression, 
unacceptable toxicity, withdrawal of consent, death or other event specified 
by the protocol.
Each patient will be followed for OS for at least 2 years after the last 
patient’s last treatment (LPLT) in the study.
Type of control
Not applicable
Data Monitoring Committee
Yes (for Phase II part)
Number of patients
Phase I: Rolling-6 clinical study design will be utilized; up to 42 patients 
are expected to be enrolled. A minimum of 50% of the enrolled and treated 
patients will be under the age of 12. Once the MTD or recommended Phase 
2 dose has been defined, up to 12 additional patients who are <12 years old 
with relapsed/refractory solid tumors or lymphoma may be enrolled to 
acquire PK data in a representative number of young patients.
Phase II: Simon 2-stage design will be utilized per indication, up to 
4 cohorts will be enrolled with up to 25 patients per cohort, up to
100 patients could be enrolled and treated. A minimum of 80% of the 


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enrolled and treated patients will be under the age of 18.
Primary variable(s)
Phase I part of the study:

maximum tolerated dose (MTD) and/or recommended Phase 2
dose (RP2D)
Phase II part of the study:

objective response rate (ORR) in neuroblastoma, Ewing sarcoma 
and rhabdomyosarcoma

disease control rate (DCR) and progression free survival (PFS) in 
osteosarcoma
Time point/frame of 
measurement for primary 
variable(s)
Phase I part
The DLT observation for the purposes of dose-escalation will be followed 
during the first cycle of therapy.
Phase II part
Primary variable of objective response rate (disease control rate for 
osteosarcoma, respectively) for each indication will be evaluated 16 weeks 
after the last patient will have started treatment for that indication. In case 
all 25 patients of osteosarcoma will be recruited, the 4 month PFS rate will 
also be evaluated descriptively.
Plan for statistical analysis
Phase I part
Individual listing of DLTs will be presented by cohort. Treatment-emergent 
AEs, drug-related AEs, AEs leading to premature study treatment 
termination/ dose reduction / study drug interruptions, serious adverse 
events (SAEs), laboratory parameters and plasma exposure to copanlisib
will be summarized by cohort using descriptive statistics for safety.
Phase II part
The primary efficacy variable ORR in neuroblastoma, rhabdomyosarcoma
and Ewing sarcoma and DCR in osteosarcoma will be summarized 
including number of patients (N), number of responders, response rates. It 
will be evaluated for the full analysis set (FAS) population. If Stage 2 is 
reached for an indication, 85% mid-p confidence intervals as well as a 
conditional p-value will be calculated for this indication. Descriptive 
summary of the safety analyses will be performed for the age group of < 1 
year old separately.
If all 25 patients on osteosarcoma are recruited (i.e. if Stage 2 is reached), 
the survival rate of PFS at 4 months will be estimated as co-primary 
endpoint using the Kaplan-Meier method and its two-sided 95% CI will 
also be provided.
Secondary efficacy variables (ORR of Phase I part, PFS (for all indications 
except osteosarcoma), OS and DOR for each indication reaching Stage 2 in 
Phase II) will be evaluated by appropriate statistical methods.


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Table of contents
Cover page of the integrated protocol.................................................................................... 1
1.
Title page............................................................................................................................ 2
Signature of the sponsor’s medically responsible person..................................................... 3
Signature of principal investigator......................................................................................... 4
2.
Synopsis.............................................................................................................................. 5
Table of contents..................................................................................................................... 11
Table of tables......................................................................................................................... 15
Table of figures....................................................................................................................... 15
List of abbreviations............................................................................................................... 16
3.
Introduction..................................................................................................................... 20
3.1
Background.................................................................................................................... 20
3.1.1
Copanlisib (BAY 80-6946) ........................................................................................ 23
3.1.2
Principal toxicology data............................................................................................ 23
3.1.3
Preclinical data in pediatrics....................................................................................... 24
3.1.4
Clinical experience ..................................................................................................... 24
3.1.5
Clinical pharmacokinetics .......................................................................................... 26
3.2
Rationale of the study .................................................................................................... 26
3.3
Benefit-risk assessment.................................................................................................. 27
4.
Study objectives............................................................................................................... 28
5.
Study design..................................................................................................................... 29
5.1
Design overview ............................................................................................................ 29
5.1.1
Study periods.............................................................................................................. 29
5.2
Phase I dose escalation design....................................................................................... 31
5.3
Phase II design............................................................................................................... 33
5.4
Primary variables ........................................................................................................... 34
5.5
Justification of the design .............................................................................................. 34
6.
Study population ............................................................................................................. 35
6.1
Inclusion criteria ............................................................................................................ 35
6.2
Exclusion criteria ........................................................................................................... 38
6.3
Justification of selection criteria.................................................................................... 40
6.4
Withdrawal of patients from study ................................................................................ 40
6.4.1
Withdrawal ................................................................................................................. 40
6.4.2
Replacement ............................................................................................................... 43
6.5
Patient identification...................................................................................................... 43
7.
Treatments....................................................................................................................... 43
7.1
Treatments to be administered....................................................................................... 43
7.2
Identity of study treatment............................................................................................. 44


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7.3
Treatment assignment.................................................................................................... 44
7.4
Dosage and administration............................................................................................. 44
7.4.1
Dosage – Phase I part ................................................................................................. 46
7.4.1.1
Selection of starting dose ........................................................................................ 46
7.4.1.2
Dose escalation schedule......................................................................................... 47
7.4.1.3
Definition of dose-limiting toxicities (DLTs)......................................................... 47
7.4.2
Dosage – Phase II ....................................................................................................... 49
7.4.3
Dose modifications..................................................................................................... 49
7.4.3.1
Dose-limiting hematological and non-hematological toxicity................................ 49
7.4.3.2
Hematological toxicity............................................................................................ 50
7.4.3.3
Non-hematological toxicity..................................................................................... 51
7.4.3.3.1
Dermatologic toxicity .......................................................................................... 52
7.4.3.3.2
Non-infectious pneumonitis................................................................................. 52
7.4.3.3.3
Glucose increases................................................................................................. 53
7.4.3.3.4
Arterial hypertension ........................................................................................... 55
7.4.4
Treatment of toxicities................................................................................................ 57
7.4.4.1
Management of transient post-infusion glucose increases that can occur with study 
treatment.................................................................................................................. 57
7.4.4.2
Treatment of blood pressure increases associated with study treatment................. 57
7.4.4.3
Guidance for monitoring and prophylaxis of opportunistic infection (OI)............. 58
7.4.4.3.1
Monitoring guidelines for Opportunistic Infections ............................................ 58
7.4.4.3.2
Prophylaxis of Opportunistic Infections .............................................................. 58
7.5
Blinding ......................................................................................................................... 58
7.6
Drug logistics and accountability................................................................................... 59
7.7
Treatment compliance.................................................................................................... 59
8.
Non-study therapy........................................................................................................... 59
8.1
Prior and concomitant therapy....................................................................................... 59
8.2
Post-study therapy.......................................................................................................... 61
9.
Procedures and variables ............................................................................................... 61
9.1
Tabular schedule of evaluations .................................................................................... 61
9.2
Visit description............................................................................................................. 67
9.2.1
Timing of assessments................................................................................................ 67
9.2.1.1
Screening period...................................................................................................... 67
9.2.1.2
Treatment period ..................................................................................................... 69
9.2.1.2.1
Treatment – Cycle 1............................................................................................. 69
9.2.1.2.2
Treatment – Cycle 2 and higher........................................................................... 72
9.2.1.3
Tumor assessments.................................................................................................. 75
9.2.1.4
End-of-treatment visit ............................................................................................. 75
9.2.1.5
Follow-up periods ................................................................................................... 76
9.2.1.5.1
Active follow-up .................................................................................................. 76
9.2.1.5.2
Long-term follow-up............................................................................................ 77
9.3
Population characteristics .............................................................................................. 77
9.3.1
Demographic .............................................................................................................. 77
9.3.2
Medical history........................................................................................................... 77


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9.3.3
Other baseline characteristics..................................................................................... 77
9.4
Efficacy.......................................................................................................................... 78
9.4.1
Radiological tumor assessments................................................................................. 78
9.5
Pharmacokinetics / pharmacodynamics......................................................................... 79
9.6
Safety ............................................................................................................................. 80
9.6.1
Adverse events............................................................................................................ 80
9.6.1.1
Definitions............................................................................................................... 80
9.6.1.2
Classifications for adverse event assessment.......................................................... 82
9.6.1.2.1
Seriousness........................................................................................................... 82
9.6.1.2.2
Intensity................................................................................................................ 82
9.6.1.2.3
Causal relationship............................................................................................... 82
9.6.1.2.4
Action taken with study treatment ....................................................................... 83
9.6.1.2.5
Other specific treatment(s) of adverse events...................................................... 84
9.6.1.2.6
Outcome............................................................................................................... 84
9.6.1.3
Assessments and documentation of adverse events ................................................ 84
9.6.1.4
Reporting of serious adverse events ........................................................................ 85
9.6.1.5
Expected adverse events.......................................................................................... 86
9.6.1.6
Adverse events of special safety interest................................................................. 86
9.6.2
Pregnancies................................................................................................................. 87
9.6.3
Further safety.............................................................................................................. 87
9.6.3.1
Physical examination............................................................................................... 87
9.6.3.2
Body weight, height and BSA calculation .............................................................. 87
9.6.3.3
Growth and dental exams........................................................................................ 88
9.6.3.4
Vital signs................................................................................................................ 88
9.6.3.4.1
Blood pressure measurement on infusion days.................................................... 88
9.6.3.5
Electrocardiogram ................................................................................................... 88
9.6.3.6
Cardiac function...................................................................................................... 89
9.6.3.7
Lansky-Karnofsky Performance status ................................................................... 89
9.6.3.8
Laboratory examinations......................................................................................... 89
9.6.3.9
Glucose measurement on infusion days.................................................................. 90
9.7
Other procedures and variables...................................................................................... 91
9.7.1
Biomarker investigations............................................................................................ 91
9.7.1.1
PD biomarker assessment........................................................................................ 91
9.7.1.2
Molecular tumor characterization / potentially predictive biomarkers ................... 92
9.8
Appropriateness of procedures / measurements ............................................................ 92
10. Statistical methods and determination of sample size ................................................. 92
10.1
General considerations................................................................................................... 92
10.2
Analysis sets .................................................................................................................. 93
10.3
Variables and planned statistical analyses..................................................................... 93
10.3.1
Primary variables........................................................................................................ 93
10.3.1.1
Primary safety variable for Phase I ......................................................................... 93
10.3.1.2
Primary efficacy variable for Phase II..................................................................... 93
10.3.2
Secondary variables.................................................................................................... 94
10.3.2.1
Efficacy variables.................................................................................................... 94


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10.3.2.2
Safety variables ....................................................................................................... 95
10.3.2.3
PK variables ............................................................................................................ 95
10.3.3
Exploratory variables.................................................................................................. 95
10.3.3.1
Biomarker/ pharmacodynamics (PD) variables ...................................................... 95
10.3.4
Statistical and analytical plans.................................................................................... 95
10.3.4.1
Demographic and other baseline characteristics ..................................................... 95
10.3.4.2
Primary efficacy (Phase II only) ............................................................................. 96
10.3.4.3
Secondary efficacy.................................................................................................. 96
10.3.4.4
Safety....................................................................................................................... 97
10.3.4.5
Pharmacodynamics.................................................................................................. 97
10.3.4.6
Biomarkers .............................................................................................................. 97
10.3.4.7
Pharmacokinetics (PK)............................................................................................ 98
10.4
Determination of sample size......................................................................................... 98
10.5
Planned interim analyses ............................................................................................... 98
11. Data handling and quality assurance ............................................................................ 99
11.1
Data recording................................................................................................................ 99
11.2
Monitoring ................................................................................................................... 100
11.3
Data processing............................................................................................................ 101
11.4
Missing data................................................................................................................. 101
11.5
Audit and inspection .................................................................................................... 101
11.6
Archiving ..................................................................................................................... 102
12. Premature termination of the study ............................................................................ 102
13. Ethical and legal aspects............................................................................................... 103
13.1
Investigator(s) and other study personnel.................................................................... 103
13.2
Funding and financial disclosure ................................................................................. 104
13.3
Ethical and legal conduct of the study......................................................................... 104
13.4
Patient information and consent .................................................................................. 105
13.5
Publication policy and use of data ............................................................................... 107
13.6
Compensation for health damage of patients / insurance ............................................ 107
13.7
Confidentiality ............................................................................................................. 107
14. Reference list.................................................................................................................. 108
15. Protocol amendments.................................................................................................... 111
15.1
Amendment 1............................................................................................................... 111
15.1.1
Overview of changes ................................................................................................ 111
15.1.2
Changes to the protocol text..................................................................................... 116
15.2
Amendment 2............................................................................................................... 116
15.2.1
Overview of changes ................................................................................................ 116
15.2.2
Changes to the protocol text..................................................................................... 118
16. Appendices..................................................................................................................... 118
16.1
RECIST v.1.1............................................................................................................... 118
16.2
SIOPEN scoring method.............................................................................................. 121
16.3
Curie scoring method................................................................................................... 123


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16.4
Performance status scales/scores ................................................................................. 125
16.5
Blood sampling in pediatric patients ........................................................................... 126
16.6
Blood pressure levels for children by age and height percentile ................................. 127
16.7
Hypertension................................................................................................................ 130
16.8
NCI-CTCAE ................................................................................................................ 130
16.9
Modified Ross Heart Failure Classification for Children............................................ 131
16.10 Serum creatinine based on age/gender......................................................................... 131
16.11 Evaluation of tumor response in lymphomas (Phase I part)........................................ 132
16.12 CYP3A4 inhibitors and inducers ................................................................................. 134
Table of tables
Table 3–1 Target activation and incidence of PI3K pathway alteration in potential pediatric 
indications (neuroblastoma, osteosarcoma, Ewing sarcoma and 
rhabdomyosarcoma) .............................................................................................. 21
Table 5–1 Decision rules for dose adjustments in Rolling-6 design........................................ 31
Table 7–1 Copanlisib dose levels for patients < 1 year............................................................ 46
Table 7–2 Copanlisib dose levels for patients ≥1 year............................................................ 47
Table 7–3 Dose modification of study treatment for hematological toxicity .......................... 50
Table 7–4 Dose modification of study treatment for non-hematological toxicity (except 
glucose increases, dermatologic toxicity, non-infectious pneumonitis and arterial 
hypertension)......................................................................................................... 51
Table 7–5 Dose modification of study treatment for dermatologic toxicity............................ 52
Table 7–6 Dose modification of study treatment for non-infectious pneumonitis (NIP) ........ 52
Table 7–7 Dose Modification of Study Treatment and Management of Glucose Increase ..... 54
Table 7–8 Dose modifications for hypertension ...................................................................... 56
Table 9–1 Study flow chart ...................................................................................................... 62
Table 9–2 Blood sample collection for copanlisib PK assessment.......................................... 79
Table 9–3 Blood pressure measurement on copanlisib infusion days ..................................... 88
Table 9–4 Glucose measurement on copanlisib infusion days ................................................ 90
Table 16–1 Response for patients with target and non-target lesions.................................... 120
Table 16–2 Response for patients with non-target lesions only............................................. 120
Table 16–3 Lansky-Play Scale conversion to Karnofsky ...................................................... 125
Table 16–4 Age ranges and corresponding volume limits for blood sampling ..................... 126
Table 16–5 Blood pressure levels for boys by age and height percentile.............................. 127
Table 16–6 Blood pressure levels for girls by age and height percentile .............................. 128
Table 16–7 Recommended dimensions for blood pressure cuff bladders ............................. 130
Table 16–8 Modified Ross Heart Failure Classification for Children ................................... 131
Table of figures
Figure 5–1 Study periods ......................................................................................................... 29
Figure 16–1 123-MIBG scoring SIOPEN-method................................................................. 121


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Figure 16–2 Age-specific percentiles for blood pressure in boys (a) and girls (b) from birth to 
12 months of age ................................................................................................. 129
List of abbreviations
5PS
5 point score for the visual assessment of PET-CT
AE
Adverse event
AESI
Adverse event of special interest
AKT
Protein kinase B
ALK 
Anaplastic lymphoma kinase
ALT
Alanine aminotransferase
amp
Amplification
ANC
Absolute neutrophil count
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
AUC
Area under the curve
BCRP
Breast cancer resistance protein
BL
Baseline
BM
Biomarker
BP
Blood pressure
BSA
Body surface area
BUN
Blood urea nitrogen
C
Cycle
CBC
Complete blood count
CI
Confidence interval
CLL
Chronic lymphocytic leukemia
Cmax
Maximum drug concentration
CMR
Complete metabolic response
CMV
Cytomegalovirus
CNS
Central nervous system
COG
Children’s Oncology Group
CR
Complete response
CRF
Case report form
CRO
Contract research organization
CRR
Complete response rate
CRu
Complete response unconfirmed
CSP
Clinical study protocol
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of variation
CYP3A4
Cytochrome P450 isoenzyme 3A4
D
Day
DBP
Diastolic blood pressure
DCR
Disease control rate
dL
Deciliter
DLBCL
Diffuse large B-cell lymphoma
DLT
Dose-limiting toxicity
DMC
Data monitoring committee
DNA
Deoxyribonucleic acid
DOR
Duration of response
ECG
Electrocardiogram


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ECHO
Echocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
e.g.
For example (exempli gratia)
EGFR
Epidermal growth factor receptor
EOT
End of treatment
EudraCT
European Union Drug Regulating Authorities Clinical Trial
EWS
Ewing sarcoma breakpoint region 1
FAS
Full analysis set
FDA
Food and Drug Administration
FDG
Fluorodeoxyglucose
FL
Follicular lymphoma
FLI1
Friend leukemia integration 1 transcription factor
FOXO3a
Forkhead box O3
FSH
Follicle stimulating hormone
FU
Follow-up
g
Gram
GCL
Global Clinical Leader
GCP
Good Clinical Practice
G-CSF
Granulocyte colony-stimulating factor
GFR
Glomerular filtration rate
GMP
Good Manufacturing Practice
GPCR
G protein-coupled receptor
GPV
Global Pharmacovigilance
h
Hour
Hb
Hemoglobin
HBcAb
Hepatitis B core antibody
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B Virus
hCG
β-human chorionic gonadotropin 
HCV
Hepatitis C Virus
HIV
Human immunodeficiency virus
HR
Heart rate
IB
Investigator’s Brochure
IC
Informed Consent
IC50
Half maximal inhibitory concentration
ICF
Informed Consent Form
ICH
International Council for Harmonization
IDMS
Isotope dilution mass spectroscopy
i.e.
That is (id est)
IEC
Independent Ethics Committee
IGF2
Insulin-like growth factor 2
IHC
Immunohistochemistry
iNHL
Indolent non-Hodgkin’s lymphoma
INR
International normalized ratio
IRB
Institutional review board
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
IxRS
Interactive Voice Response System /Interactive Web Response System
kg
Kilogram
LDH
Lactate dehydrogenase


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LDi
Longest diameter
LDL
Low-density lipoprotein
LPFT
Last patient first treatment
LPLT
Last patient last treatment
LTFU
Long-term follow-up
MAb
Monoclonal antibody
MAPK
Mitogen-activated protein kinase
MATE2K
Multidrug and toxin extrusion protein 2
MD
Medical Doctor
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
min
Minute
MIBG
Iodine-123 metaiodobenzylguanidine
mL
Milliliter 
mmHg
Millimeter of mercury
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
mTOR
Mammalian target of rapamycin
MUGA
Multiple gated acquisition
mut
Mutation
MYCN
v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog
MZL
Marginal-zone lymphoma
NA, N/A
Not available
NCI
National Cancer Institute
NE
Not evaluable (by investigator / oncologist)
NHL
Non-Hodgkin’s lymphoma
NIP
Non-infectious pneumonitis
nM
Nanomolar
NMR
No metabolic response, equivalent with stable disease
NRU
Neutral red uptake
OI
Opportunistic infection
ORR
Objective response rate
OS
Overall survival
pAKT
Phosphorylated AKT (protein kinase B [PKB])
PAX3
Paired box gene 3
PAX7
Paired box gene 7
PCR
Polymerase chain reaction
PD
Progressive disease
PDGFR
Platelet-derived growth factor receptor
PET 
Positron emission tomography 
PET-CT
Positron emission tomography-computed tomography
PFS
Progression-free survival
P-gp
Permeability glycoprotein
pH
Negative log of hydrogen ion concentration
PI3K
Phosphatidylinositol-3-kinase
PID
Patient identification number
PIK3R3
Phosphatidylinositol 3-kinase regulatory subunit gamma
PIP3
Phosphatidylinositol-3,4,5-trisphosphate
PK
Pharmacokinetic(s)
PMD
Progressive metabolic disease, equivalent with progressive disease
PMR
Partial metabolic response
PO
Orally (per os)
PopPK
Population PK 
PPD
Product of perpendicular diameters


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PPS
Per protocol set
PR
Partial response
PT
Prothrombin time
PTEN
Phosphatase and tensin homolog
PTT
Partial thromboplastin time
QT
QT interval in ECG
QTc
QT interval in ECG corrected for heart rate
R2PD
Recommended Phase 2 dose
RAVE
Validated electronic data capture system used by Bayer
RBC
Red blood cell count
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
RP2D
Recommended phase 2 dose
RR
Respiration rate
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical analysis plan
SAS
Statistical analysis system
SBP
Systolic blood pressure
SD
Stable disease
SDi
Shortest diameter
SFU
Safety follow-up
SLL
Small lymphocytic lymphoma
SmPC
Summary of Product Characteristics
SOC
Standard of care
SPD
Sum of the product of the diameters
SUSAR
Suspected, unexpected, serious adverse reaction
TEAE
Treatment-emergent adverse event
TTP
Time to progression
ULN
Upper limit normal
UMVCUE
Unbiased minimum variance unbiased conditional
US/USA
United States (of America)
vs.
Versus
WBC
White blood cell count
WHO
World Health Organization


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3.
Introduction
3.1
Background
PI3K pathway
Phosphatidylinositol-3-kinases (PI3Ks) play critical roles in cell proliferation and cell survival 
signaling. They function downstream of receptor tyrosine kinases, cytokine receptors, GPCRs 
and integrins, generating PIP3 second messengers that regulate multiple signal transduction 
pathways. The PI3K pathway is a critical regulator of multiple signal transduction pathways 
that promote cell survival and cell proliferation. Among the most critical of these is the 
PI3K-AKT axis that regulates proliferation and survival through both positive and negative 
regulatory mechanisms that modulate kinase and transcriptional activities.
Many components of the PI3K/AKT pathway have been shown to be mutated or otherwise 
dysregulated in tumors leading to diverse mechanisms of activation. This includes 
amplification/overexpression or mutation of receptors that are at the entry of PI3K signaling, 
alterations of the genes encoding the catalytic or regulatory subunits of class I PI3Ks by
mutations and/or amplification/overexpression, and loss-of-function mutations of genes that 
encode negative regulators of the pathway. These characteristics underpinning the importance 
of PI3K signaling in tumors gave rise to the development of inhibitors of several components 
of the pathway, including the PI3K, AKT, mTOR kinases, and Rapamycin analogs that inhibit 
mTORC1. PI3K has been recognized as a key cancer target for PI3K/AKT pathway in the 
drug development. Currently multiple PI3K inhibitors including PI3Kα selective 
(e.g. BYL719), PI3Kβ selective (e.g. GSK2636771 and SAR260301), PI3Kδ selective 
(e.g. idelalisib, INCB40093, AMG319, TRG1202), PI3Kγ/δ selective (e.g. IPI-145), 
Pan-PI3K (e.g. BKM120) and dual PI3K/MTOR (e.g. BEZ235, GDC-0980, SAR245409, 
VS-5584) agents are under clinical development (1). Among these, only idelalisib, a PI3Kδ 
selective inhibitor has been approved for the treatment of chronic lymphocytic leukemia (CLL)
in combination with rituximab, and for follicular lymphoma (FL) and small lymphocytic 
lymphoma (SLL).
Target pediatric indications for copanlisib
Activating mutations of PI3Ks are more common in adult cancers and associated with a more 
aggressive clinical course than in pediatric malignancies. In childhood malignancies, various 
mechanisms of the PI3K/AKT pathway activation are reported to be frequent (≥50%) in 
neuroblastoma, osteosarcoma, Ewing sarcoma and rhabdomyosarcoma (Table 3–1).


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Table 3–1 Target activation and incidence of PI3K pathway alteration in potential pediatric 
indications (neuroblastoma, osteosarcoma, Ewing sarcoma and rhabdomyosarcoma)
Potential pediatric 
indications
Mechanism of PI3K pathway 
alteration
Preclinical activity by 
PI3K inhibition
Incidence 
of PI3K 
pathway 
alteration 
Neuroblastoma
Over expression of PI3Kp85 / 
PI3Kp110 (IHC)-54%, ALK 
mut/amp-10-15%, or decrease 
of PTEN expression-5%; 
MYCN-amp-20% (2, 3).
High PI3K activity and low 
FOXO3a activity were each 
associated with poor 
prognosis. PI3K/AKT 
inhibition induced 
apoptosis (4, 5). 
50-70%
Osteosarcoma
Massive genomic instability. 
EGFR expression (~80%) and 
genomic gains at the EGFR 
locus (~60%), PTEN deletion 
(~20%) and copy number loss 
(~44%) are prevalent (6).
The alternative activation 
pathways may be relevant 
to mechanisms of tumor 
escape following treatment 
with PI3K inhibitors, and 
warrant a rationale based 
combination e.g. with 
MAPK inhibition (7).
60-80%
Ewing sarcoma
EWS/FLI1 fusion (~85%)          
-> involving IGF1 (IGFR)-
paracrine and autocrine-> to 
activate PI3K. In addition, over-
expression of PIK3R3 and loss 
of PTEN may be associated 
with PI3K pathway activation 
and oncogenic promotion (8,
9).
PI3K inhibition may serve 
to decrease chemotherapy 
resistance, in addition to its 
direct anticancer effects. 
(10).
~85%
Rhabdomyosarcoma
PAX3 or PAX7-FOXO1-> down 
regulated PTEN-> PI3K/AKT; 
IGF2-> pAKT. PI3K pathway 
activation was seen in 82.5% 
rhabdomyosarcomas, however 
with co-activated MAPK in 36% 
and 46% of alveolar and 
embryonal sub-types 
respectively (11).
Various co-activation 
oncogenic alternations 
along with PI3K/AKT 
activation in 
rhabdomyosarcoma may 
limited the single agent 
activity by PI3K inhibitors 
(12).
60-80% 
ALK = Anapalastic lymphoma kinase; amp = Amplification; e.g. =For example (exempli gratia);  EGFR = 
Epidermal growth factor receptor; EWS = Ewing sarcoma breakpoint region 1; FLI1 = Friend leukemia 
integration 1 transcription factor; FOXO3a = Forkhead box O3; IGF2 = Insulin-like growth factor 2; IHC = 
Immunohistochemistry; MAPK = Mitogen-activated protein kinase; mut = Mutation; MYCN = v-myc avian 
myelocytomatosis viral oncogene neuroblastoma derived homolog;  pAKT = Phosphorylated AKT (protein 
kinase B [PKB]);  PAX3 =Paired box gene 3;  PAX7 = Paired box gene 7; PI3K =Phosphatidylinositol-3-
kinase;  PIK3R3 = Phosphatidylinositol 3-kinase regulatory subunit gamma; PTEN = Phosphatase and 
tensin homolog
Based on published data on PI3K implication in tumorigenesis and the mode of action by 
copanlisib to potentially block the PI3K/AKT pathway activated in high risk pediatric cancers, 
the following pediatric tumors were selected as target pediatric indications for copanlisib: 
neuroblastoma, osteosarcoma, rhabdomyosarcoma and Ewing sarcoma.


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These diseases are highly heterogeneous and the overall prognosis depends on the stage of the 
disease and outcome of the initial therapy. Long term prognosis remains poor for children 
with advanced and recurrent cancers.
Neuroblastoma is a tumor of early childhood and is the most common malignancy diagnosed 
in the first year of life, with 25–50 cases per million individuals. 90% of tumors arise in 
children who are < 10 years of age, and neuroblastoma has a median age at diagnosis of 
18 months. Neuroblastoma is a neuroendocrine tumor that arises in the developing 
sympathetic nervous system (from any neural crest element), which results in tumors in the 
adrenal glands and/or sympathetic ganglia (13). For patients with high risk-neuroblastoma the 
5-years overall survival (OS) rate has been estimated as 29% to 50%, with better outcome 
observed for patients diagnosed after 2000, when consolidation with high-dose therapy and 
stem-cell rescue was routinely included in the treatment plan for high-risk patients (14). In 
patients with relapsed neuroblastoma, survival for > 1-3 years without further recurrence of 
disease, or without death, is rarely possible, although more recent chemotherapy combinations 
have been successful in eliciting a partial or complete remission.
Osteosarcoma is an aggressive bone cancer and the most common histologic form of primary 
bone malignancy. This disease affects mainly young adults and children, it is slightly more 
common in males and the incidence is about 20% of all primary bone cancers (15). Almost 
70% of newly diagnosed resectable osteosarcoma will be cured with initial treatment, while 
prognosis for unresectable and relapsed/refractory disease remains poor with response rate up 
to 29% and median progression free survival (PFS) only 1.4-4 months (16).
Ewing sarcoma is a rare disease involving bones and soft tissue with the incidence reported 
at 1 to 3 per million people per year (17). Ewing Sarcoma is a malignancy of childhood and 
adolescence and here represents the second most common primary malignant tumor of bone, 
accounting for ~ 42% of cases in those patients who are 15 years or older. While overall 
5-years OS for patients with Ewing sarcoma is 60%-70%, prognosis for patients with 
relapsed/refractory or metastatic disease is poor – with 5-years OS of 15%-30% (18).
Rhabdomyosarcoma is a cancer affecting connective tissues and it is derived from skeletal 
and muscle progenitor cells. It occurs most commonly in the area of the neck, head and 
genitourinary tract. Five major types are identified according to the International 
Classification of Rhabdomyosarcoma (19). Embryonal rhabdomyosarcoma and alveolar 
rhabdomyosarcoma are two most common forms, with the first diagnosed most often in 
younger children and the second in older children and teenagers. Overall, rhabdomyosarcoma 
occurs most often in children from 1 to 5 years of age. Patients with high risk 
rhabdomyosarcoma have a 5-years OS of 20%-40% (20).
Even though there have been noticeable improvements in the treatment in recent decades, 
curative therapy remains unattainable for many patients with these poor prognosis pediatric 
cancers. Available therapeutic options include highly toxic chemotherapeutic agents with 
some of them having long term toxic effect on cardiovascular system (anthracyclines) or 
reproductive system. Improving and providing new therapeutic options for children with
recurrent disease remains a high clinical unmet need. This includes finding more efficacious 
and safe therapies.


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3.1.1
Copanlisib (BAY 80-6946)
Copanlisib is a novel pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor with 
predominant activity against both PI3Kα and PI3Kδ isoforms being evaluated in adults for the 
treatment of a wide variety of advanced malignancies relapsed or refractory to prior therapy 
either as a single agent or in combination with other investigational agents. The PI3K gene 
product is a key component of the PI3K-AKT cell-signaling pathway. This pathway is one of 
the prominent pathways that promote cellular survival and is constitutively activated in many 
types of cancers (21, 22). Class I PI3Ks can be activated by PI3K gene 
mutation/amplification/overexpression and/or upstream membrane receptors, such as 
epidermal growth factor receptor [EGFR], human epidermal growth factor receptor 2 [HER2], 
insulin-like growth factor-1 receptor [IGFR], platelet-derived growth factor receptor 
[PDGFR], vascular endothelial growth factor, proto-oncogene c-KIT or mesenchymal 
epithelial transition factor receptor [Met]. In addition to mediating cancer-associated signals, 
activation of the PI3K/AKT pathway is also one of the major mechanisms by which tumors 
escape from, and become resistant to, the effects of cytotoxic chemotherapy, targeted agents 
such as trastuzumab (21), and radiation (21, 23). Therefore, PI3K inhibitors are expected to be 
effective in tumors with known or expected intrinsic PI3K activation and to overcome the 
resistance in combination with other chemotherapy and/or targeted agents.
3.1.2
Principal toxicology data
A comprehensive preclinical toxicology program was conducted to support clinical studies in 
patients with advanced cancers.
Study results confirm that the rat and dog are relevant and sensitive species for toxicological
testing of copanlisib. Significant toxicities were observed in these species at doses resulting in 
plasma concentrations in the range of those observed in humans. Target organs based on 
clinical pathology or morphological findings in repeat dose studies with IV infusion of 
copanlisib were the lymphoid and hematopoietic system, liver, kidneys, teeth, 
bone/femorotibial growth plates, heart, and male and female genital systems in the rat and the 
lymphoid and hematopoietic system and stomach (gastric mucosa) in the dog. Effects on 
glucose homeostasis were seen after repeated infusion of copanlisib to both the rat and dog. 
Copanlisib showed no genotoxic potential in vitro or in vivo. Specific reproductive toxicity 
studies have not been conducted. 
Copanlisib is expected to adversely affect human reproduction based on findings in the male
and female reproductive system in the repeat-dose toxicity studies. Additionally, due to the
mechanism of action of copanlisib as a PI3K inhibitor, adverse effects on development, 
including potential teratogenicity, have to be considered. Maternal toxicity of increasing 
severity, severe post-implantation loss, and developmental toxicity, including teratogenicity, 
were seen in a rat pilot developmental toxicity study beginning at a low dose.
Appropriate precautions should be taken to avoid pregnancy in female patients included in the 
clinical trials. Results of the local tolerance studies indicate that accurate IV injection in 
humans is necessary to prevent possible local incompatibility reactions due to inadvertent 
paravenous injection. BAY 84-1236 was identified as a non-phototoxic compound in the 
recommended in vitro 3T3 neutral red uptake (NRU) phototoxicity test.


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In conclusion, the non-clinical toxicology program with copanlisib supports the conduct of 
clinical studies in cancer patients with IV administration.
3.1.3
Preclinical data in pediatrics
Preclinical evaluation of copanlisib in pediatric cell lines demonstrated potent activity in a 
subset of pediatric Ewing sarcomas, rhabdomyosarcomas and leukemia cell lines. The 
majority of the copanlisib combinations showed additive effects on the IC50-level. However, 
on the IC80/IC90-level more than additive (synergistic) anti-proliferative efficacy was observed 
for the combinations with cisplatin, etoposide, SN-38, and melphlan in A-204 
(rhabdomyosarcoma), SH-SY5Y (neuroblastoma) and Saos-2 (osteosarcoma) cells, as well as 
for the cisplatin combination in RH-30 (rhabdomyosarcoma) cells. This enhanced 
combination effect on IC80/IC90 level may hint on an increased induction of cell 
death/apoptosis at higher compound concentrations. In vivo testing of copanlisib in the two 
rhabdomyosarcoma models A204 and RH-30 in mice showed only slight inhibition of tumor 
growth in monotherapy and some improvement by combination with carboplatin.
3.1.4
Clinical experience
As of 21 JUN 2018, approximately 980 patients with advanced cancer have been treated with 
copanlisib in different studies.
Study 12871
First–in–man study 12871 was an open-label, uncontrolled, Phase I dose-escalation study to 
determine the safety, tolerability, pharmacokinetics (PK) and maximum tolerated dose (MTD) 
of copanlisib in patients with advanced cancer. As a single agent, the MTD for copanlisib was 
determined to be 0.8 mg/kg. The recommended (Phase II) dose of copanlisib in adults is 
60 mg given intravenously in a 3 weeks on/1 week off schedule based on an evaluation of 
pharmacokinetic and clinical data from ongoing single agent studies. 57 patients started 
copanlisib treatment: 48 patients with solid tumors (including 6 diabetic patients) and 
9 patients with non-Hodgkin lymphoma (NHL) (6 FL and 3 diffuse large B-cell lymphoma
[DLBCL]). Out of the 48 patients with solid tumor, complete response (CR) as best overall 
response was achieved in 1 patient (2.1%) with endometrial cancer, 2 patients (4%) had 
partial response, 15 (31%) achieved stable disease (SD), and 15 (31%) had disease 
progression by investigator assessment, according to Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1. Ten patients (20.8%) had disease progression by clinical
judgment and 5 patients (10.4%) were not assessed. Clinical benefit (CR, partial response 
[PR], or SD) was observed in 18 patients (38%) overall, by investigator assessment. Among 
the 9 NHL patients, all 6 with follicular lymphoma (FL) responded (one CR and 5 PRs) and 
one patient with diffuse large B-cell lymphoma had a PR; 2 patients with FL achieved CR 
(per subsequent post hoc independent radiologic review), and 2 FL patients were on treatment 
> 3 years.
The most common drug-related treatment-emergent adverse events (TEAEs) by Medical 
Dictionary for Regulatory Activities Preferred Term (MedDRA PT) of all CTCAE (Common 
Terminology Criteria for Adverse Events) v3.0 grades that occurred in ≥20% of the 


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57 patients (all cohorts) were: hyperglycemia (63.2%); nausea (38.6%); and hypertension 
(21.1%). 
Phase II Study 16349 (Part A)
In the Phase II Study 16349 (Part A) various indolent and aggressive, relapsed or refractory 
NHL have been treated. The data presented corresponds to an update with cut-off date of 
01 OCT 2015. There were 7 patients (8.3%) still ongoing with treatment, including 4 patients 
in the indolent non-Hodgkin’s lymphoma (iNHL)/chronic lymphocytic leukemia (CLL) 
cohort and 3 patients in the aggressive NHL cohort. Of the 32 indolent lymphoma patients in 
the per protocol set (PPS), 14 patients achieved objective tumor response (CR+CRu 
[complete response unconfirmed] +PR) based on independent assessment resulting in 
objective tumor response rate (ORR) of 43.75% (90% confidence interval: 28.73; 59.68). Of 
all 14 patients who achieved a response, 2 patients had CR (6.25%), 1 patient had CRu 
(3.13%) and 11 patients had PR (34.38%). A total of 15 patients (46.88%) achieved SD as 
best overall response and 1 patient (3.13%) was classified with a best response of progressive 
disease. Of the 48 aggressive lymphoma patients in the PPS, 13 patients achieved objective 
tumor response (CR+CRu+PR) based on independent assessment resulting in ORR of 27.08% 
(90% confidence interval: 16.83; 39.57). Of all 13 patients who achieved a response, there 
were 2 patients with CR (4.17%), also 2 patients with CRu (4.17%) and 9 patients had PR 
(18.75%). Further, 11 patients (22.92%) achieved SD as best overall response and total of 
16 patients (33.33%) were classified with a best response of progressive disease.
The most commonly experienced TEAEs by MedDRA PT that occurred in ≥20% of the 
patients in Study 16349 part A (cut of date of 01 OCT 2015) were: hyperglycemia (57.1%), 
hypertension (54.8%), diarrhea (40.5%), fatigue (35.7%), nausea (33.3%), neutropenia 
(28.6%), anemia (27.4%) and pyrexia (20.2%). Of these, hyperglycemia (63.6% vs. 52.9%), 
fatigue (48.5% vs. 27.5%), hypertension (69.7% vs. 45.1%), anemia (33.3% vs. 23.5%) and 
pyrexia (30.3% vs. 13.7%) were more common in the indolent group than in the aggressive 
group, respectively. 


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3.1.5
Clinical pharmacokinetics 
Copanlisib PK is linear and plasma exposure as measured by maximum drug concentration 
(Cmax) and area under the curve (AUC) increased in a dose-proportional manner over an 
absolute dose range of 5 to 93 mg (dose range 0.1 to 1.2 mg/kg). There was no indication for 
time-dependency and no accumulation in the pharmacokinetics of copanlisib. The geometric 
mean terminal elimination half-life (CV%) of copanlisib was 39.1 h (40.8%). The geometric 
mean clearance (CV%) was 17.9 L/hr (45.6%). Copanlisib is excreted as unchanged 
compound and metabolites (about 50:50). Metabolism of copanlisib is mediated by CYP3A4 
(> 90%) and to a minor extent by cytochrome P450 isoenzyme 1A1 (CYP1A1) (< 10%).
Itraconazole, a strong CYP3A4 inhibitor and a P-gp and BCRP transporter inhibitor, 
increased the mean AUC of a single IV dose of copanlisib (60 mg) 1.53-fold with no effect on
Cmax (1.03-fold) in cancer patients. Rifampicin, a strong CYP3A4 and a /P-gp inducer, 
decreased the mean AUC of copanlisib by 63% with minor effect on Cmax (15%). PK of 
copanlisib is not affected by age (18 to 90 years), body weight, sex, gender, race, mild and 
moderate renal impairment, mild hepatic impairment and smoking. Copanlisib does not 
prolong QT/QTc interval.
Further details can be found in the latest available version of the investigator's brochure, 
which contains comprehensive information on the study drug.
3.2
Rationale of the study
Based on published data on PI3K implication in tumorigenesis and the mode of action of
copanlisib to potentially block the PI3K/AKT pathway activated in high risk pediatric cancers, 
the following pediatric tumors were selected as target pediatric indications for copanlisib: 
neuroblastoma, osteosarcoma, rhabdomyosarcoma and Ewing sarcoma.
Neuroblastoma, osteosarcoma, rhabdomyosarcoma and Ewing sarcoma in children have been 
reported to frequently harbor activated PI3K/AKT pathways (frequency of ≥50%). It is 
therefore hypothesized that inhibition of the PI3K/AKT pathway with copanlisib, a PI3K 
inhibitor that targets all four class I isoforms with predominant activity against α and δ 
isoforms, may have a positive impact on the treatment outcomes in these sub-entities and the 
probability of success of a development in these malignancies could be higher compared to 
other types of neoplasm.
Even though there have been noticeable improvements in the treatment in recent decades, 
curative therapy remains unattainable for many. Available therapeutic options include highly 
toxic chemotherapeutic agents with some of them having long term toxic effect on 
cardiovascular system (anthracyclines) or reproductive system. Improving and providing new 
therapeutic options for children with recurrent disease remains a high clinical unmet need. 
Efficacy data for copanlisib administered as monotherapy in solid tumors in adults have 
shown clinical responses in few patients with breast and endometrial cancer. Although these 
are not relevant indications for the pediatric population, it is not excluded that copanlisib, 
through its mechanism of action, could be active also in solid tumors studied in this trial.


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3.3
Benefit-risk assessment
This study will be conducted in compliance with the protocol, GCP, applicable regulatory 
requirements, and ICH guidelines.
Front line of treatment for mentioned childhood malignancies is well established and effective. 
Due to lack of available standard of care and remaining high unmet need in relapse/refractory 
disease, a pediatric indication in relapsed and/or refractory neuroblastoma, osteosarcoma, 
rhabdomyosarcoma and Ewing sarcoma is warranted. 
This study is designed to investigate whether the use of copanlisib is safe, feasible and 
beneficial to pediatric patients with solid malignant tumors that are recurrent or refractory to 
standard therapy. 
Copanlisib has been evaluated so far only in adults in a number of clinical studies to establish 
efficacy and safety of copanlisib as a single agent and in combination with other treatments in 
various solid and hematologic malignancies. As of 21 JUN 2018, approximately 980 patients 
with advanced cancer have been treated with copanlisib in different studies.
Based on PK analysis of copanlisib showing no correlation between body weight, body 
surface area, or other body size-related factors and copanlisib clearance, the flat dose of 
60 mg copanlisib administered as a 1 hour IV infusion on days 1, 8 and 15 of a 28-day cycle
(3 weeks on and 1 week off) is indicated in all ongoing or planned clinical studies in adults. 
In the Phase I dose escalation part, the starting dose for the dose-escalation phase will be 60% 
for patients < 1 year old and 80% for patients ≥1 year old of the dose (60 mg/weekly, 
3 weeks on/1 week off) in the adult population recommended for copanlisib development.
The safe and effective dose for the treatment of patients below the age of 22 years has not 
been established. Dosing in a pediatric population should only proceed in a schedule that will 
be defined as per this study for further development. The toxicity profile of copanlisib in 
adults is manageable and is expected to be better tolerated in contrast to cytotoxic agents that 
are currently used as the primary treatment of pediatric tumors. Hyperglycemia and 
hypertension were among the most common adverse events that were in general transient and 
manageable.
Safety will be monitored on an ongoing basis with frequent teleconferences between the 
investigators and the sponsor’s medically responsible personnel to ensure patients’ safety, 
wellbeing and overall integrity of the study.
During Phase I, all decisions on dose escalation, de-escalation will be made after discussion 
between the investigators and sponsor to ensure the safety of each patient and the study 
population.
The individual benefit to the participants is to provide an option to potentially prolong life 
expectancy and to at least maintain quality of life of patients, whose current disease state is 
such that there is no known effective therapy.
Since there is often no alternative for pediatric patients with advanced, recurrent or refractory
cancer, the benefit-risk ratio for this Phase I/II clinical trial should be acceptable to the
participants in this study. The existing positive benefit-risk assessment of copanlisib in adults 


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with hematological malignancies has been confirmed in solid tumors and indolent and 
aggressive NHL.
This clinical trial will be discontinued in the event of new findings that indicate a relevant 
deterioration of the benefit-risk assessment of copanlisib in either pediatric or adult patients. 
Based on the known safety profile of copanlisib, the potential risk of treatment in pediatric 
patients where no standard of care is available outweighs possible risk associated with 
copanlisib therapy. On the basis of the data available to date, the conduct of the clinical trial is 
regarded as justified.
4.
Study objectives
Phase I (dose escalation) part: 
The primary objective:

To establish the safety, maximum tolerated dose (MTD) and/or recommended Phase 2 
dose (RP2D) of copanlisib in pediatric patients with a relapsed/refractory solid tumor 
or lymphoma 
The secondary objectives:

To characterize the PK of copanlisib 

To assess the antitumor activity of copanlisib and to identify specific potential tumor 
type(s) for further development
The exploratory objectives:

To evaluate pharmacodynamics of copanlisib

To evaluate biomarkers of efficacy, mode-of-action-related effect, and / or the 
pathomechanism of the disease
Phase II (extension) part
The primary objective:

To determine the objective response rate (ORR) of copanlisib in pediatric patients 
with relapsed/refractory neuroblastoma, rhabdomyosarcoma or Ewing sarcoma. 

To determine the disease control rate (DCR) and progression free survival (PFS) in 
pediatric patients with relapsed/refractory osteosarcoma
Secondary objectives: 

To evaluate PFS (in indications other than osteosarcoma), overall survival (OS), and 
duration of response (DOR)

To evaluate safety 
Exploratory objectives:

To characterize population PK of copanlisib


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
To evaluate pharmacodynamics of copanlisib

To evaluate biomarkers of efficacy, mode-of-action-related effect, and/or the 
pathomechanism of the disease
5.
Study design
5.1
Design overview
This study 19176 (COG study number ADVL1721) is an open-label, non-controlled, 
dose-escalating trial to evaluate the pharmacokinetics, pharmacodynamics, safety and activity 
of copanlisib in pediatric patients from 6 months to ≤ 21 years of age with a relapsed or 
refractory solid malignant tumor or lymphoma and an extension in pediatric patients from 
6 months to ≤ 21 years with a relapsed or refractory neuroblastoma, osteosarcoma, 
rhabdomyosarcoma or Ewing sarcoma.
The study includes two parts. The Phase I (dose escalation) part will use the Rolling-six 
design with expansion cohort at the maximum tolerated dose. The Phase II (extension) part 
will use Simon 2-stage design in arms by tumor type.
A schematic of the study periods is presented in Figure 5–1. The following design applies to 
both Phase I and Phase II parts.
Figure 5–1 Study periods
On study
Off study
Screening
Treatment
                Active FU a
Long-term
FU
Informed
consent
First dose of 
study 
treatment 
Last dose of study 
treatment/
End of last cycle
Last protocol-
stipulated 
procedure
a: Mandatory SFU visit and other active follow-up visits, if applicable
5.1.1
Study periods
The study will comprise on the following periods: screening, treatment, active follow-up
and long-term follow-up
Screening 
Screening period starts after the patient and/or patient’s parents (or legal guardians) have 
signed the informed consent form (and an assent from the patient is obtained, where 
applicable), and ends just before the start of treatment with copanlisib.
Treatment 
The start of the treatment period is defined by first administration of study drug copanlisib.
Copanlisib will be administered IV on Days 1, 8 and 15 of each 28-day treatment cycle. 
Treatment will be continued until radiological progressive disease, unacceptable toxicity, 
withdrawal of consent, death or other event specified by the protocol (see Section 6.4).


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An End-of-treatment (EOT) visit will be performed within 7 days after the decision is made to 
discontinue study treatment.
Active Follow–up:
The active follow-up period is the interval from the end of study drug intake to the end of all 
clinical study protocol (CSP)-specified post-treatment interventions. 
All patients who discontinue study treatment for any reason will be followed for safety at a 
mandatory safety follow-up visit except for patients and/or parents (or legal guardians) who 
refuse follow-up data collection. This safety follow-up (SFU) visit will take place 30+5 days 
after the last administration of study drug.
Patients who discontinue study treatment without radiological PD will be followed for 
radiological tumor assessments during the active FU until radiological PD is documented or 
until the start of first subsequent anti-cancer therapy, whichever occurs first. During this 
period only AEs and SAEs assessed as related to the study procedures by the investigator will 
be reported. AE pages of the electronic case report form (eCRF) and the SAE form should be 
completed in the usual manner and forwarded to the sponsor’s GPV department.
Long-term follow-up (LTFU):
All patients will be followed up for survival for at least 2 years after the end of the Phase I
(dose-escalation) and Phase II (extension) parts. 
All patients who discontinue from study treatment or from active follow-up for any reason
will enter long-term follow-up period during which survival data will be collected except for 
the cases when patients and/or parents (or legal guardians) refuse follow-up data collection.
Patients’ parents (or legal guardians) will continue to be contacted approximately every 
3 months to determine survival status until death or at least 2 years after the last patient’s last 
treatment (LPLT) in the study (See Section 9.2.1.5.2). Those patients who reached adult age 
during the long-term follow-up can be contacted directly or via patients’ parents (or legal 
guardians).
Study procedures
Standard tumor measurement procedures will be used. Solid tumors will be evaluated based 
on RECIST v1.1. For neuroblastoma patients with MIBG-avid disease, the SIOPEN or Curie 
score will be used (see Appendix 16.2 and Appendix 16.3) and for lymphoma patients, the 
modified Lugano Classification 2014 will be used (see Appendix 16.11). Tumor assessments 
will be performed at screening (within 28 days prior to start of treatment), during treatment 
period: every 8 weeks (± 7 days) until radiological tumor progression, at EOT and during 
active FU period: every 12 weeks (± 14 days) until radiological tumor progression or start of 
new anti-cancer therapy, whichever occurs first. Tumor assessment is not required at the EOT 
visit if the patient discontinued due to PD which has been radiologically confirmed within the 
4 weeks preceding EOT visit.
Safety evaluations will be done at screening, on the first day of study drug administration 
(Cycle 1 Day 1), at each clinic visit during the treatment, at EOT visit and at the SFU visit. 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) version 4.03 will be used to grade toxicities/AEs.


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Sparse blood samples for pharmacokinetic (PK) analysis will be collected in all patients to 
characterize the PK of copanlisib as outlined in Section 9.5.
Blood samples for pharmacodynamic and biomarker analyses will be collected from all 
patients (except ≤1 year old) at screening and at selected time points during treatment. In 
addition, tumor archival tissue (when available) and fresh paired tumor biopsy (when feasible) 
will be collected. See Section 9.7.1.
5.2
Phase I dose escalation design 
The Phase I (dose-escalation) part of the study will determine the safety, MTD and/or RP2D
of copanlisib in a pediatric population by using stepwise dose-escalation design based on 
Rolling-6 rule (see Table 5–1) with expansion cohort at the maximum tolerated dose.
For the dose levels of copanlisib in the Phase I part, see Section 7.4.
In the Rolling-6 study design, up to 6 patients are enrolled concurrently. Accrual to the study 
is suspended when 6 patients are enrolled. Accrual can be stopped earlier in any given 
cohort/dose level once DLTs are established and reviewed. Decisions as to whether to enroll a 
new patient onto the current, at next highest, or next lowest dose level will be made based on 
available data at the time of new patient enrollment. 
Dose level assignment will be based on the number of patients enrolled in the cohort, the
number of DLTs observed, and the number of patients at risk for developing a DLT (i.e., 
patients enrolled but who are not yet evaluable for toxicity). If the DLT criteria are amended 
for any reason, the next cohort under amended criteria will start at the last dose level assessed 
under the previous DLT criteria.
For example, when three patients to be enrolled onto a dose cohort, if toxicity data will be 
available for all three when the fourth patient is to be entered and the patients have no DLTs, 
the dose will be escalated and the fourth patient will be enrolled to the subsequent dose level. 
If data are not yet available for one or more of the first three patients, or if one DLT has been 
observed, the new patient will enter at the same dose level. Lastly, if two or more DLTs have 
been observed, the dose level will be de-escalated. The process to be repeated for patients five 
and six. In place of suspending accrual after every three patients, accrual should only be 
suspended when a cohort of six will be filled. 
Patients who discontinue during Cycle 1 because of any reason other than a DLT or other 
TEAE requiring discontinuation of treatment, and patients who were non-compliant in 
Cycle 1 to the extent that precludes the assessment of study objectives according to the 
sponsor’s decision in consultation with the investigator, will be replaced to ensure the 
required number of evaluable patients per cohort. 
Table 5–1 Decision rules for dose adjustments in Rolling-6 design
Number of 
patients enrolled
Number of 
patients with DLT
Number of patients 
with data pending
Decision


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Table 5–1 Decision rules for dose adjustments in Rolling-6 design
Number of 
patients enrolled
Number of 
patients with DLT
Number of patients 
with data pending
Decision
2
2
-
De-escalate a
0 or 1
-
Same dose level
3
≥ 2
-
De-escalate a
0
0
Escalate b
1
-
Same dose level
4
≥ 2
-
De-escalate a
0
0
Escalate b
1
-
Same dose level
5
≥ 2
-
De-escalate a
0
0
Escalate b
1
-
Same dose level
6
≥ 2
-
De-escalate a
≤ 1
1
Escalate b
0
Escalate b
DLT = Dose-limiting toxicity; MTD = Maximum tolerated dose
a: If 6 patients already entered at the next lower dose level, the MTD has been defined; 
if de-escalation occurs at the lowest dose level (for patients ≥1 year old (lowest dose level -1) 
and for patients < 1 year old (lowest dose level -2), please see Table 7–2 and Table 7–1, 
respectively), then the study is discontinued.
b: Dose escalation will take place only after comprehensive review of all collected safety data and 
careful evaluation by the investigators and sponsor.
Source: (24).
The recruitment will continue according to the Rolling-6 design, until the MTD is declared or 
copanlisib plasma exposure is assessed as being equivalent to the exposure in adult patients 
receiving the recommended treatment schedule. Once escalation is stopped, the last cohort 
will be expanded from 6 up to 12 patients in order to collect more safety and tolerability data 
and establish the RP2D. Intra-patient dose escalation is not permitted.  Once the MTD or 
recommended Phase 2 dose has been defined, up to 12 additional patients who are <12 years 
old with relapsed/refractory solid tumors or lymphoma may be enrolled to acquire PK data in 
a representative number of young patients.
Assessment of dose-limiting toxicities (DLTs) will be performed during Cycle 1 (for the 
definition of DLT, please refer to Section 7.4.1.3). If ≥2 patients report DLTs in a cohort size 
of 3-6, that dose level is declared as toxic dose. If 6 patients already entered at the next lower 
dose level, the MTD has been defined. If de-escalation occurs at the lowest dose level, the 
study will be discontinued. 
Maximum tolerated dose (MTD) for copanlisib will be defined as the highest dose level 
where 6 patients have been treated and ≤ 1 patient experiences a DLT. 


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
The MTD of copanlisib for patients < 1 year old will be established and analyzed 
separately from the patients ≥1 year old and the results will be provided in a 
descriptive statistical analysis. 
If in the Phase I part of the study the MTD will not be established in patients < 1 year old, the 
MTD determination in patients < 1 year old will continue in parallel with the Phase II part and 
will be stopped when the Phase II part has been closed. Patients < 1 year old may not be 
enrolled in the Phase II part of the study until the MTD and RP2D for that age group has been 
established. However, if in the Phase I part a certain cohort of pediatric patients < 1 year old 
reaches the copanlisib plasma exposure of adult patients treated with the recommended dose 
before the pediatric MTD is defined, no higher dose level will be tested.
Equivalence to adult copanlisib plasma exposure will be defined as the geometric mean of the 
individual AUCs in the cohort with the highest dose level being within ± 25% of the adult 
exposure after dosing recommended for copanlisib development.
Recommended Phase II dose (RP2D) for copanlisib therapy will be determined by the 
investigators and the sponsor after having reviewed the data from all dose levels including 
available PK data, overall incidence and intensity of AEs and MTD.
For the detailed description of dosing and schedule, please refer to Section 7.4.
Transition from Phase I part to Phase II part 
The protocol will be amended after completion of the Phase I part to update information on 
RP2D and other related topics (e.g. toxicities management guidance).
5.3
Phase II design
The Phase II part (extension) of the study will establish efficacy signal of copanlisib single 
agent treatment in pediatric patients with relapsed/refractory neuroblastoma, osteosarcoma, 
rhabdomyosarcoma or Ewing sarcoma.
A Simon 2-stage design will be used (30). According to Simon 2-stage design, after 10 FAS 
patients per indication will have been treated in Stage 1 for at least of 4 cycles, recruitment 
will be paused until decision for go/no-go into Stage 2 (see Section 10.5 for further 
information).
The RP2D as determined in the Phase I part of this study, will be used for the Phase II part of 
the study. This dose will be determined by the investigators and the sponsor after having 
reviewed the data from all evaluated dose levels in Phase I, including PK data, overall 
incidence and intensity of AEs and MTD. 
The number of study participants in the Phase II part: planned 10 pediatric patients per opened 
arm in first stage and, if at least 2 responses occur, in the second stage 15 additional pediatric 
patients in the neuroblastoma, osteosarcoma, rhabdomyosarcoma or Ewing sarcoma arms. Up 
to 25 patients per arm and up to 100 patients could be enrolled and treated.


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5.4
Primary variables
The primary variable of Phase I part of the study is:

maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D)
The primary variable of Phase II part of the study is:

objective response rate (ORR) in neuroblastoma, Ewing sarcoma and 
rhabdomyosarcoma

disease control rate (DCR) and progression free survival (PFS) in osteosarcoma
5.5
Justification of the design
The study design (open-label, non-randomized, single-arm, multiple-dose administration) is a 
standard approach for a pediatric Phase I / dose escalation and PK study intended to 
investigate the pharmacokinetics and safety profile of a new compound in cancer patients or 
of a known compound in a new population – in this case, pediatric oncology patients. The 
study design for Phase I part is based on well-established and widely accepted methodologies 
where initially dose limiting toxicities will be established and the recommended dose will be 
selected for the next study. 
The Rolling-6 study design is appropriate to minimize exposure of pediatric patients to
ineffective treatment and to accelerate development in this setting. Age from 6 months to 
≤21 years old and tumor types are selected based on proposed indications. Treatment 
duration is based on available data from adult studies and will depend on sensitivity to the 
treatment with copanlisib. Patients will be treated until disease progression or until another 
event pre-specified in the protocol is met. 
The Rolling-6 design has been chosen because it allows for temporal overlap of the two 
cohorts of three patients used in the 3+3 design. Hence, the probability of trial suspension to 
further accrual is lower in the Rolling-6 design compared to the 3+3 design. Advantage of 
Rolling-6 design is, therefore, shortening the total trial duration without putting patient safety 
at risk, as the number and frequency of DLTs are similar when the two designs are compared
(24). The inclusion of a placebo control or blinding of the treatment is considered not 
applicable for the objectives of this clinical Phase I part of the trial.
Phase II part of the study will establish efficacy signal of copanlisib in pediatric patients with 
relapsed/refractory neuroblastoma, osteosarcoma, rhabdomyosarcoma or Ewing sarcoma. 
Simon 2-stage design and sample size are considered most appropriate to minimize the 
exposure to ineffective treatment for pediatric patients with relapsed or refractory disease. The 
study primary and secondary endpoints for both phases are considered most appropriate for 
assessment of initial safety and efficacy signals of the investigational product. Eligibility 
criteria are focused on inclusion of pediatric patients with various solid malignancies after at 
least one line of treatment and will allow inclusion of patients with performance status and 
laboratory parameters appropriate for each individual clinical study. At least 2-year long term 
follow-up will be performed. If a certain safety signal will be observed in Phase I of the study, 
extended follow-up for survival may be implemented.


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End of study
The end of the study as a whole will be reached as soon as the last contact of the last patient
has been reached in all centers in all participating countries.
Primary completion
The primary completion event for this study is the last primary endpoint of the last patient 
after 4 cycles of treatment of all cohorts in the Phase II part.
The primary completion date for this study according to the FDA Amendment Act is specified 
in a separate document (not part of this study protocol).
6.
Study population
Eligibility
6.1
Inclusion criteria
1. Signed informed consent form by patients and/or patients’ parents/legal guardians and 
age appropriate assent form by the patients obtained before any study specific 
procedure.
2. Male or female patients from 6 months to ≤ 21 years old at the time of study 
enrollment.
3. Confirmation of diagnosis:

Phase I: Patients must have histologic verification of a solid tumor or lymphoma 
malignancy at diagnosis, with measurable or evaluable disease, for which there is 
no standard curative anti-cancer treatment or treatment is no longer effective and 
must have received ≥ 1 prior line of therapy.

Phase II: patients must have histologically verified tumor at initial diagnosis and 
radiologically or histologically confirmed status at inclusion as indicated in the 
following: neuroblastoma, osteosarcoma, rhabdomyosarcoma or Ewing sarcoma.
In Phase II, patients with solid tumors must have measurable disease (evaluable 
disease is acceptable for neuroblastoma and Ewing sarcoma). Tumor assessment 
will be done via computed tomography (CT), magnetic resonance imaging (MRI)
or positron emission tomography-computed tomography (PET-CT) (See Section 
9.4 for details). Tumor lesions situated in a previously irradiated area, or in an 
area subjected to other loco-regional therapy, may be considered measurable if 
there has been demonstrated progression in the lesion. Bone scans (if clinically 
indicated) should be obtained within ≤4 weeks prior to the start of treatment.
4. The following tumor type specific inclusion criteria must be met:
Lymphoma (Phase I part):
Patients with lymphoma must have measurable disease (at least one bi-
dimensionally measurable site of disease that has not been previously irradiated): 


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nodal disease > 1.5 cm or an extranodal lesion > 1.0 cm in longest perpendicular 
diameter) according to the Lugano classification 2014.
Phase I and II parts:
Neuroblastoma:

Recurrent after treatment or refractory or progressive during initial treatment with 
two or more agents, including an alkylating agent and a platinum-containing 
agent 

Neuroblastoma patients must have measurable (MIBG non-avid disease) and/or 
non-measurable disease (MIBG-avid disease). Tumor evaluation will be 
performed within 4 weeks prior to the start of treatment.
o Patients with measurable (MIBG non-avid) disease will have tumor 
assessments according to RECIST v.1.1. (See Section 16.1).
o Patients with MIBG-avid disease will have tumor evaluation by MIBG scan 
according to SIOPEN or Curie score. MIBG-avid lesion that has been 
previously irradiated needs to have a biopsy performed at least 4 weeks 
post-radiation and must show viable neuroblastoma.
Osteosarcoma:

Relapsed or refractory disease after treatment with two or more agents, including 
patients with pulmonary and/or osseous metastases.
Ewing sarcoma:

Relapsed or refractory metastatic evaluable or measurable disease including 
single lung metastases and/or bone marrow involvement disease.
Rhabdomyosarcoma: 

Embryonal, alveolar and other histologies, recurrent after treatment or refractory 
or progressing during treatment with two or more agents, including 
cyclophosphamide or ifosfamide.
5. Life expectancy of at least 12 weeks from the time of signing informed consent/assent
6. Performance level: Lansky ≥ 50% for patients ≤ 16 years of age and Karnofsky ≥ 50% 
for patients > 16 years of age.
Note: the performance level should not be considered reduced by limitations to 
movement or play caused by motor paresis or paralysis due to disease. Patients who 
are unable to walk because of paralysis, but who are up in a wheelchair, will be 
considered ambulatory for the purpose of assessing the performance score. 
7. Adequate bone marrow, liver and renal function as assessed by the following 
laboratory requirements conducted within 7 days before start of study treatment:

Absolute neutrophil count (ANC): ≥ 1.0 x 109/L.


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
Platelet count: ≥ 75 x 109/L. For patients with confirmed cancer bone marrow 
infiltration, platelet count ≥50,000 /mm3. Platelet transfusion should not be 
given within 7 days before the first administration of the study drug.

Hemoglobin: ≥ 8.0 g/ dL. Packed red blood cell transfusion or erythropoietin 
should not be given within 7 days before the first administration of the study 
drug.

Creatinine clearance based on Schwartz Estimate ≥ 70 ml/min/1.73 m2 or a 
serum creatinine based on age/gender (see Appendix 16.10).

International normalized ratio (INR) ≤ 1.5 and partial thromboplastin time (PTT) 
or activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN. Prophylactic 
anticoagulation of venous or arterial access devices is allowed provided that the 
requirements for INR and PTT or aPTT are met. Therapeutic anticoagulation is 
not allowed.

Random or fasting serum glucose ≤ 126 mg/dL. If the initial glucose 
measurement is a random sample that is outside of this limit, then a fasting 
blood glucose can be obtained and must be ≤ 126 mg/dL.  Note: For this 
protocol, fasting is defined as 8 hours elapsed since the prior meal.

Lipase ≤ 1.5 x ULN.

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤3.0 x ULN.

Alkaline phosphatase limit ≤ 2.5 x ULN (≤ 5 x ULN for patients with bone 
tumors or metastasis to bone).

Total bilirubin ≤ 1.5 x ULN; patients with known Gilbert’s syndrome or for 
patients with cholestasis due to compressive adenopathies of the hepatic hilum 
or documented liver involvement by tumor infiltration/progression - total 
bilirubin ≤5 x ULN may be enrolled.
See also Section 6.4.1 for the allowed re-screening of the laboratory tests.
8. Females of childbearing potential and males must agree to use effective contraception 
when sexually active. This applies for the time period between signing of the informed 
consent form and 1 month after the last administration of study drug. A female is 
considered of childbearing potential, i.e. fertile, following menarche and until 
becoming post-menopausal unless permanently sterile. Permanent sterilization 
methods include but are not limited to hysterectomy, bilateral salpingectomy and 
bilateral oophorectomy. A postmenopausal state is defined as no menses for 
continuous 12 months without an alternative medical cause. A high follicle stimulating 
hormone (FSH) level in the postmenopausal range may be used to confirm a post-
menopausal state in females not using hormonal contraception or hormonal 
replacement therapy. 
The investigator or a designated associate is requested to advise the patient how to 


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achieve highly effective birth control method (failure rate of less than 1%) e.g. 
intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal 
occlusion, vasectomized partner, and sexual abstinence. The use of condoms by male 
patients is required for one month after the last administration of study drug, unless 
the female partner is permanently sterile.
6.2
Exclusion criteria
Patients who meet any of the following criteria at the time of screening will be excluded
1.
Previous assignment to treatment during this study. Patients permanently withdrawn 
from study participation will not be allowed to re-enter the study.
2.
Previous anti-cancer or immunosuppressive treatment including immunotherapy and 
cytotoxic chemotherapy (within 28 days or less than 5 half-lives of the drug before 
start of study treatment whichever is less [or within 6 weeks for mitomycin C]) unless 
specifically mentioned in another exclusion criteria.
Concomitant participation in another clinical study with investigational medicinal 
product(s).
3.
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).
4.
Patients who previously received therapy with copanlisib or other PI3K inhibitors are 
not eligible for enrollment.
5.
Arterial or venous thrombotic or embolic events such as cerebrovascular accident
(including transient ischemic attacks), deep vein thrombosis or pulmonary embolism 
within 3 months before the start of study medication.
6.
Patients with central nervous system (CNS) malignancies.
7.
Patients with any of the following as the only site(s) of disease: palpable lymph nodes 
not visible on imaging studies, skin lesions, or bone marrow involvement only unless 
otherwise specified in the inclusion criteria (e.g. Neuroblastoma or Ewing sarcoma).
8.
Active or uncontrolled infection (NCI-CTCAE Grade ≥ 2).
9.
Positive cytomegalovirus (CMV) PCR test at baseline.
10. Hepatitis B (HBV) or hepatitis C (HCV). All patients must be screened for HBV and 
HCV up to 28 days prior to study drug start using the routine hepatitis virus 
laboratorial panel. 
o
Patients positive for HBsAg or HBcAb will be eligible if they are negative for 
HBV-DNA.
o
Patients positive for anti-HCV will be eligible if they are negative for 
HCV-RNA.
11. Known history of human immunodeficiency virus (HIV) infection.


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12. Major surgical procedure or significant traumatic injury within 28 days before start of 
study medication. Bone marrow biopsy, central line placement and tumor biopsy by 
needle or core-biopsy (with exception of excisional biopsy) will not be considered as 
a major surgical procedure.
13. Non-healing wound or ulcer.
14. Seizure disorder requiring treatment.
15. Diabetes mellitus.
16. Concurrent diagnosis of phaeochromocytoma.
17. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in 
the formulation.
18. Unresolved acute toxicity higher than NCI-CTCAE v. 4.03 Grade 1 attributed to any 
prior antineoplastic therapy/procedure (excluding alopecia, chemotherapy-induced 
ototoxicity, absolute lymphocyte count (ALC) decreased, anemia, and white blood 
cell count (WBC) decreased). Note: Peripheral (sensory or motor) neuropathy related 
to limb sparing procedure or amputation is allowed.
19. Uncontrolled arterial hypertension despite optimal medical management (per 
institutional guidelines).
20. Cardiac abnormalities such as congestive heart failure (Modified Ross Heart Failure 
Classification for Children ≥ class 2, see Appendix 16.9) and cardiac arrhythmias 
requiring anti-arrhythmic therapy.
21. History of organ allograft (including allogeneic bone marrow transplant).
22. Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding 
event within 4 weeks prior to screening.
23. History or concurrent condition of interstitial lung disease of any severity and/or 
severely impaired lung function (as judged by the investigator). 
24. Pregnancy or breast-feeding patients. Female patients of childbearing potential must 
have a pregnancy test performed a maximum of 7 days before start of study treatment, 
and a negative result must be documented before start of study treatment.
25. Any other serious or unstable illness, or medical, psychological or social condition, 
that could jeopardize the safety of the patients and/or his/her compliance with study 
procedures or may interfere with the patient’s participation in the study or evaluation 
of the study results.
26. For Phase II only: Any other malignancy within last 3 years except for curatively 
treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder 
tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1(tumor invades 
lamina propria)].


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Excluded previous therapies and medications:
27. Use of CYP3A4 strong inhibitors and/or inducers are prohibited within two weeks 
prior to start of study treatment.
28. Myeloid growth factors within 14 days before start of study treatment.
29. Removed in Integrated Protocol Amendment 2.
30. Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-MIBG), cellular 
therapy (e.g. modified T cells, NK cells, dendritic cells, etc.) within 6 weeks before start 
of study treatment.
31. Radiation therapy:
o ≤ 4 weeks prior to start of study treatment
o
≥ 6 months must have elapsed if ≥ 50% radiation of pelvis
Note: palliative radiotherapy is permitted (see Section 8.1).
32. Stem cell infusions: autologous stem cell transplant ≤ 3 months after infusion.
33. Antibodies: ≥ 3 weeks must have elapsed from infusion of last dose of antibody, and 
toxicity related to prior antibody therapy must be recovered to Grade ≤ 1.
6.3
Justification of selection criteria
The selection criteria are chosen to ensure that patients with specific risks for administration 
of the study drug and/or patients with conditions which may have an impact on the aims of 
the study are excluded.
6.4
Withdrawal of patients from study
6.4.1
Withdrawal
Withdrawal of patients from study treatment
Patients must be withdrawn from the study treatment if any of the following occurs:

At their own request or at the request of their parent or legally acceptable 
representative. At any time during the study and without giving reasons, a patient may 
decline to participate further. The patient will not suffer any disadvantage as a result.

If, in the investigator's opinion after the consultation with the sponsor, continuation of 
the study would be harmful to the patient's well-being.

Occurrence of unacceptable toxicity from any study treatment.

Severe allergic reactions to study drug ≥ CTCAE Grade 3 such as hypersensitivity 
reaction, exfoliate erythroderma, anaphylaxis, or vascular collapse.

Progressive disease, as defined in the RECIST, version 1.1 (See Appendix 16.1) (or by 
SIOPEN or Curie score for neuroblastoma patients with MIBG-avid disease, (see 


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Appendix 16.2 and 16.3), or for patients with lymphoma as defined in the modified
Lugano Classification, 2014 (see Appendix 16.11).

Use of illicit drugs or other substances, which, in the opinion of the investigator or 
designated associate(s), may have a reasonable chance of contributing to toxicity or 
otherwise confound the results.

Development of any intercurrent illness or situation, which, in the judgment of the 
investigator, may affect assessments of clinical status and study endpoints to a 
relevant degree.

Substantial non-compliance with the requirements of the study.

The development of a malignancy other than cancer treated in this study. New 
malignancy will be reported as an SAE.

Patients with a β-human chorionic gonadotropin (hCG) test consistent with pregnancy. 
Pregnancy will be reported along the same timelines as an SAE.

Start of a new anti-cancer regimen.

Delay of more than 28 days from the last dose of study treatment due to toxicities
related to copanlisib. Delays of study drug dosing due to reasons other than toxicity is 
not included in this definition.

Adverse events or toxicities that are attributed to copanlisib and require 
discontinuation of protocol therapy as described in Section 7.4.3.

Patient does not tolerate study drug at the protocol lowest dose level (for patients 
≥1 year old (lowest dose level -1) and for patients < 1 year old (lowest dose level -2), 
please see Table 7–2 and Table 7–1, respectively).
Withdrawal of patients from study 
Patients must be withdrawn from the study if any of the following occurs:

At the specific request of the sponsor and in liaison with the investigator (e.g. obvious 
non-compliance, safety concerns).

Death.

Lost to follow-up.

Withdrawal of consent for any required observations or data submission.
A withdrawn patient is referred to “screening failure” as specified below:
Screening failure
A patient who, for any reason (e.g. failure to satisfy the selection criteria), terminates the 
study before assignment to the study treatment is regarded a “screening failure”. 


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Re-starting the defined set of screening procedures to enable the “screening failure” patient’s 
participation at a later time point is not allowed – with the following exceptions:

The patient had successfully passed the screening procedures but could not start 
subsequent treatment on schedule.

The in- / exclusion criteria preventing the patient’s initial attempt to participate have 
been changed (via protocol amendment).
In any case, the investigator has to ensure that the repeated screening procedures do not 
expose the patient to an unjustifiable health risk. 
Re-screening of patients may only be allowed once after discussion and approval by the 
sponsor. Sponsor approval of re-screening for the patient who has failed screening must be
documented. 
The screening failure will be registered in Interactive Voice/Web Response System (IxRS) to 
close the patient identification number (PID), and re-screening will start again by signing a 
new informed consent form and being assigned a new PID.
Laboratory tests at screening
If one or more screening laboratory tests do not support eligibility, laboratory re-test is 
permitted only once without the need of re-consent. Only the laboratory tests which are out of 
range could be repeated and it should be in compliance with the requirement for blood sample 
volume. However, if this re-testing cannot be completed within 7 days of the Cycle 1 Day 1, 
the patient will be declared as a screening failure. Patients may not begin study drug treatment 
until the results of re-testing are available and documented to be within protocol-required 
range.
General procedures
Any patient removed from the study will remain under medical supervision until discharge or
transfer is medically acceptable. In all cases, the reason for discontinuing study treatment and 
the completion of the follow-up periods must be clearly documented in the eCRF and in the 
patient’s medical records. 
All patients who discontinue due to AEs or clinical laboratory abnormalities should be 
followed up until they recover or stabilize, and the subsequent outcome recorded. If any 
patient dies during the study or within 30 days of the last dose of study drug, the investigator
or his/her designated associate(s) will inform the sponsor. The cause of death should be 
recorded in detail within 24 h of awareness on an SAE form and transmitted to the sponsor. 
The patient may object to the generation and processing of post-withdrawal data as specified 
in Section 13.4. For patients who withdraw consent and refuse follow-up data collection, no 
further study related procedures will be allowed, and no further data, including survival data, 
will be collected. The patients will not suffer any disadvantage as a result.
Details for the premature termination of the study as a whole (or components thereof) are 
provided in Section 12.


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6.4.2
Replacement
Phase I part
Patients in the Phase I part who discontinue because of a DLT or other related toxicity that led 
to discontinuation of treatment during the DLT evaluation period will not be replaced.
Patients in the Phase I part who discontinue during Cycle 1 because of any reason other than a 
DLT or other TEAE requiring discontinuation of treatment, and patients who were 
non-compliant in Cycle 1 to the extent that precludes the assessment of study objectives 
according to the sponsor’s decision in consultation with the investigator, will be replaced to 
ensure the required number of evaluable patients per cohort. 
Phase II part
No patients will be replaced in the Phase II part.
6.5
Patient identification
At screening upon signing the ICF, each patient will be assigned a unique PID by IxRS for 
unambiguous identification. 
The patient number is a 9-digit number consisting of:
Digits 1 to 5
= Unique center number
Digits 6 to 9
= Current patient number within the center
Patients participating in the Phase I part of study have a ‘1’ as the 6th digit. As an example, 
PIDs in the Phase I part have the structure ‘aabbb1ccc’. Patients participating in the Phase II
part of study have a ‘2’ as the 6th digit, e.g.‘aabbb2ccc’.
Once allocated, the patient’s PID number will identify the patient throughout the study and 
will be entered into the Site Enrollment Log and will be populated in the eCRF.
7.
Treatments
7.1
Treatments to be administered
The following treatment will be administered in this study:

Copanlisib (BAY 80-6946) solution for IV infusion (test drug/investigational 
medicinal product)
Patients will receive copanlisib IV infusion as single agent on Days 1, 8 and 15 of each 
28-day treatment cycle.
Phase I part: The starting dose for the dose-escalation phase of this study will be 60% for 
patients < 1 year old and 80% for patients ≥1 year old of the dose (60 mg/weekly, 3 weeks 
on/1 week off) in the adult population recommended for copanlisib development. See 
Section 7.4.1 for further details. The dosing will be based on BSA.
Phase II part: The RP2D in mg/m2 will be based on findings in the Phase I portion of this 
study.


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7.2
Identity of study treatment
Copanlisib (test drug)
Copanlisib is supplied as lyophilized preparation in a 6-mL injection vial. The total amount of 
BAY 80-6946 per vial is 60 mg. The solution for IV infusion is obtained after reconstitution 
of the lyophilisate with 0.9% sodium chloride solution. 
Please refer to the Pharmacy Manual for detailed instructions for the reconstitution of the 
lyophilisate and for further dilution of the reconstituted solution.
Please refer to IB for copanlisib for more details regarding drug properties and formulation.
Study drug 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 the study drug, a system of numbering in accordance with all requirements of Good 
Manufacturing Practice (GMP) will be used, ensuring that each dose of study drug can be 
traced back to the respective bulk batch of the ingredients. Lists linking all numbering levels 
will be maintained by the sponsor’s clinical supplies Quality Assurance 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.
An approved representative at the site will ensure that all received study drug is stored in a 
secured area on site, under recommended storage conditions and in accordance with 
applicable regulatory requirements.
7.3
Treatment assignment
This is an open-label study. All eligible patients will receive the same treatment, copanlisib 
intravenously.
After the informed consent form has been signed, the investigator will register the patient and 
a unique patient identification number will be assigned via IxRS. 
Patients who satisfy all inclusion and exclusion criteria, will be assigned to the study drug
treatment. The treatment will be assigned based on information obtained from IxRS. 
The IxRS procedure is described in detail in a separate IxRS instruction manual that will be 
maintained in the trial master file (TMF), and in each center’s investigator’s trial file (ITF).
7.4
Dosage and administration
Study drug copanlisib is administered in a normal saline solution, intravenously, over 
approximately 1 h. See Pharmacy Manual for additional details. No intravenous glucose 
preparations should be administered on the days of infusion.
Planned dosing is weekly for the first 3 weeks of a 28-day cycle (on Days 1, 8, and 15), 
followed by a 1-week break (i.e., no infusion on Day 22). 


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Pre-dose blood pressure will be measured twice with at least a 15 min interval between the 
assessments prior to start of each infusion of study drug (any time on dosing day). See Section 
9.6.3.4.1 and Table 9–3 for measurement instructions and Section 7.4.3.3.4 for details on 
blood pressure management/dose modifications. Antihypertensive medication may be given 
to control the arterial hypertension.

For patients <18 years, 2 consecutive results of the pre-dose blood pressure ≤ 95th
percentile for age, height, and gender will be required start copanlisib infusion. See 
Table 16–5, Table 16–6, Table 16–7, and Figure 16–2.

For patients ≥ 18 years old, 2 consecutive results of the pre-dose blood pressure 
<150/90 mmHg will be required to start infusion (see Section 7.4.3.3.4 for further 
information).
After Cycle 1 Day 1, laboratory tests prior to each infusion may be performed either the day 
before or on the planned day of infusion, with the exception of blood glucose, which must be 
performed on the day of infusion. All laboratory results must be assessed by the investigator 
and/or appropriate site personnel prior to administration of planned dose. Study drug will be 
administered only if the following laboratory test criteria are met prior to each infusion:

ANC: ≥ 1.0 x 109/L

Platelet count: ≥ 75 x 109/L. For patients with confirmed cancer bone marrow 
infiltration, platelet count ≥ 50,000 /mm3. Platelet transfusion should not be given 
within 7 days before the administration of the study drug

Hemoglobin: ≥ 8.0 g/ dL (transfusion permitted) 

AST and ALT ≤ 3.0 x ULN 

Lipase and Amylase ≤ 5 x ULN

Glucose < 160 mg/dL (fasting) or < 200 mg/dL (non-fasting)
o
The investigator will accurately document the time of last meal intake and 
fasting/non-fasting status for each glucose measurement done at the site prior 
to drug infusion. 
o
Fasting refers to a ≥ 8 h fast. Non-fasting status includes any meal intake
within 8 hours prior to infusion.
o
From Cycle 1 Day 1 onwards, glucose measurements at the site may be done 
either by laboratory analysis or in capillary blood.
A delay due to adverse events of more than 7 days for the scheduled dose within a cycle will 
be considered a missed dose. Missed doses due to AEs will not be replaced and will be 
considered DLT during cycle 1. The minimum interval needed between two infusions of 
study drugs is 5 days. Patients that do not meet criteria to initiate a subsequent cycle within 28 
days from the last dose of study treatment will permanently discontinue protocol therapy.


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Recommendations on meal timing on infusion days 
Because of inhibitory effect on PI3K α-isoform, which is implicated in insulin metabolism, 
copanlisib infusions could be associated with temporarily increase in blood glucose. Addition 
of meal in close proximity to study drug infusion may exacerbate glucose increase. It is 
recommended that timing of meal intake on infusion days is managed and monitored by the 
investigators. Consultation with treating physician or pediatric endocrinologist is advised.
All glucose measurements pre-dose, during and post the study drug infusions, administration 
of insulin or other glucose lowering medications, if applicable, fasting/non-fasting status and 
timing of meal intake on infusion days will be collected as part of the clinical source 
documentation and reviewed by the investigator.
7.4.1
Dosage – Phase I part
Copanlisib treatment will be administered on Day 1, Day 8 and Day 15 of every 28-day cycle.
Patients who meet the eligibility criteria will receive copanlisib IV infusion with intermittent 
(3 weeks on / 1 week off) dosing schedule at the assigned dose level.
7.4.1.1
Selection of starting dose
The starting dose for the dose-escalation phase of this study will be 60% for patients < 1 year 
old and 80% for patients ≥1 year old of the dose (60 mg/weekly, 3 weeks on/1 week off) in 
the adult population recommended for copanlisib development.
The first cohort of patients in this trial will be treated with a dose of 21 mg/m2/week for 
patients < 1 year old and 28 mg/m2/week for patients ≥1 year old by taking in consideration 
the average adult BSA of 1.73 m2. It is estimated that 2 or 3 dose cohorts may be evaluated in 
this part of the study. Please refer to Table 7–1 and Table 7–2 for dose levels of copanlisib for 
patients < 1 year old and ≥1 year old, respectively.
Table 7–1 Copanlisib dose levels for patients < 1 year
Dose level
Copanlisib dose
% of adult dose
mg/m2
-2
40
14
-1
60 a
21
1
80
28
2
100
35
a: Starting dose for patients < 1 year 
After patients are tested at dose level 1, the population PK (popPK) analysis will determine 
whether the exposure has reached at least 75% of adult exposure.


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Table 7–2 Copanlisib dose levels for patients ≥1 year
Dose level
Copanlisib dose
% of adult dose
mg/m2
-1
60
21
1
80 a
28
2
100
35
3 b
120
42
a: Starting dose for patients ≥1 year old 
b: Dose level 3 will only be tested if the geometric mean of the copanlisib plasma exposure in the 
already tested cohorts is less than 75% of the adult plasma exposure of copanlisib of 60 mg. 
After patients are tested at dose level 2, the popPK analysis will determine whether the 
exposure has reached at least 75% of adult exposure.
7.4.1.2
Dose escalation schedule 
In the Phase I part, decision about dose escalation or reduction for subsequent cohorts will be 
determined based on DLT evaluation according to the Rolling-6 design, see Section 5.2. If in 
the Phase I part a certain cohort of pediatric patients reaches the copanlisib plasma exposure 
of adult patients treated with the recommended dose (60 mg/weekly, 3 weeks on/1 week off)
before the pediatric MTD is defined, no higher dose level will be tested.
For patients < 1 year old, if dose level -1 (starting dose) is not tolerable, copanlisib dose will 
be reduced to 40% of the dose in adult (60 mg/weekly, 3 weeks on/1 week off) (dose level -2). 
If dose level -1 is tolerable, copanlisib dose will be escalated to 80% of the dose in adult (dose 
level 1). If dose level 1 is tolerable, copanlisib dose can be escalated further to achieve 100% 
of total copanlisib adult dose (dose level 2) (please refer to Table 7–1).
For patients ≥ 1 year old, if dose level 1 (starting dose) is not tolerable, copanlisib dose will 
be reduced to 60% of the dose in adult (dose level -1). If dose level 1 is tolerable, copanlisib
dose will be escalated to achieve 100% of total copanlisib adult dose (dose level 2). If dose 
level 2 is tolerable, copanlisib dose can be escalated further to 120% of the dose in adult (dose 
level 3) (please refer to Table 7–2).
All safety and PK data will be reviewed at the completion of the first cycle of treatment at 
each dose level. The sponsor and investigators will review the data to determine if further 
dose escalation is warranted.
7.4.1.3
Definition of dose-limiting toxicities (DLTs)
DLT is defined as any of the following adverse reactions observed during first cycle of 
treatment, and assessed as possibly, probably or definitely related to treatment with copanlisib. 
The DLT observation period for the purposes of dose-escalation will be the first cycle of 
therapy.
NCI-CTCAE Version 4.03 will be used to assess toxicities/adverse events (AEs).


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DLTs will include:

Non-hematological AEs:
o
Grade ≥ 2 non-infectious pneumonitis
o
Grade ≥ 2 rash which despite maximal supportive care persists for more than 7 
days duration will be considered a DLT.
o
Grade 2 blood pressure elevation that does not return to ≤ 95th percentile for age, 
height, and gender and results in a missed dose as per Table 7–8.
o
Any ≥Grade 3 AE attributable to protocol therapy with the specific exclusion of:
-
Grade 3 fatigue lasting < 3 days
-
Grade 3 nausea and vomiting lasting < 3 days
-
Grade 3 or 4 fever < 5 days duration.
-
Grade 3 infection < 5 days duration.
-
Grade 3 rash (papulopustular, maculopapular, or acneiform or NOS) that 
returns to baseline or grade ≤ 1 within 7 days with or without supportive 
care.  NOTE: Any grade 3 rash that requires radiologic or operative 
intervention will be considered a DLT.
-
Grade 3 liver enzyme elevation, including ALT/AST/GGT that returns to 
levels that meet infusion criteria in Section 7.4 within 7 days.
-
Grade 3 electrolyte laboratory abnormalities including, but not limited to,
hypophosphatemia, hypokalemia, hypocalcemia, or hypomagnesemia 
responsive to supplementation
-
Grade 3 asymptomatic elevated lipase or amylase that returns to grade < 2 
within 7 days
-
Grade 3 or 4 elevated alkaline phosphatase will not be considered a DLT
-
Hyperglycemia: hyperglycemia will not be considered as a DLT except in 
the following conditions: 
- Hyperglycemia of any grade that results in delay of start of Cycle 2 
by >7 days, missed dose during Cycle 1, or reduction of dose in Cycle 
1 as per Table 7–7 will be considered a DLT
- Grade 4 hyperglycemia (>500 mg/dL) with life-threatening 
consequences will be considered a DLT
Note: Allergic reactions leading to discontinuation of study drug will not be considered
as DLT.

Hematological AEs:
o
Grade 4 neutropenia lasting ≥3 days
o
Grade 3 thrombocytopenia with bleeding


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o
Grade 4 thrombocytopenia lasting ≥3 days 
o
Grade 4 anemia (in the absence of marrow disease progression)
o
Grade ≥3 INR increase or PTT increase with bleeding
Notes: 

See Section 7.4.3.2 for management of hematologic toxicity.

Hematological AEs listed above will not be considered as DLT in patients with 
proven bone marrow involvement at baseline. 

Grade 3 or 4 febrile neutropenia will not be considered as DLT (unless neutropenia 
criteria above are fulfilled). 

Lymphopenia will not be considered a DLT.
Generally, any AE during cycle 1 that is attributed to copanlisib and results in a missed dose 
or results in delayed start of cycle 2 by >7 days will be considered a DLT.
7.4.2
Dosage – Phase II
The protocol will be amended after completion of the Phase I part to update information on 
the recommended dose of copanlisib for the Phase II part (RP2D).
7.4.3
Dose modifications
Copanlisib dose modifications must be done according to the guidelines given in 
Section 7.4.3.2 and Section 7.4.3.3. If the dose is reduced or interrupted, the investigator’s 
decision is to be clearly documented in the patient’s records and in the eCRF. If a patient 
experiences several toxicities and there are conflicting recommendations, the recommended 
dose adjustment which reduces the dose to the lowest level should be used.
Please refer to Table 7–1 and Table 7–2 for the dose levels of copanlisib for patients < 1 year 
old and ≥1 year old, respectively.
7.4.3.1
Dose-limiting hematological and non-hematological toxicity 
Section was removed by amendment 1.


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7.4.3.2
Hematological toxicity
The guidelines for dose modifications in case of hematological toxicity which occurred during
study treatment are given in Table 7–3.
Table 7–3 Dose modification of study treatment for hematological toxicity
Hematological toxicity of CTCAE Grade
(any of the following) which occurred during 
study treatment
Study drug action 
Grade 4 thrombocytopenia lasting ≥ 3 days 
(platelet < 25,000/mm3) or Grade 3 
(platelet < 50,000/mm3) with bleeding
Delay infusion until return to laboratory 
criteria displayed in dosing criteria (see 
Section 7.4) c. Patient should be treated at 
one dose level lower b. If more dose 
reductions are required than allowed per 
protocol or infusion delayed more than 28 
days from last dose, discontinue study 
treatment permanently. For the lowest dose 
level for patients ≥1 year old (dose level -1)
and for patients < 1 year old (dose level -2), 
please see Table 7–2 and Table 7–1, 
respectively.

Grade 4 neutropenia (ANC < 500/mm3) a lasting 
≥3 days

Grade ≥3 INR or PTT with bleeding

Grade 4 anemia
ANC = Absolute neutrophil count; CBC = Complete blood count; CTCAE = Common Terminology Criteria of 
Adverse Events; Hb = Hemoglobin; INR = International normalized ratio, PTT = Partial thromboplastin 
time.
a: For patients who develop CTCAE Grade 4 neutropenia or febrile neutropenia, repeat of ANC every 3 days is 
recommended until patient meets dosing criteria in Section 7.4.
Note: G-CSF may be administered as outlined in Section 8.1 Permitted Concomitant Therapy
b: After having recovered from toxicity to CTCAE Grade ≤1 and in the absence of any criteria for further dose 
reduction or study drug discontinuation for at least one full cycle, a dose re-escalation at the following 
cycle will be allowed.
c: Treatment with pRBC or platelet transfusion is allowed, however dosing criteria for platelets  in Section 7.4
must be transfusion independent (criteria met at least 7 days after most recent transfusion).


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7.4.3.3
Non-hematological toxicity 
Dose modifications for non-hematological toxicities except glucose increases, dermatologic 
toxicity, NIP and arterial hypertension are outlined in Table 7–4.
Table 7–4 Dose modification of study treatment for non-hematological toxicity (except 
glucose increases, dermatologic toxicity, non-infectious pneumonitis and arterial 
hypertension)
Study drug action
Toxicity (CTCAE)
Occurrence
For current course 
of therapy
For next course 
of therapy
Grade 1-2
Any appearance
No change
No change
Grade 3 a
1st appearance
Interruption until Grade 1
Decrease by one dose level b
2nd appearance
Interruption until Grade 1
Decrease by one dose level b
3rd appearance
Permanent discontinuation
–
Grade 3 
severe allergic 
reactions c
1st appearance
Permanent discontinuation
–
Grade 4
Any appearance
Permanent discontinuation
–
CTCAE = Common Terminology Criteria of Adverse Events.
a: Despite maximum supportive therapy. Laboratory-based toxicities including but not limited to elevated lipase, 
amylase, ALT/AST/GGT that are not considered clinically significant do not require dose reduction by one 
level. Grade 3 toxicities that are excluded as a DLT in Section 7.4.1.3 do not require a dose reduction.
b: Not applicable for the lowest dose level, see Table 7–1and Table 7–2.
c: Including infusion reactions.
A delay > 28 days from the last dose of study treatment due to toxicities requires permanent discontinuation of 
study treatment.
Study treatment must be discontinued if the lowest dose level of is not tolerated (for patients ≥1 year old 
[lowest dose level -1] and for patients < 1 year old [lowest dose level -2], please see Table 7–2 and Table 
7–1, respectively).
After having fully recovered from toxicity and in the absence of any criteria for further dose reduction or study 
drug discontinuation, a dose re-escalation will be allowed at the investigator’s discretion.
Management and treatment of non-hematological toxicity will be performed by the 
investigator per local standard of care (SOC).


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7.4.3.3.1
Dermatologic toxicity
The guidelines for dose modifications in case of dermatologic toxicity are given in Table 7–5.
Table 7–5 Dose modification of study treatment for dermatologic toxicity
Study drug action
Toxicity
(CTCAE)
Occurrence
For current course of therapy
For next course of therapy
Grade 1
Any appearance
No change
No change
Grade 2 a
1st appearance
Interruption until Grade ≤1
No change
2nd appearance
Interruption until Grade ≤1
No change 
3rd appearance
Interruption until Grade ≤1
Decrease by one dose level b
4th appearance
Permanent discontinuation 
–
Grade 3 a
1st appearance
Interruption until Grade ≤1
Decrease by one dose level b
2nd appearance
Permanent discontinuation
–
Grade 4
1st appearance
Permanent discontinuation
–
CTCAE = Common Terminology Criteria of Adverse Events. Toxicities according to CTCAE version 4.03.
a: Despite maximum supportive therapy.
b: Not applicable for lowest dose level (for patients ≥1 year old [lowest dose level -1] and for patients < 1 year 
old [lowest dose level -2], please see Table 7–2 and Table 7–1, respectively).
    If a patient is already on the lowest dose level and meets criteria for further dose decrease, study treatment 
will be discontinued permanently.
In case of dose reductions due to dermatologic toxicity, no re-escalation is allowed after the dose reduction.
7.4.3.3.2
Non-infectious pneumonitis 
In the event of NIP, an adjustment as described in Table 7–6 must be applied.
Table 7–6 Dose modification of study treatment for non-infectious pneumonitis (NIP)
Study drug action
Suspected or confirmed 
NIP of CTCAE
For current course of therapy
For next course of therapy
Grade 1
No change
Not applicable
Grade 2
Interruption until recovery to ≤Grade 1
Decrease by one dose level a
Grade 2 re-occurrence
Permanent discontinuation
No
Grade ≥3
Permanent discontinuation
No
NIP = Non-infectious pneumonitis; CTCAE = Common Terminology Criteria for Adverse Events.
a: Not applicable for lowest dose level (for patients ≥1 year old [lowest dose level -1] and for patients < 1 year 
old [lowest dose level -2], please see Table 7–2 and Table 7–1, respectively). No re-escalation is allowed 
after the dose reduction. If a patient is already on the lowest dose level and meets criteria for further dose 
decrease, study treatment will be discontinued permanently.
Pneumonitis is to be reported as such only in the event of NIP. 
The investigator is requested to differentiate between NIP and infectious pneumonitis (viral, 
bacterial, fungal), aspiration pneumonitis, or other pneumonitis clearly not due to a potential 
hypersensitivity reaction to the copanlisib infusion; and provide the basis for his/her 
assessment that it is infectious or other, as appropriate. The investigator is requested to report 
with the most specific clinical terms to describe the condition, not simple “pneumonitis”.


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7.4.3.3.3
Glucose increases
Mild to moderate asymptomatic increases of blood glucose may occur with copanlisib 
infusion, and with larger increases potentially occurring post-prandially. 
Hyperglycemia of any grade that results in delay of cycle 2 by more than 7 days, missed dose 
during cycle 1, or reduction of dose in cycle 1 as per Table 7–7 will be considered a DLT.
For the guidelines for the management of transient post-infusion glucose increases and dose 
modification of copanlisib, refer to the following Table 7–7.


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Table 7–7 Dose Modification of Study Treatment and Management of Glucose Increase
Criteria
Glucose increase management
Copanlisib dose 
modification
Blood Glucose ≤160 
mg/dL (fasting) or ≤200 
mg/dL (non-fasting)
Monitor glucose per Table 9–1 (Study Flow 
Chart) and Table 9–4 (Monitoring on infusion 
days)
Continue copanlisib at 
current dose level
Blood Glucose > 160 
mg/dL (fasting) 
or > 200 mg/dL (non-
fasting) up to 499 mg/dL 
(fasting or non-fasting)
-Hydration if appropriate
-Repeat laboratory glucose determination 
approximately every 1 hour until glucose 
level decreases on at least 2 consecutive 
measurements, then monitor glucose as 
clinically indicated and at least as outlined in 
Table 9–1 (Study Flow Chart) and Table 9–4
(Monitoring on infusion days)
-If the repeated glucose value is decreasing, 
the glucose may be followed without glucose 
lowering treatment if hydration status is 
normal as clinically assessed
-Consultation with pediatric endocrinologist is 
recommended, initiate glucose lowering 
agent as indicated per local standard of care 
as indicated.
-The patient may continue to receive 
concomitant insulin or an oral glucose 
lowering agent for the management of 
hyperglycemia while receiving copanlisib.
Hold copanlisib until 
fasting glucose is 160 
mg/dL or less, or a 
random/non-fasting blood 
glucose of 200 mg/dL or 
less.  Subsequent dosing 
can maintain at current 
dose level.
Blood Glucose ≥500 
mg/dL (fasting or non-
fasting)
-Hydration 
-Repeat laboratory glucose determination 
approximately every 1 hour until glucose 
level decreases on at least 2 consecutive 
measurements, then monitor glucose as 
clinically indicated and at least as outlined in 
Table 9–1 (Study Flow Chart) and Table 9–4
(Monitoring on infusion days)
-Consultation with pediatric endocrinologist is 
recommended, initiate glucose lowering 
agent (e.g. insulin or oral agent) as indicated 
per local standard of care.
- The patient may continue to receive 
concomitant insulin or an oral glucose 
lowering agent for the management of 
hyperglycemia when copanlisib is restarted
On first occurrence: 
Hold copanlisib until 
fasting blood glucose 
≤160 mg/dL or 
random/non-fasting blood 
glucose of ≤200 mg/dL. 
Then reduce copanlisib by 
one dose level.
On subsequent 
occurrences: Hold 
copanlisib until fasting 
blood glucose is ≤160 
mg/dL or random/non-
fasting blood glucose of 
≤200 mg/dL. Then reduce 
copanlisib by an additional 
dose level.  If patient is at 
the lowest dose level, 
permanently discontinue
copanlisib. 
- Permanently discontinue
copanlisib in case of 
symptoms or life 
threatening 
consequences.


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7.4.3.3.4
Arterial hypertension
Pre-dose blood pressure will be measured twice with at least a 15 min interval between the 
assessments prior to start of infusion of study drug (any time on dosing day). 

For patients < 18 years, 2 consecutive results of the pre-dose blood pressure ≤ 95th
percentile for age, height, and gender will be required to start copanlisib infusion.

For patients ≥18 years old, 2 consecutive results of the pre-dose blood pressure 
< 150/90 mmHg will be required to start infusion. 
The guidelines for dose modifications for hypertension are provided in Table 7–8.
The recommendations for the treatment of blood pressure increases are given in 
Section 7.4.4.2.
Patients with a blood pressure of CTCAE Grade 4 must permanently discontinue the study 
drug (see Section 6.4.1).


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Table 7–8 Dose modifications for hypertension
Toxicity (hypertension) CTCAE 
modified for age, height, and 
gender c, d
Study drug action
Recommendation
Grade 1 SBP or DBP 90th percentile to 
≤ 95th percentile for age, height, and 
gender

Continue copanlisib

Consider increased BP 
monitoring
Grade 2 SBP and/or DBP ˃ 95th 
percentile for age, height, and gender
to the ≤99th percentile for age, height, 
and gender plus 5 mmHg

Infusion should be 
interrupted and may be 
resumed when BP has 
returned to ≤ 95th 
percentile for age, height, 
and gender or skipped 
otherwise

Continue subsequent study 
drug administrations at the 
same dose level and 
infusion rate

Intensify BP monitoring a until 
BP returns to ≤ 95th percentile
During infusion: Grade 3 SBP and/or 
DBP > 99th percentile for age, height, 
and gender plus 5 mmHg

Infusion should be 
interrupted and may be 
resumed when BP has 
returned to ≤ 95th 
percentile for age, height, 
and gender or skipped 
otherwise

Subsequent study drug 
administrations should be 
reduced by 1 dose level 
and continued at the same 
infusion rate b

Intensify BP monitoring a until 
BP returns to ≤ 95th percentile
Post-dose: Drug-related Grade 3 
SBP and/or DBP > 99th percentile for 
age, height, and gender plus 5 mmHg

Subsequent study drug 
administrations should be 
reduced by 1 dose level 
and continued at the same 
infusion rate b

Treat with the aim to achieve 
BP ≤ 95th percentile:
o
Start antihypertensive 
medication
AND / OR
o
Increase current 
antihypertensive medication
AND / OR
o
Add additional 
antihypertensive
medications
CTCAE hypertension of grade 4 
Life-threatening consequences (e.g., 
malignant hypertension, transient or 
permanent neurologic deficit, 
hypertensive crisis)

Permanent discontinuation
-


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Table 7–8 Dose modifications for hypertension
CTCAE = Common Terminology Criteria for Adverse Events; BP = Blood pressure; DBP = Diastolic blood 
pressure; HR = Heart rate; RR = Respiration rate; SBP = Systolic blood pressure.
a: BP, HR and RR assessments every 15 min (± 5 min).
b: If a patient is already on the lowest dose level (for patients ≥1 year old [lowest dose level -1] and for patients
< 1 year old [lowest dose level -2], please see Table 7–2 and Table 7–1, respectively) and experiences 
post-dose hypertension of CTCAE Grade 3 or SBP and/or DBP > 99th percentile for age, height, and 
gender plus 5 mmHg, consider more intensive therapy than previously used.
c: CTCAE modified will be utilized to determine the grade of hypertension in patients < 18 years old. The upper 
limit of normal (ULN) is defined as a BP equal to the 95th percentile for age, height, and gender.
d: CTCAE v.4.03 will be utilized to determine the grade of hypertension in patients ≥18 years old. For study 
drug action and recommendations, use SBP/DBP of > 150/90 for > 95th percentile for age, height, gender 
and use SBP/DBP of > 160/100 for > 99th percentile for age, height, gender in patients ≥18 years old.
In case of dose reductions due to arterial hypertension, no re-escalation is allowed after the dose reduction.
The selection of anti-hypertensive medication used in this setting should be performed at the 
investigator's discretion, considering possible site-specific treatment guidelines. All 
medication should be recorded in the patient’s eCRF and the patient’s medical record.
7.4.4
Treatment of toxicities
7.4.4.1
Management of transient post-infusion glucose increases that can occur 
with study treatment
Management of transient post-infusion glucose increases that can occur with study 
treatment
Mild to moderate asymptomatic increases of blood glucose may occur with copanlisib 
infusion, and with larger increases potentially occurring post-prandially. 
The guidelines for the management of transient post-infusion glucose increases are given in 
Table 7–7.
The need for further glucose monitoring at home should be determined by the investigator 
based on post-infusion glucose profile and clinical status of the patient.
7.4.4.2
Treatment of blood pressure increases associated with study treatment
It is important that patients with pre-existing arterial hypertension adhere to their regular 
medication schedule and take their usual doses on the days of study drug infusion. The 
management of acute arterial hypertension following study treatment will need to be 
individualized for each adult/pediatric patient per local SOC. 
The guidelines for dose modifications for hypertension are provided in Section 7.4.3.3.4.


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7.4.4.3
Guidance for monitoring and prophylaxis of opportunistic 
infection (OI) 
7.4.4.3.1
Monitoring guidelines for Opportunistic Infections
In addition to the weekly clinical review and laboratory tests outlined in the schedule of 
assessment, the following should be performed in all patients prior to IV infusion of 
copanlisib:

Evaluation of any new onset or worsening of pulmonary symptoms (i.e. cough, 
dyspnea or fever) that includes a lung examination at each visit prior to infusion.
Enhanced monitoring when prior medical history or laboratory parameters could be associated 
with one of the following risk factors:

History of CMV, herpes.

History of lower respiratory tract infection, history of immunodeficiency in the last 
12 months.

Lymphocytes count < 500/mm3 while on treatment in clinical study.
For patients with identified risk factors and those who presented with new onset or worsening 
of pulmonary symptoms or developed OI on study treatment, any additional laboratory and
diagnostic methods will be strongly recommended and performed per local SOC and reported 
as unscheduled laboratory and diagnostic methods of assessment in the eCRF.
Note: Treatment of opportunistic infections should be based on local SOC.
7.4.4.3.2
Prophylaxis of Opportunistic Infections
OI prophylaxis may be initiated at the discretion of the treating investigator’s judgment of the 
benefit/risk ratio in any patient, irrespective of whether a high-risk feature is present, per local 
SOC. If so, drug name, indication, dosage and route of administration must be reported on the 
concomitant medication page of the eCRF. 
Prophylactic treatment of OI should be based on local SOC.
7.5
Blinding
Not applicable; this is an open-label study.


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7.6
Drug logistics and accountability
The study drug will be stored at the investigational site in accordance with GCP and GMP 
requirements and the instructions given by the clinical supplies department of the sponsor (or 
its affiliate) and will be inaccessible to unauthorized personnel. Special storage conditions and 
a complete record of batch numbers and expiry dates can be found in the sponsor’s study file; 
the site-relevant elements of this information will be available in the investigator site file. On 
the day of receipt, the responsible site personnel will confirm receipt of study drug via IxRS. 
The personnel will use the study drug only within the framework of this clinical study and in 
accordance with this protocol. Receipt, distribution, return, administration and destruction (if 
any) of the study drug must be properly documented according to the sponsor’s agreed and 
specified procedures.
Vial number and other relevant information per treatment will be recorded on the eCRF and 
the appropriate drug dispensing form. Reason(s) for dose delay and reduction will also be 
recorded in the eCRF.
Drug accountability on patient level must be done every cycle, starting on Day 1 of Cycle 1. 
Written instructions on medication destruction will be made available to affected parties as 
applicable.
If performing drug accountability implies a potential risk of contamination, a safety process/ 
guidance for handling returned drug will be provided.
7.7
Treatment compliance
The administration of intravenous copanlisib will be performed in the clinic on a weekly basis
on Days 1, 8, and 15 of each 28-day cycle, and must be recorded in the eCRF.
8.
Non-study therapy
8.1
Prior and concomitant therapy
All medications taken by the patients in addition to the study medication are defined as 
concomitant medication. Medication other than the study drug must not be taken during the 
study without consulting the investigator. All therapies that are considered necessary for the 
patient’s welfare and that are not expected to interfere with the evaluation of the study drug
may be given at the discretion of the investigator. Where the use of drugs is medically 
indicated (e.g. in case of emergency), the pediatric patient/parent/legal guardian must inform 
the investigator within a reasonable time period after intake of concomitant medication.
All concomitant medications (including start / stop dates, dose and dose frequency, route of 
administration, and indication) must be recorded in the patient’s source documentation as well 
as in the appropriate pages of the eCRF. 
Administration of contrast media for protocol-specified radiological procedures does not need 
to be reported, unless there is an AE related to the contrast medium administration (e.g. 
allergic reaction).
For prohibited prior therapy please refer to Section 6.2.


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Prohibited concomitant therapy

Strong CYP3A4 inhibitors and inducers (see Appendix 16.12). Copanlisib is primarily 
metabolized by CYP3A4. Therefore, concomitant use of strong inhibitors of CYP3A4 
(e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir and 
saquinavir), and inducers of CYP3A4 (e.g., rifampicin, phenytoin, carbamazepine, 
phenobarbital, St. John Wort) are not permitted within two weeks prior to start of 
study treatment until the SFU visit.

Grapefruit and grapefruit juice, Seville oranges, and star fruit (CYP3A4 inhibitor) 
consumption is not permitted during the study.

Concomitant therapy with any other anticancer agent than copanlisib, 
immunosuppressive agents, other investigational therapies until the SFU visit. 

Anti-arrhythmic therapy other than beta blockers or digoxin until the SFU visit.

Prophylactic myeloid growth factor in the first cycle of therapy in Phase I part of the 
study.

Since high levels of biotin (vitamin B7) can interfere with the results of the immune 
assay tests including biomarker analysis, HBc-Ab, HBe-Ag, HBs-Ag, HCV-Ab, HIV-
Ag/Ab combo, and HIV combo, patients should refrain from taking biotin 
supplements for at least 72 hours prior to immunoassay test collection.
Permitted concomitant therapy

Standard therapies for concurrent medical conditions.

Treatment with non-conventional therapies (for example herbs or acupuncture), and 
vitamin/mineral supplements is acceptable provided that they do not interfere with the 
study endpoints, in the opinion of the Investigator.

Bisphosphonates per investigator’s discretion.

Prophylactic anticoagulation of venous or arterial access devices is allowed provided 
that the requirements for INR and PTT or aPTT are met. Close monitoring is 
recommended according to standard of care. If either of these values is above the 
therapeutic range, the doses should be modified and the assessments should be 
repeated weekly until it is stable. Low-dose aspirin and low-dose heparin are permitted.

Therapeutic anti-coagulation with monitoring of coagulation parameters according to 
standard of care will be permitted based on medical judgement of the local 
investigator and on the benefit-risk assessment. Localized anti-coagulation for central 
line (e.g. tissue plasminogen activator [TPA], urokinase, heparin etc.) is permitted.

Antiemetics: prophylactic anti-emetics may be administered according to standard 
practice. The routine use of standard antiemetics, including 5-HT3 blockers, such as 
granisetron, ondansetron, or an equivalent agent, is allowed as needed. The use of 
corticosteroids as antiemetics prior to study drug administration will be not allowed. 


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
Palliative and supportive care for the other disease-related symptoms and for toxicity 
associated with treatment will be offered to all patients in this trial.

Palliative irradiation shall be permitted provided that:
o In the opinion of the investigator, the patient does not have PD.
o The radiation field does not encompass a target lesion
o The radiation field does not encompass a lung field (to reduce the risk for 
pneumonitis).

Patients taking narrow therapeutic index medications should be monitored proactively, 
if these medications cannot be avoided. 

Substrates of the renal drug transporter MATE2K (e.g. cimetidine, procainamide and 
N-methylnicotinamide) need to be used with caution.

G-CSF may be administered if ANC< 500/mm3 for 3 days or if experienced febrile 
neutropenia or grade 4 CTCAE v.4.03 neutropenia in previous cycle and should be 
administered as per label and local SOC. Long acting G-CSF should not be 
administered.

The maximum allowed dose of corticosteroids will be 0.5 mg/kg or 10 mg/day of 
prednisone whichever is less. Note: Topical or inhaled corticosteroids are permitted.
8.2
Post-study therapy
During the active follow-up, after the end of study treatment period is completed, patients will 
not be restricted with regard to pursuing available treatments for their disease. All patients
enrolled should be followed for overall survival for at least two years after end of treatment.
9.
Procedures and variables
9.1
Tabular schedule of evaluations


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Table 9–1 Study flow chart
Screening a
maximum days 
before C1D1
Treatment
Active FU
Long 
Term
FU x
EOT
Safety
FU v
Other 
active FU
visits
Cycle 1
Cycle 2 and higher
Within (days) after
decision 
to stop
last 
dose
Days
-28
-7
D1
D8
D15
D1
D8
D15
7
30 
every
3 months
every 
3 
months
Acceptable time window (unless otherwise 
specified) (in days)
-1 to + 2 days
-1 to + 2 days
-7
days
+ 5
days 
14
days
14
days
Screening and enrollment
Patient informed consent (including consent 
for both genetic and non-genetic test using 
plasma and tumor tissues) b
Written informed consent must be obtained prior to any study-specific procedures.
Check in- and exclusion criteria
X
X
X
Medical and surgical history 
X
Disease confirmation
X
Demographics
X
Height (length for infants), weight, body 
surface area calculation c
X
X
X
X
X
X
X c
IxRS transaction 
X
X
X
X
X
X
X
X
Serum pregnancy test for females of 
childbearing potential d
X
X
X 
HBsAg, HBcAb, anti-HCV f
X
CMV PCR
X
ECHO or MUGA g
X
X
Safety
Toxicity / AE assessment h
X
X
X
X
X
X
X
X
X
X
Concomitant medication 
X
X
X
X
X
X
X
X
X
X
Physical examination and vital signs 
(including performance status) i
X
X
X
X
X
X
X
X
X


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Table 9–1 Study flow chart
Screening a
maximum days 
before C1D1
Treatment
Active FU
Long 
Term
FU x
EOT
Safety
FU v
Other 
active FU
visits
Cycle 1
Cycle 2 and higher
Within (days) after
decision 
to stop
last 
dose
Days
-28
-7
D1
D8
D15
D1
D8
D15
7
30 
every
3 months
every 
3 
months
Acceptable time window (unless otherwise 
specified) (in days)
-1 to + 2 days
-1 to + 2 days
-7
days
+ 5
days 
14
days
14
days
Heart rate and respiration rate i
X
X
X
X
X
X
12 or 15 -lead ECG j
X
X
X
X
Complete blood count with differential and 
platelet count k
X
X k
X
X
X
X
X
X
X
Chemistry panel l
X
Xl
X
X
X
X (C2)
X(C2)
X
X
Coagulation panel m
X
X
X
Urinalysis (dipstick or local lab)
X
X
X
Glucose 
X n
X o
X o
X o
X o
X o
Blood pressure
X
Xp
Xp
Xp
Xp
Xp
Xp
X
Creatinine clearance or serum creatinine q
X
X
X
Biomarkers
Tumor archival tissue (when available) r
X
Fresh paired tumor biopsy (when feasible) r
X
X
X
Blood (platelet rich plasma) sampling for 
pAKT (2.5mL) for patients > 1 year old s
X
X
X 
Blood sample for plasma biomarker analysis
(3mL) for patients > 1 year old s
X
X
X 
X


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Table 9–1 Study flow chart
Screening a
maximum days 
before C1D1
Treatment
Active FU
Long 
Term
FU x
EOT
Safety
FU v
Other 
active FU
visits
Cycle 1
Cycle 2 and higher
Within (days) after
decision 
to stop
last 
dose
Days
-28
-7
D1
D8
D15
D1
D8
D15
7
30 
every
3 months
every 
3 
months
Acceptable time window (unless otherwise 
specified) (in days)
-1 to + 2 days
-1 to + 2 days
-7
days
+ 5
days 
14
days
14
days
Efficacy
Tumor evaluation (CT or MRI scan or 
PET-CT, or MIBG scan) t
X
Every 8 weeks (± 7 days) until radiological tumor 
progression
X t
X t
Bilateral bone marrow biopsy and/or bone 
marrow aspiration (patients with lymphomas 
or neuroblastoma) e
X
Will be done at the discretion of the local investigator 
and to confirm first CR for patients with bone marrow 
involvement at baseline.
Study treatment administration
Copanlisib infusion
X
X
X
X
X
X
Pharmacokinetic sample u
X
X
Long-term follow-up
Survival status (for at least 2 years after last 
patient’s last treatment)
X
Document other anticancer therapies
X
AE = Adverse event; ANC = Absolute neutrophil count; aPTT = Activated partial thromboplastin time; BM = Biomarker; C = Cycle; CBC = Complete blood count; 
CMV = Cytomegalovirus; CR = Complete response; CT = Computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; D = Day; ECG = 
Electrocardiogram; ECHO = Echocardiogram; EOT = End of Treatment; FU = Follow-up; HBcAb = Hepatitis B core antibody; HBsAg = Hepatitis B surface 
antigen; HCV = Hepatitis C Virus; INR = International normalized ratio; IxRS = Interactive Voice Response System /Interactive Web Response System; LDL = 
Low-density lipoprotein; MIBG = Iodine-123 metaiodobenzylguanidine; MRI = Magnetic resonance imaging; MUGA = Multiple gated acquisition; NCI = National 
Cancer Institute; PCR = Polymerase chain reaction; pAKT = Phosphorylated AKT (protein kinase B [PKB]); PD = Progressive disease; PET-CT = Positron 
emission tomography-computed tomography; PK = Pharmacokinetics; PTT = Partial thromboplastin time; SFU = Safety follow-up visit; SOC = Standard of care.
a Screening procedures may be completed during multiple visits but must be completed within specified timeframes before the first dose of study drug.
b Informed consent/assent form must be signed before any study-related procedures are performed (including screening procedures). The Informed 


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consent/assent form includes consent for plasma sample and archival and fresh biopsy tumor tissue collection for the analysis of non-genetic and genetic 
biomarkers, these samples should be collected where feasible/available.
c Height (length for infants) and weight will be measured at Cycle 1 Day1 and every dosing visit thereafter. At EOT, only weight will be checked as part of 
safety assessment. See Section 9.6.3.2.
d Female patients of childbearing potential must have a negative pregnancy test result 7 days prior to start of study treatment. After Cycle 1 serum pregnancy 
test is mandatory at every cycle and at the EOT visit for countries where it is required by local regulations. More frequent evaluation for pregnancy may be 
required in certain countries; all local regulations regarding pregnancy testing in clinical study patients must be followed.
e Bilateral bone marrow biopsy and/or bone marrow aspiration will be performed within 28 days before first study drug infusion in patients with lymphomas or 
neuroblastoma and in any tumor with marrow disease involvement at baseline or if suspicion for involvement at study entry. During the study period, bilateral 
bone marrow biopsy and/or bone marrow aspiration will be done at the discretion of the local investigator and to confirm first CR for patients with bone 
marrow involvement at baseline. Bone marrow biopsy/aspiration will be performed as per local standard of care.
f For patients of ≤1 year old, HBsAg, HBcAb, anti-HCV measurements to be done prior to -7 day visit. For other ages, measurements can be done any time 
within 28 days prior to the first study drug administration.
g ECHO or MUGA: to be done at screening, end of treatment and as clinically indicated.
h AE assessment is to be started from signing of informed consent until 30 days after the last dose of study drug. In addition, during the Active follow-up period, 
AEs considered to be related to study drug or study-related procedures will be reported. Any new findings or worsening of any ongoing medical history 
conditions after the patient has signed the informed consent are to be listed as adverse events (See Section 9.6.1.3).
i Physical examination including vital signs (heart rate, pulse oximetry, respiration rate and temperature), blood pressure measurement and performance 
status(Lansky / Karnofsky performance) (See Section 9.6.3.1). On infusion days, heart rate and respiration rate will be assessed at pre-dose and every 
15 min (± 5 min) during the study drug infusion. In addition, at each visit prior to infusion, evaluation of any new onset or worsening of pulmonary symptoms 
(i.e. cough, dyspnea or fever) that includes a lung examination (see Section 7.4.4.3 for further information). Dentition examination per local SOC should be 
performed as part of the physical exam at screening.
j 12-lead (or 15-lead) ECG will be performed at Screening, on Cycle 1 Day 1 prior to infusion and at the end of infusion. In subsequent cycles: D1 of every cycle 
at the end of infusion and at the EOT visit.
k Complete blood count (CBC) with differential and platelet count: see Section 9.6.3.8. In case of cytopenias NCI-CTCAE Grade ≥ 3 (e.g. platelet 
< 50,000/mm3, hemoglobin < 8 g/dl, ANC< 1000/mm3), CBC may be performed more frequently as per investigator discretion and per local SOC. If done 
within 7 days, it may not be repeated.
l Chemistry panel: See Section 9.6.3.8. Total cholesterol, LDL and triglycerides will be tested only at screening, on Day 1 of every 2nd cycle starting from Cycle 
2, and at the EOT visit. If done within 7 days it may not be repeated.
m Coagulation panel: aPTT or PTT and INR.
n On C1D1 glucose will be measured at pre-dose <1 h prior to start of study drug infusion and post-dose after the end of study drug infusion according to 
instructions in Table 9–4. Additional measurements to be performed at the clinic as clinically indicated.
o Glucose test <1 h prior to study drug infusion and post-dose after the end of study drug infusion according to instructions in Table 9–4. Additional 
measurements to be performed at the clinic as clinically indicated.
p Pre-dose blood pressure will be measured twice with at least a 15 min interval between the assessments prior to start of infusion of study drug (any time on 
dosing day) See Section 7.4 for the required pre-dose blood pressure values before infusion can be started. After start of infusion, a single blood pressure 
measurement is conducted at 4 time points according to instructions given in Table 9–3 (mid-dose and post-dose blood pressure measurements). See also 


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guidance in Table 7–8. The patient should rest for at least 10 min before blood pressure is recorded. For blood pressure levels for children by age, height and 
gender percentile, see Appendix 16.6. For recommended dimensions for blood pressure cuff bladders, see Appendix 16.7.
q Creatinine clearance based on Schwartz Estimate ≥ 70 ml/min/1.73 m2 or a serum creatinine based on age/gender (see Appendix 16.10).
r Collection of fresh biopsy is optional and encouraged to be performed when it is feasible. Samples can be collected at baseline (screening), on C1D15 or 
C1D16 within 24 hours after start of infusion or EOT. Available archival tumor samples must be submitted with date of material collection to investigate or 
identify biomarkers that may be predictive of copanlisib effects/efficacy and to contribute to better understanding the disease.
s BM plasma and platelet rich plasma samples. At screening: for patients > 1 year and < 6 years old BM samples should be collected any time within screening 
but prior to -7 day visit. For patients ≥6 years old BM samples should be taken within 7 days prior to the first study drug administration.
At C1D15: for patients > 1 year and < 6 years old, BM plasma samples will be collected at C1D15 only at 3 hours (± 30 min) after start of infusion. For 
patients ≥6 years old, BM samples will be collected before infusion (up to 30 min prior to start of infusion) and 3 hours (± 30 min) after start of infusion. 
Patients ≤1 year old will be excluded from blood sample collection. 
t Tumor evaluation will be performed at screening (within 28 days prior to start of treatment), during treatment period: every 8 weeks (± 7 days) until radiological 
tumor progression, at EOT visit, and during active FU period every 12 weeks (± 14 days) until radiological tumor progression or start of new anti-cancer 
therapy, whichever occurs first. Please note: Tumor assessment is not required at the EOT visit if the patient discontinues due to PD which has been 
radiologically confirmed within the 4 weeks preceding EOT.
u PK sampling will be performed in all patients for copanlisib. The samples will be obtained during Cycle 1 on Days 1 and 15 according to Table 9–2. 
PK sampling for copanlisib: Pre-dose PK: pre-infusion (< 30 min prior to start of infusion).Post-dose PK: 1-1.25 hour, 1.5-3 hour (patients ≥6 years only) and 
22-24 hours after start of the infusion. If sampling is not feasible at Cycle 1, samples may be collected at Cycle 2 (see Section 9.5).
v Patients discontinuing the study treatment for any reason will enter active follow-up. The mandatory safety follow-up (SFU) visit will take place 30+5 days 
after the last administration of study drug.
x After active follow-up period patients will continue to be followed for overall survival for at least 2 years after the LPLT until death or unless consent is 
withdrawn.


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9.2
Visit description
9.2.1
Timing of assessments
If not stated otherwise, the measurements listed in the following sections will be performed 
by or under the supervision of an investigator or a delegate.
All procedures during the treatment period should be done according to the relative days 
mentioned in this CSP. For assessments during the treatment period, deviations of -1 day and 
+2 days are acceptable unless otherwise specified in the protocol.
The assessments apply to both Phase I and Phase II parts unless otherwise specified.
9.2.1.1
Screening period
Procedures performed prior to informed consent as standard of care may be used as screening 
assessments, if performed within the specified window (relative to start of dosing) and 
according to the protocol requirements.
Up to 28 days prior to the first study drug administration:

Obtain written informed consent/assent. The Informed Consent/Assent Form includes 
consent for plasma sample, archival tumor tissue and optional fresh paired tumor 
biopsy collection for the analysis of genetic and non-genetic biomarkers.

Check inclusion/exclusion criteria (see Section 6.1 and 6.2).

Complete medical and surgical history including demographics (See Section 9.3.1), 
relevant medical history findings, concomitant illnesses, allergy history, prior 
surgeries, most recent histology of tumor, most recent staging and grading of tumor, 
history of anticancer treatments (including type of treatment, type of response, date 
and duration of response and date of subsequent relapse), assessment of baseline 
toxicity 

Disease confirmation

IxRS transaction to register the patient in the system.

Bilateral bone marrow biopsy and/or bone marrow aspiration will be performed within 
28 days before first study drug infusion in patients with lymphomas or neuroblastoma
and in any tumor with marrow disease involvement at baseline or if suspicion for 
involvement at study entry (see Section 9.4).

Blood test for HBV and HCV: HBsAg, HBcAb and anti-HCV antibody. 
(If HBsAg or HBcAb positive also HBV DNA; if HCV IgG positive also HCV RNA).
For patients of ≤1 year old, HBsAg, HBcAb, anti-HCV measurements to be done 
prior to -7 day visit. For other ages, measurements can be done any time within 
28 days prior to the first study drug administration.

Blood test for CMV infection per local SOC. Patients who are CMV test positive at 
baseline will not be eligible. 


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Care should be taken to minimize the amount of blood taken, and consideration given 
regarding the timing and volumes of blood required for other assessments at 
screening, such that the recommended limits for blood loss in children is not exceeded 
(see Appendix 16.5).

MUGA or echocardiogram (see Section 9.6.3.6).

Toxicity and assessment of adverse events. Any new findings or worsening of any 
ongoing medical history conditions after the patient has signed the informed consent 
are to be listed as adverse events (see Section 9.6.1.3). 

Concomitant medications
o
Note: contrast media does not need to be recorded as concomitant medication 
unless there is an AE related to its administration (e.g. allergic reaction).

Fresh tumor tissue samples (optional) will be collected when feasible, and available 
archival tumor samples must be submitted with date of material collection to 
investigate or identify biomarkers that may be predictive of copanlisib effects/efficacy 
and to contribute better understanding of the disease.

Radiological tumor evaluations (IV [and oral, if indicated, as per institutional 
standards] contrast enhanced CT, MRI or PET-CT as per local standards, of the 
primary tumor location area, and all other areas which could be targeted and/or 
suspected in the malignancy the patient has (see Section 9.4.1).

Plasma sample for biomarker analyses (for patients > 1 year and < 6 years old).

Platelet rich plasma samples for pAKT biomarker analysis (for patients > 1 year and < 
6 years old).
Within 7 days prior to the first study drug administration:

Review of inclusion/exclusion criteria (See Section 6.1 and 6.2).

Pregnancy test (for females of childbearing potential only) (See Section 9.6.3.8.)

Toxicity and assessment of adverse events (See Section 9.6.1.3).

Concomitant medications
o
Note: contrast media does not need to be recorded as concomitant medication 
unless there is an AE related to its administration (e.g. allergic reaction).

Physical examination including vital signs, and performance status (see 
Section 9.6.3.1 and 9.6.3.4). Dentition examination per local SOC should be 
performed as part of the physical exam at screening. Recommendation for blood 
pressure cuff sizes is provided in Appendix 16.7.

12 or 15-lead ECGs (see Section 9.6.3.5).

Creatinine clearance based on Schwartz Estimate ≥ 70 ml/min/1.73 m2 or a serum 
creatinine based on age/gender (See Section 9.6.3 and Appendix 16.10).


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
Blood tests for CBC with differential and platelet count, chemistry, and coagulation 
panels (see Section 9.6.3.8).
Care should be taken to minimize the amount of blood taken, and consideration given 
regarding the timing and volumes of blood required for other assessments at 
screening, such that the recommended limits for blood loss in children is not exceeded 
(see Appendix 16.5).

Urinalysis (e.g. dipstick or local lab). Microscopy as clinically indicated (see 
Section 9.6.3.8).

Plasma sample for biomarker analyses (for patients ≥ 6 years old).

Platelet rich plasma samples for pAKT biomarker analysis (for patients ≥ 6 years old).
Based on the information obtained from the above assessments, the patient’s eligibility will be 
decided upon eligibility check; no patient will be assigned to treatment unless all selection 
criteria are met.
9.2.1.2
Treatment period
After all screening assessments have been completed and the patient’s eligibility has been 
confirmed and documented, the patient will be registered for treatment via IxRS.
The following assessments should be performed at each visit before receiving study 
treatment 
In addition to the weekly clinical review and laboratory tests outlined in the schedule of 
assessment, the following should be performed in all patients prior to IV infusion of 
copanlisib: 

Evaluation of any new onset or worsening of pulmonary symptoms (i.e. cough, 
dyspnea or fever) that includes a lung examination at each visit prior to infusion (see 
Section 7.4.4.3 for further information).
9.2.1.2.1
Treatment – Cycle 1
Cycle 1 Day 1

Review of inclusion/exclusion criteria

IxRS treatment assignment

Height (length), weight measurement, BSA calculation (see Section 9.6.3.2).

Toxicity and AE assessment (see Section 9.6.1.3).

Complete physical examination including performance status, vital signs, and 
complete review of body systems (see Sections 9.6.3.1 and 9.6.3.4).

Heart rate and respiration rate. On infusion days, heart rate and respiration rate will be 
assessed at pre-dose and every 15 min (± 5 min) during the study drug infusion (see 
Section 9.6.3.4).


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
12 or 15-lead ECGs will be performed prior to infusion and at the end of infusion.

Concomitant medication review. 

Pre-dose blood pressure will be measured twice with at least a 15 min interval 
between the assessments prior to start of infusion of study drug (any time on dosing 
day). See Section 7.4 for the required pre-dose blood pressure values before infusion 
can be started.
After start of infusion, a single blood pressure measure is conducted at 4 timepoints 
according to instructions in Table 9–3 (mid-dose and post-dose blood pressure 
measurements). 
The patient should rest for at least 10 min before blood pressure is recorded. See 
Section 9.6.3.4.1 for further information. 

Glucose will be measured at pre-dose <1 h prior to start of study drug infusion and 
post-dose after the end of study drug infusion according to instructions in Table 9–4. 
Additional measurements to be performed at the clinic as clinically indicated.

Complete blood count with differential and platelet count (see Section 9.6.3.8).

Chemistry panel. If done within 7 days prior to C1D1 does no need to be repeated (see 
Section 9.6.3.8).

PK sampling for copanlisib: 
Pre-dose PK: pre-infusion (< 30 min prior to start of infusion)
Post-dose PK: 1-1.25 hour, 1.5-3 hour (patients ≥6 years only) and 22-24 hours after 
start of the infusion.
If sampling is not feasible at Cycle 1, samples may be collected at Cycle 2. A separate 
IV line should be used for PK draws (see Section 9.5).

Study drug IV infusion.
Cycle 1 Day 8

Height (length), weight measurement (see Section 9.6.3.2).

Toxicity and AE assessment (see Section 9.6.1.3).

Concomitant medication review. 

Complete physical examination including performance status, vital signs and complete 
review of body systems (see Sections 9.6.3.1 and 9.6.3.4).

Heart rate and respiration rate. On infusion days, heart rate and respiration rate will be 
assessed at pre-dose and every 15 min (± 5 min) during the study drug infusion (see 
Section 9.6.3.4).

Complete blood count differential and platelet count (see Section 9.6.3.8).

Chemistry panel (see Section 9.6.3.8). 


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
Glucose test <1 h prior to study drug infusion and post-dose 1 h after the end of study 
drug infusion according to instructions in Table 9–4. Additional measurements to be 
performed at the clinic as clinically indicated. 

Pre-dose blood pressure will be measured twice with at least a 15 min interval 
between the assessments prior to start of infusion of study drug (any time on dosing 
day). See Section 7.4 for the required pre-dose blood pressure values before infusion 
can be started.
After start of infusion, a single blood pressure measure is conducted at 4 timepoints 
according to instructions in Table 9–3 (mid-dose and post-dose blood pressure 
measurements).
The patient should rest for at least 10 min before blood pressure is recorded. See 
Section 9.6.3.4.1 for further information. 

IxRS transaction for medication dispensing.

Study drug IV infusion.
Cycle 1 Day 15

Height (length), weight measurement (see Section 9.6.3.2).

IxRS transaction for medication dispensing.

Toxicity and AE assessment (see Section 9.6.1.3).

Concomitant medication review. 

Complete physical examination including performance status, weight, vital signs,
pressure, and complete review of body systems and complete review of body systems
(see Sections 9.6.3.1 and 9.6.3.4). 

Heart rate and respiration rate. On infusion days, heart rate and respiration rate will be 
assessed at pre-dose and every 15 min (± 5 min) during the study drug infusion (see 
Section 9.6.3.4).

Complete blood count with differential and platelet count (see Section 9.6.3.8).

Chemistry panel (see Section 9.6.3.8).

Glucose test <1 h prior to study drug infusion and 1 h after the end of study drug 
infusion according to instructions in Table 9–4. Additional measurements to be 
performed at the clinic as clinically indicated. 

Pre-dose blood pressure will be measured twice with at least a 15 min interval 
between the assessments prior to start of infusion of study drug (any time on dosing 
day). See Section 7.4 for the required pre-dose blood pressure values before infusion 
can be started.


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After start of infusion, a single blood pressure measure is conducted at 4 timepoints 
according to instructions in Table 9–3 (mid-dose and post-dose blood pressure 
measurements).
The patient should rest for at least 10 min before blood pressure is recorded. See 
Section 9.6.3.4.1 for further information. 

Plasma sample for biomarker analyses: for patients > 1 year and < 6 years old, plasma 
samples will be collected at C1D15 only at 3 hours (± 30 min) after start of infusion. 
For patients ≥ 6 years old, BM samples will be collected up to 30 min prior to start of
infusion and 3 hours (± 30 min) after start of infusion. Patients ≤ 1 year old will be 
excluded from blood sample collection.

Platelet rich plasma samples for pAKT biomarker analysis: for patients > 1 year and 
< 6 years old, plasma samples will be collected at C1D15 only at 3 hours (± 30min) 
after start of infusion. For patients ≥ 6 years old, BM samples will be collected up to 
30 min prior to start of infusion and 3 hours (± 30 min) after start of infusion. Patients 
≤ 1 year old will be excluded from blood sample collection.

Fresh tumor tissue samples when consent provided and when feasible.

PK sampling for copanlisib:
Post-dose PK: 1-1.25 hour, 1.5-3 hour (patients ≥6 years only) and 22-24 hours after 
start of the infusion.

Study drug IV infusion.
9.2.1.2.2
Treatment – Cycle 2 and higher
Cycle 2 and higher, Day 1

Height (length for infants) and weight measurement (see Section 9.6.3.2).

IxRS transaction for medication dispensing.

Serum pregnancy test (if applicable): after Cycle 1 serum pregnancy test is mandatory 
at every cycle for countries where it is required by local regulations.

Toxicity and AE assessment (see Section 9.6.1.3).

Concomitant medication review. 

Complete physical examination including performance status, vital signs, blood 
pressure, and complete review of body systems (see Sections 9.6.3.1 and 9.6.3.4). 

Heart rate and respiration rate. On infusion days, heart rate and respiration rate will be 
assessed at pre-dose and every 15 min (± 5 min) during the study drug infusion (see 
Section 9.6.3.4).

12 or 15 -lead ECG will be performed on D1 of Cycle 2 and every subsequent cycle at 
the end of infusion (see Section 9.6.3.5).


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
Complete blood count with differential and platelet count (see Section 9.6.3.8).

Chemistry panel. Total cholesterol, LDL and triglycerides will be tested only at 
screening, on Day 1 of every 2nd cycle starting from Cycle 2, and at the EOT visit. If 
done within 7 days it may not be repeated (see Section 9.6.3.8).

Coagulation panel: INR and PTT or aPTT

Urinalysis (e.g. dipstick or local lab). Microscopy as clinically indicated (see 
Section 9.6.3.8).

Glucose test <1 h prior to study drug infusion and post-dose 1 h after the end of study 
drug infusion according to instructions in Table 9–4. Additional measurements to be 
performed at the clinic as clinically indicated. 

Pre-dose blood pressure will be measured twice with at least a 15 min interval 
between the assessments prior to start of infusion of study drug (any time on dosing 
day). See Section 7.4 for the required pre-dose blood pressure values before infusion 
can be started.
After start of infusion, a single blood pressure measure is conducted at 4 timepoints 
according to instructions in Table 9–3 (mid-dose and post-dose blood pressure 
measurements). The patient should rest for at least 10 min before blood pressure is 
recorded. See Section 9.6.3.4.1 for further details.

Creatinine clearance based on Schwartz Estimate ≥ 70 ml/min/1.73 m2 or a serum 
creatinine based on age/gender (See Section 9.6.3.8 and Appendix 16.10).

Study drug IV infusion.
Cycle 2 and higher, Day 8

Height (length for infants) and weight measurement (see Section 9.6.3.2).

IxRS transaction for medication dispensing.

Toxicity and AE assessment (see Section 9.6.1.3).

Concomitant medication review. 

Complete physical examination including performance status, vital signs, blood 
pressure, and complete review of body systems (see Sections 9.6.3.1 and 9.6.3.4). 

Heart rate and respiration rate. On infusion days, heart rate and respiration rate will be 
assessed at pre-dose and every 15 min (± 5 min) during the study drug infusion (see 
Section 9.6.3.4).

Complete blood count with differential and platelet count (see Section 9.6.3.8).

Cycle 2 only: Complete chemistry panel (See Section 9.6.3.8).


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
Pre-dose blood pressure will be measured twice with at least a 15 min interval 
between the assessments prior to start of infusion of study drug (any time on dosing 
day). See Section 7.4 for the required pre-dose blood pressure values before infusion 
can be started.
After start of infusion, a single blood pressure measure is conducted at 4 timepoints 
according to instructions given in Table 9–3 (mid-dose and post-dose blood pressure 
measurements). The patient should rest for at least 10 min before blood pressure is 
recorded. See Section 9.6.3.4.1

Glucose test <1 h prior to start of study drug infusion and 1 h after the end of study 
drug infusion according to instructions in Table 9–4. Patients are not required to be 
fasting prior to pre-dose glucose measurement.

Study drug IV infusion.
Cycle 2 and higher, Day 15

Height (length for infants) and weight measurement (see Section 9.6.3.2).

IxRS transaction for medication dispensing.

Toxicity and AE assessment (see Section 9.6.1.3).

Concomitant medication review. 

Complete physical examination including performance status, vital signs, blood 
pressure, and complete review of body systems (see Sections 9.6.3.1 and 9.6.3.4). 

Heart rate and respiration rate. On infusion days, heart rate and respiration rate will be 
assessed at pre-dose and every 15 min (± 5 min) during the study drug infusion (see 
Section 9.6.3.4).

Complete blood count with differential and platelet count (see Section 9.6.3.8).

Cycle 2 only: Complete chemistry panel (see Section 9.6.3.8).

Glucose test <1 h prior to study drug infusion and post-dose 1 h after the end of study 
drug infusion according to instructions in Table 9–4. Patients are not required to be 
fasting prior to pre-dose glucose measurement.

Pre-dose blood pressure will be measured twice with at least a 15 min interval 
between the assessments prior to start of infusion of study drug (any time on dosing 
day). See Section 7.4 for the required pre-dose blood pressure values before infusion 
can be started.
After start of infusion, a single blood pressure measure is conducted at 4 timepoints 
according to instructions given in Table 9–3 (mid-dose and post-dose blood pressure 
measurements).
The patient should rest for at least 10 min before blood pressure is recorded. See 
Section 9.6.3.4.1.


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
Study drug IV infusion.
9.2.1.3
Tumor assessments
Please refer to Section 9.4 for the schedule of radiological tumor assessments and bilateral 
bone marrow biopsy and/or bone marrow aspiration.
9.2.1.4
End-of-treatment visit
The procedures to be performed at the EOT visit will take place not later than 7 days after
the decision is made to discontinue the study treatment. They will comprise the following:

Only weight will be checked as part of safety assessment. See Section 9.6.3.2.

IxRS transaction to register end of treatment.

Serum pregnancy test (if applicable): mandatory for countries where it is required by 
local regulations (see Section 9.6.3.8).

Toxicity and AE assessment (see Section 9.6.1.3).

Concomitant medication review

Complete physical examination including performance status, vital signs, and 
complete review of body systems (see Sections 9.6.3.1 and 9.6.3.4). 

A 12 or 15-lead ECG: necessary only if not recorded within the previous 4 weeks.

Complete blood count with differential and platelet count (see Section 9.6.3.8).

Chemistry panel (see Section 9.6.3.8). Total, conjugated and unconjugated bilirubin, 
alkaline phosphatase, ALT, AST. Total cholesterol, LDL and triglycerides. If a patient 
can’t adhere to fasting requirements, the evaluation of lipid-panels including 
triglycerides is considered not feasible (lipid panels will be omitted).

Coagulation panel: INR and PTT or aPTT 

MUGA or echocardiogram.

Urinalysis (e.g. dipstick or local lab). Microscopy as clinically indicated (see 
Section 9.6.3.8).

Creatinine clearance based on Schwartz Estimate ≥ 70 ml/min/1.73 m2 or a serum 
creatinine based on age/gender (see Section 9.6.3.8 and Appendix 16.10).

Fresh tumor tissue samples when consent provided and when feasible.

Plasma sample for biomarker analysis (except patients ≤1 year old).


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9.2.1.5
Follow-up periods
An additional contact with the patient may be required before the next scheduled visit or 
telephone call if the most recent data on survival is needed at a specific time point during 
Active follow-up or Long-term follow-up (e.g. for a DMC meeting or data analysis). 
9.2.1.5.1
Active follow-up
The active follow-up period is the interval from the end of study drug intake to the end of all 
CSP-specified post-treatment interventions. All patients who discontinue study treatment for 
any reason will be followed for safety at a mandatory safety follow-up visit except for the 
cases when patients and/or parents (or legal guardians) refuse follow-up data collection. 
Safety follow-up (SFU) visit will take place 30 + 5 days after the last administration of study 
drug.
Patients who discontinue study treatment for reasons other than radiological PD will have 
radiological assessments as outlined in this CSP from the time of discontinuation of treatment 
of until PD is documented or new anti-tumor treatment is administered. 
Safety follow-up visit:
If a patient discontinues study treatment at any time during the study for any reason (except 
death or lost to follow-up) a safety follow-up evaluation should be performed 30 days 
(window of + 5 days is allowed) after the last dose of study medication. Please note that 
adverse events should be reported up to 30 days after the last dose of study drug

Toxicity/AE assessment (see Section 9.6.1.3).

Concomitant medication review.
If clinically indicated: 

Physical examination including performance status, weight, vital signs, blood 
pressure, and review of body systems (see Section 9.6.3.1). 

Complete blood count with differential and platelet count and chemistry (see 
Section 9.6.3.8).

If a patient has begun treatment with another anticancer agent and is no longer being 
seen in the clinic, the post-treatment safety assessment can be conducted via 
telephone.
Other active follow-up visits
Patients who discontinue study treatment for reasons other than radiological PD will enter the 
active follow-up period, except for patients and/or parents (or legal guardians) who object to 
follow-up data collection. The patients in the active follow-up will have radiological 
assessments as outlined in this CSP from the time of discontinuation of treatment until 
radiological PD for this patient is observed or until the start of first subsequent anti-cancer 
therapy, whichever occurs first.


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During this period only AEs and SAEs assessed as related to the study procedures by the 
investigator will be reported. AE pages of the eCRF and the SAE form should be completed 
in the usual manner and forwarded to the applicable sponsor’s GPV department.
During the study for up to 2 years after the last patient first treatment (LPFT), routine growth 
and dentition examinations will be performed for patients on study until the end of active FU 
per local SOC. A hand-wrist and dental imaging studies may be performed per local SOC and 
per investigator’s discretion, if any abnormality is observed.
9.2.1.5.2
Long-term follow-up 
All patients will be followed-up for survival for at least 2 years after the end of the phase I
(dose-escalation) and phase II (extension) parts. Following completion of the active follow-up 
study period, patients’ parents (or legal guardians) will continue to be contacted 
approximately every 3 months (± 14 days) to determine survival status until death or for at 
least 2 years after the LPLT in the study, independent of the reason for study termination, 
except for patients who object to follow-up data collection. Patients or their parents or legal 
guardians or their healthcare providers will be contacted either in person or by telephone.
Those patients who reached adult age during the long-term follow-up can be contacted 
directly or via patients’ parents (or legal guardians).
Information to be recorded at these contacts:

Survival status, including date of contact.

Documentation of the first new anti-cancer treatment regimen including response, if 
given. 

Date and cause of death, if applicable.
9.3
Population characteristics
9.3.1
Demographic
For demographic assessment the following parameters will be recorded: age, sex/gender, 
race/ethnicity.
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 patient’s study eligibility.
Detailed instructions on the differentiation between (i) medical history and (ii) adverse events 
can be found in Section 9.6.1.1.
9.3.3
Other baseline characteristics

Date of diagnosis and stage of disease

Tumor site and size, site(s) and date(s) of metastases, type of surgery conducted


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
Karnofsky / Lansky performance status

Prior anti-neoplastic therapies, including the response to the therapies

All medications and significant non-drug therapies taken before study entry, including 
the following
o Medication trade name and dose
o Reason for medication
o Start date and end date, or if continuing at the time of study entry
9.4
Efficacy
9.4.1
Radiological tumor assessments
Standard tumor measurement procedures will be used. Radiological tumor evaluations will be 
performed based on IV [and oral, if indicated, as per institutional standards] contrast enhanced 
CT, MRI or PET-CT as per local standards, of the primary tumor location area and all other 
areas which could be targeted and/or suspected in the malignancy the patient has. The method 
chosen at the baseline should be the same throughout the study. If at baseline IV (or oral) 
contrast-enhanced CT is medically contraindicated, sites may acquire MRI (contrast-
enhanced) of the primary tumor location area and all other areas which could be targeted 
and/or suspected in the malignancy the patient has. Only if a patient develops contra-
indication to both CT and MRI contrast medium during the study, the case examinations 
could be continued without contrast medium.
Tumor assessments will be performed at screening (within 28 days prior to start of treatment), 
during treatment period every 8 weeks (± 7 days) until radiological tumor progression, at EOT 
visit and during active FU period every 12 weeks (± 14 days) until radiological tumor 
progression or start of new anti-cancer therapy, whichever occurs first. Scans done up to 
28 days prior to first dose can be used as baseline studies. Please note: tumor assessment is 
not required at the EOT visit if the patient discontinues study treatment due to PD which has 
been radiologically confirmed within the 4 weeks preceding EOT visit.
NOTE: post-base line imaging performed within 7 weeks after the date of baseline tumor 
evaluation will not be evaluable for DCR analysis of stable disease (SD) in patients with 
osteosarcoma.
For neuroblastoma patients with MIBG-avid disease, MIBG scan will be used and assessment 
will be done according to SIOPEN or Curie score (see Appendix 16.2 and 16.3). Bone scan 
will be done if bone metastases are suspected (not applicable for neuroblastoma patients). 
Modified Lugano Classification 2014 will be used for evaluation of lymphoma (see 
Appendix 16.11) and RECIST v1.1 (see Appendix 16.1) will be used for solid tumors 
evaluation.
MRI/CT/PET-CT/MIBG scans must meet the standard of care for the imaging of lesions in 
the respective organ system(s) and preferably evaluated by the same investigator/radiologist. 
However, CT scans of PET-CT images used for lesion assessments must be of diagnostic CT 
quality (CT is required for lesion assessments). Copies of all imaging performed for tumor 


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assessment in all enrolled patients will be stored electronically at the site. Copies of the 
imaging studies may be requested for an optional retrospective review.
Bilateral bone marrow biopsy and/or bone marrow aspiration will be performed within 
28 days before first study drug infusion in patients with lymphomas, or neuroblastoma and in 
any tumor with marrow disease involvement at baseline or if suspicion for involvement at 
study entry. 
During the study period, bilateral bone marrow biopsy and/or bone marrow aspiration will be 
done at the discretion of the local investigator and to confirm first CR for patients with bone 
marrow involvement at baseline. Bone marrow biopsy/aspiration will be performed as per 
local standard of care.
9.5
Pharmacokinetics / pharmacodynamics
For PK: Each patient will provide blood samples during Cycle 1 (or, optionally, during Cycle 
2 if it was not done on Cycle 1) on Days 1 and 15 according to Table 9–2. PK sampling will 
be performed in all patients for copanlisib.
Table 9–2 Blood sample collection for copanlisib PK assessment
Age ≥6 years
Cycle
Study Day
Time window 
Volume of 
blood (mL)
Pre-dose PK
1
Day 1
pre-infusion (< 30 min prior to start of infusion
1.0
Post-dose PK (after start of infusion)
1
Day 1
1 – 1.25 h
1.0
1
Day 1
1.5 – 3 h
1.0
1
Day 1/2
22 – 24 h
1.0
1
Day 15
1 – 1.25 h
1.0
1
Day 15
1.5 – 3 h
1.0
1
Day 15/16
22 – 24 h
1.0
Total blood volume to be collected per patient
7 mL
Age < 6 years
Cycle
Study Day
Time window 
Volume of 
blood (mL)
Pre-dose PK
1
Day 1
pre-infusion (< 30 min prior to start of infusion
1.0
Post-dose PK (after start of infusion)
1
Day 1
1 – 1.25 h
1.0
1
Day 1/2
22 – 24 h
1.0
1
Day 15
1 – 1.25 h
1.0
1
Day 15/16
22 – 24 h
1.0
Total blood volume to be collected per patient
5 mL
H = hour; PK = Pharmacokinetic


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PK samples taken outside of protocol specified planned sampling time will be recorded but 
will not be considered as protocol deviations. The date and clock time of each sample as well 
as dates and times of the doses will be recorded in the electronic Case Report Form (eCRF) as 
PK calculations will be based on the sampling times relative to dosing times Samples may be 
collected irrespective of any dose modifications during the treatment cycle.
A separate IV line must be used for PK blood draws. This line must not be used for IV 
infusion of the drug.
The PK will be evaluated using population PK (popPK) model.
Details about the collection, processing, storage and shipment of samples will be provided
separately (please refer to Laboratory Manual). 
Concentration data of copanlisib from this study will be analyzed to estimate the individual 
maximum drug concentration (Cmax) and area under the curve (AUC), and to measure the 
variability of copanlisib PK in this population and to compare the mean exposure of the all 
cohorts to the adult exposure. A popPK model will be used for the analysis. 
A separate data evaluation plan, providing details of the evaluation will be provided prior to 
the beginning of the population PK analysis. Evaluation of the data will be presented in a
separate report. Individual PK parameters derived from the population PK model will be
statistically summarized for each cohort.
9.6
Safety
9.6.1
Adverse events
9.6.1.1
Definitions
Definition of adverse event (AE)
In a clinical study, an AE is any untoward medical occurrence (i.e. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation 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 patient should not be recorded as an AE (however, the condition for which the surgery is 
required may be an AE).


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


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9.6.1.2 Classifications for adverse event assessment
All AEs will be assessed and documented by the investigator according to the categories 
detailed below. 
9.6.1.2.1
Seriousness
For each AE, the seriousness must be determined according to the criteria given in 
Section 9.6.1.1.
9.6.1.2.2
Intensity
The intensity of AEs should be documented using the National Cancer Institute Common 
Terminology Criteria for Adverse Events, version 4.0 (NCI-CTCAE, v. 4.03). For events not 
listed in the NCI-CTCAE version 4.03, the following scale will be used:
-
Grade 1: Mild
-
Grade 2: Moderate
-
Grade 3: Severe
-
Grade 4: Life-threatening
-
Grade 5: Fatal
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.
Causality should be assessed separately for each study treatment as detailed in the CRF. If the 
investigator feels that the event cannot be firmly attributed to one of the study treatments 
(e.g. owing to a suspected underlying interaction), the same assessment will be documented 
for each study treatment.
The assessment is based on the question whether there was a “reasonable causal relationship” 
to the study treatment in question.
Possible answers are “yes” or “no”
An assessment of “no” would include:
1. The existence of a highly likely alternative explanation, e.g. mechanical bleeding at 
surgical site.
or
2. Non-plausibility, e.g. the patient is struck by an automobile when there is no 
indication that the drug caused disorientation that may have caused the event; cancer 
developing a few days after the first drug administration.


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An assessment of “yes” indicates that that the AE is reasonably associated with the use of the 
study treatment.
Important factors to be considered in assessing the relationship of the AE to study treatment 
include:
- The temporal sequence from drug administration: The event should occur after the drug 
is given. The length of time from drug exposure to event should be evaluated in the 
clinical context of the event.
-
Recovery on drug discontinuation (de-challenge), recurrence on drug re-introduction 
(re-challenge): Patient’s response after de-challenge or re-challenge should be 
considered in view of the usual clinical course of the event in question.
-
Underlying, concomitant, intercurrent diseases: 
Each event should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the patient may have.
-
Concomitant medication or treatment: 
The other drugs the patient is taking or the treatment the patient receives should be 
examined to determine whether any of them might have caused the event in question.
- Known response pattern for this class of drug: Clinical/preclinical
- Exposure to physical and/or mental stresses: The exposure to stress might induce adverse 
changes in the recipient and provide a logical and better explanation for the event
-
The pharmacology and pharmacokinetics of the study treatment: 
The pharmacokinetic properties (absorption, distribution, metabolism and excretion) 
of the study treatment, coupled with the individual patient’s pharmacodynamics 
should be considered.
- The assessment is not possible
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

Drug interrupted

Dose reduced

Dose not changed


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
Not applicable

Unknown
9.6.1.2.5
Other specific treatment(s) of adverse events

None

Remedial drug therapy

Other
9.6.1.2.6
Outcome
The outcome of the AE is to be documented as follows: 

Recovered/resolved

Recovering/resolving

Recovered/resolved with sequelae

Not recovered/not resolved

Fatal

Unknown
9.6.1.3
Assessments and documentation of adverse events
All patients who discontinue due to AEs or clinical laboratory abnormalities should be 
followed up until they recover or stabilize, and the subsequent outcome recorded. If any 
patient dies during the study or within 30 days of the last dose of study drug, the investigator 
or his/her designated associate(s) will inform the sponsor. The cause of death should be 
recorded in detail within 24 h of awareness on an SAE form and transmitted to the sponsor.
A laboratory test abnormality considered clinically significant, e.g., causing the patient to 
withdraw from the study, requiring treatment or causing apparent clinical manifestations, or 
judged significant by the investigator, should be reported as an AE. Each event should be 
described in detail along with start and stop dates, intensity, relationship to investigational 
product, action taken and outcome.
AEs observed or mentioned upon open questioning by a member of the investigator team or 
spontaneously reported by the patients or their parents/legal guardians will be documented. 
Parents/legal guardians will be encouraged and carefully instructed to report adverse reactions 
and events to the investigator in a timely manner, particularly in young children, who may not 
be able to identify adverse reactions. AEs will be documented in an event-based manner, 
using NCI-CTCAE v.4.03 guidelines.
The observation phase for AEs will start after signing of informed consent/assent and will end 
in general at the safety follow-up visit. During the active follow-up period, after the SFU visit,
AEs and SAEs considered related to the study drug or study-related procedures will be 
reported and documented.


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The investigator has to record on the respective CRF pages all adverse events occurring in the 
period that starts with the signing of the informed consent and will end 30 days after the last 
dose of study drug. The safety follow-up will occur 30 days (window of +5 days is allowed) 
after the last dose of study drug. AE pages of the eCRF and the SAE form should be 
completed in the usual manner and forwarded to the applicable sponsor’s GPV department.
After the end of the follow-up phase there is no requirement to actively collect AEs including 
deaths. 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 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 an SAE only if the 
underlying event which resulted in death is unknown.  
For all serious adverse events (SAEs) the sponsor has to carry out a separate assessment for 
expectedness, seriousness and causal relationship to study drug.
9.6.1.4
Reporting of serious adverse events
The definition of serious adverse events (SAEs) is given in Section 9.6.1.1. Each SAE must 
be followed up until resolution or stabilization by submission of updated reports to the 
designated recipient.
If disease progression leads to signs and symptoms that meet the criteria for seriousness (see 
Section 9.6.1.1), the associated signs and symptoms should be reported as SAEs, not the 
underlying cause (i.e. “progressive disease” should not be reported as SAE). In this case, 
disease progression should be mentioned on the SAE form as “alternative explanation”.
Investigator’s notification of the sponsor
If a new primary malignancy is noted at any time it must be reported as an SAE, whether or 
not it is assessed as related to study therapy.
In the event of a fatal or life-threatening reaction, the investigator must seek relevant follow-
up information and must complete a follow-up reported to the sponsor as soon as possible but 
not later than 8 calendar days after the initial report is sent.
For all SAEs, the investigator is required to document in full the course of the SAE and any 
therapy given, including any relevant findings/records in the report. For documentation of 
laboratory findings as SAE, please refer to Section 9.6.3.8.
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 hours of the investigator’s awareness) all 
SAEs occurring during the observation period defined in Section 9.6.1.3 to the recipient 
detailed in the instructions for SAE reporting included in the Investigator File. 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.
If the investigator becomes aware of bone or teeth alterations after the end of long-term 
follow-up for safety, he/she should report this as an SAE
Notification of the IECs / IRBs
Notification of the IECs / IRBs about all relevant events (e.g. SAEs, suspected, unexpected, 
serious adverse reactions [SUSARs]) will be performed by the sponsor and/or by the 
investigator according to all applicable regulations.
Notification of the authorities
The processing and reporting of all relevant events (e.g. SAEs, SUSARs) to the authorities 
will be done by the sponsor according to all applicable regulations.
Sponsor’s notification of the investigational site
The sponsor will inform all investigational sites about reported relevant events (e.g. SUSARs) 
according to all applicable regulations.
9.6.1.5
Expected adverse events
For this study, the applicable reference document is the most current version of the 
investigator’s brochure (IB)
Overview listings of frequent events that have occurred so far in the clinical development are 
shown in the current IB. If relevant new safety information is identified, the information will 
be integrated into an update of the IB and distributed to all participating sites.
The expectedness of AEs will be determined by the sponsor according to the applicable 
reference document and according to all local regulations.
9.6.1.6
Adverse events of special safety interest
Copanlisib is an investigational drug and current knowledge of the AEs associated with this 
compound is limited. As with any new chemical entity, there is always potential for AEs that 
may be class related. Non-infectious pneumonitis (NIP) has been observed with copanlisib, as 
with other PI3K drugs, and since the sponsor wishes to be aware of any such reports rapidly, 
NIP has been designated as an AE of special interest (AESI). Regardless of whether an AE 
consistent with NIP is assessed as causally related/not related to study drug, or as serious/non-
serious, the investigator should notify the sponsor within 24 hours as outlined in 
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non-serious, the non-serious assessment should be noted in the form. The AESI will be also 
entered in the eCRF.
9.6.2
Pregnancies
The investigator must report to the sponsor any pregnancy occurring in a female study patient
during her participation in this study. The outcome of the pregnancy should be followed up 
carefully, and any outcome of the mother and the child at delivery should be reported.
For a pregnancy in the partner of a male study patient, all efforts will be made to obtain 
similar information on course and outcome, subject to the partner’s consent.
For all reports, the forms provided are to be used. The investigator should submit them within 
the same timelines as an SAE.
9.6.3
Further safety
9.6.3.1
Physical examination
Physical examination includes performance status assessment (see grading definitions in 
Appendix 16.4), vital signs (see Section 9.6.3.4), and complete review of body systems.
The physical examination (by means of inspection, palpation, auscultation) will be performed 
by a physician at the investigational site.
For this examination, the investigator will assess / examine the following:

General appearances

Skin

Eyes

Ears, nose and throat

Head and neck

Lungs

Heart

Abdomen

Lymph nodes

Musculoskeletal system (including 
extremities and spine)

Neurological findings
If indicated by the patient’s history, the following will be examined by specialists, if 
applicable:

Genito-urinary system

Gynecological organs

Rectum
Abnormal physical examination findings are recorded either as medical history or as adverse 
events (see Section 9.6.1.1).
9.6.3.2
Body weight, height and BSA calculation 
Body weight and height (length for infants) will be measured upon arrival by a member of the 
investigator’s team: 
BSA will be calculated at Cycle 1 Day 1 based on either the Mosteller formula or the DuBois 
formula. Mosteller formula is recommended as it combines accurate BSA calculation with 
ease of use. However, the formula that is chosen at Cycle 1 Day 1 must be used throughout 
the study.
Mosteller: BSA (m²) = ([Height(cm) x Weight(kg)]/ 3600)½


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DuBois: BSA (m²) = 0.20247 x Height(m)0.725 x Weight(kg)0.425
9.6.3.3
Growth and dental exams 
During the study for up to 2 years after the LPFT routine growth and dentition examinations 
may be performed for patients on study until the end of active FU per local SOC. A hand-
wrist and dental imaging studies may be performed per local SOC and per investigator’s 
discretion, if any abnormality is observed.
9.6.3.4
Vital signs 
Heart rate, pulse oximetry, respiration rate, blood pressure and temperature will be assessed 
according to the schedule summarized in the flow chart of Section 9.1. If clinically indicated, 
it is at the investigator’s discretion to perform these measurements more frequently.
On infusion days, heart rate and respiration rate will be assessed at pre-dose and every 15 min 
(± 5 min) during the study drug infusion.
9.6.3.4.1
Blood pressure measurement on infusion days
Pre-dose blood pressure will be measured twice with at least a 15 min interval between the 
measurements prior to infusion of study drug (any time on dosing day). After start of infusion, 
a single measurement is conducted at 4 time points after start of infusion (see Table 9–3).
The patient should rest for at least 10 min before blood pressure is recorded. For blood 
pressure levels for children by age and height percentile, see Appendix 16.6. For 
recommended dimensions for blood pressure cuff bladders, see Appendix 16.7
Table 9–3 Blood pressure measurement on copanlisib infusion days
Pre-dose BP 
measurement a
Mid-dose BP 
measurement
Post-dose BP measurement
2 measures with least a 
15 min interval between 
assessments                      
30 min (+/-10 min) after 
start of infusion (mid-
infusion)
0h (+10 min) after end of infusion (equivalent 
to 1h post start of infusion)
1h (+/-10 min) after end of infusion
(equivalent to 2h post start of infusion)
2h (+/-10 min) after end of infusion 
(equivalent to 3h post start of infusion)
BP = Blood pressure; H = Hour; Min = Minute.
a: Any time on dosing day
9.6.3.5
Electrocardiogram
12 or 15-lead ECG at screening (within 28 days of Cycle 1 Day 1), on Cycle 1 Day 1 prior to 
and at the end of copanlisib infusion and on Day 1 of every cycle at the end of copanlisib 
infusion. At EOT visit, a 12 or 15-lead ECG is necessary only if not recorded within the 
previous 4 weeks.


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9.6.3.6
Cardiac function
Cardiac function test: echocardiogram or MUGA scan at screening (within 28 days of Cycle 1 
Day 1), and at EOT visit, and as clinically indicated. At EOT, a test is necessary only if not 
recorded within the previous 4 weeks.
The method chosen at baseline (i.e. either echocardiogram or MUGA scan) must be used 
throughout the whole study period. Additional cardiac function tests are required if any signs 
or symptoms of cardiac dysfunction occur. 
The study number, patient number, visit and the date of the echocardiogram/MUGA scan are 
noted on every echocardiogram/MUGA scan. The overall interpretation of the 
echocardiogram/MUGA scan and findings will be recorded in the source documentation and 
in the eCRF.
9.6.3.7
Lansky-Karnofsky Performance status
Patients’ ability to manage activities of daily living will be appraised utilizing the 
performance status scale by Lansky/Karnofsky (see Appendix 16.4). The patient’s 
performance score will be estimated according to the schedule summarized in Section 9.1.
The same scale will be used throughout the study which was used at the baseline.
9.6.3.8
Laboratory examinations 
Local laboratory will be used for the analysis of blood and urine samples collected to address 
safety parameters. The following blood and urine samples will be collected by a member of 
the investigator’s team:

Complete blood count: Hemoglobin, hematocrit, RBC, WBC (with differential to 
include absolute neutrophil, lymphocyte, monocyte, basophil and eosinophil counts)
and platelet count. 

Chemistry panel: Creatinine, urea/BUN, lipase, amylase, total protein, albumin, uric 
acid, LDH, calcium, sodium, potassium, chloride, phosphorus, magnesium, 
bicarbonate (or carbon dioxide if bicarbonate is not routinely measured at the site) and 
serum glucose. Total, conjugated and unconjugated bilirubin, alkaline phosphatase, 
ALT, AST. Total cholesterol, LDL and triglycerides will be tested only at screening, 
on Day 1 of every 2nd cycle starting from Cycle 2, and at the EOT visit. On these dates 
patients must be fasting prior to sampling according to local standards. If a patient 
can’t adhere to fasting requirements, the evaluation of lipid-panels including 
triglycerides is considered not feasible (lipid panels will be omitted).

Coagulation panel: aPTT (activated partial thromboplastin time) or PTT (partial 
thromboplastin time) and INR (international normalized ratio)

Urinalysis (dipstick): blood cells, glucose, ketones, bilirubin, protein, and pH 
(dipstick). Additional microscopic examinations will be performed if clinically 
indicated. If dipstick use is not permitted at site, local lab may be used for sample 
analysis.


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
Creatinine clearance based on Schwartz Estimate ≥ 70 ml/min/1.73 m2 or a serum 
creatinine based on age/gender (see Appendix 16.10).

Pregnancy test (for females of childbearing potential only). 
Care should be taken to minimize the amount of blood taken, and consideration given 
regarding the timing and volumes of blood required for other assessments at each visit, such 
that the recommended limits for blood loss in children is not exceeded (see Appendix 16.5).
For patients with identified risk factors and those who presented with new onset or worsening 
of pulmonary symptoms or developed OI on study treatment, any additional laboratory and 
diagnostic methods according to local SOC reported as unscheduled laboratory and diagnostic 
methods of assessment. 
An isolated laboratory abnormality that meets the criteria for a CTCAE Grade 4 classification 
is not reportable as an SAE, unless the investigator assesses that the event meets standard ICH 
criteria for an SAE (SAE definition in Section 9.6.1.1). 
Baseline laboratory abnormalities that are part of the disease profile should not be reported as 
an AE, specifically when they are allowed or not excluded by the protocol inclusion/exclusion 
criteria. If an investigator is in doubt about the applicable reporting obligations, he / she 
should consult with the study monitor of the sponsor.
9.6.3.9
Glucose measurement on infusion days
On Cycle 1 Day 1 and on subsequent infusion days glucose will be measured according to 
instructions given in Table 9–4. 
Table 9–4 Glucose measurement on copanlisib infusion days
Pre-dose glucose 
measurement
Post-dose glucose measurement
Cycle 1 Day 1 a
<1 h prior to start of 
copanlisib infusion
0 h (+ 5 min) after end of infusion (equivalent to 1h 
post start of infusion) 
1h (+/- 5 min) after end of infusion (equivalent to 2h 
post start of infusion)  
2h (+/- 5 min) after end of infusion (equivalent to 3h 
post start of infusion)  
Subsequent infusion 
days a (Cycle 1 Day 8 
onwards)
<1 h prior to start of 
copanlisib infusion
1h (+/- 5 min) after end of infusion (equivalent to 2h 
post start of infusion)  
H = Hour; Min = Minute.
a: Additional measurements to be performed at the clinic as clinically indicated.


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9.7
Other procedures and variables
9.7.1
Biomarker investigations
Biomarker investigations in the current study will include both PD biomarker assessments to
examine the effect of copanlisib on signaling pathway activity and downstream tumor cell 
processes, as well as potentially predictive biomarkers to determine which molecular subsets 
may respond to treatment. The biomarker results may be reported separately from the main 
clinical study report (CSR).
9.7.1.1
PD biomarker assessment
PD biomarkers reflecting the effect of copanlisib on signaling pathway activity will be 
evaluated. For example, pharmacodynamic biomarker assessments may include analysis of 
changes in tumor cell signaling (e.g. pAKT, pS6), downstream tumor effects (e.g. Ki67, 
reflecting cell proliferation, and cleaved caspase 3, reflecting apoptosis), and tumor gene 
expression; changes in pAKT in platelet rich plasma as a surrogate tissue; and changes in 
plasma protein levels.
Collection and use of biomarker specimens for pharmacodynamic biomarker assessment:

Blood (plasma) sampling for biomarker evaluation: Blood samples will be 
obtained and used for plasma preparation at screening (baseline) and at C1D15 before 
infusion (up to 30 min prior to start of infusion) and 3 hours (± 30 min) after start of 
infusion. For patients > 1 year and < 6 year old BM plasma samples will be collected 
at C1D15 only at 3 hours (± 30min) after start of infusion. Patients of ≤ 1 year old will 
be excluded from blood sample collection. Plasma may be used to quantify the 
circulating levels of various proteins via enzyme linked immunosorbent assay or other 
immunoassay (e.g. multiplex).

Blood (platelet rich plasma) sampling for pAKT assay: Blood samples will be 
obtained and used for platelet rich plasma preparation at screening (baseline) and 
C1D15 before infusion (up to 30 min prior to start of infusion) and 3 hours (± 30 min) 
after start of infusion. For patients > 1 year and < 6 year old BM plasma samples will 
be collected at C1D15 only at 3 hours (± 30min) after start of infusion. Patients of 
≤1 year old will be excluded from blood sample collection.

Tumor tissue samples (optional if feasible): Fresh biopsy tissue will be collected 
from patients during screening and treatment (C1D15 or C1D16) or at EOT when 
feasible. Tumor tissue may be a source of nucleic acids (e.g. DNA or RNA) or protein, 
used to study, for example, gene expression and protein levels / signaling status (e.g. 
pAKT, Ki67) for target engagement and resistance mechanism evaluation.
All samples will be collected and processed as per instruction in the Laboratory Manual. 


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9.7.1.2
Molecular tumor characterization / potentially predictive biomarkers
Baseline candidate biomarkers will be evaluated for correlation with the response to treatment 
(“predictive biomarkers”). Baseline candidate predictive biomarkers may include, for 
example, tumor genetics, tumor proteins, RNA profiles, and plasma proteins. Many of the 
pharmacodynamic biomarkers will also be evaluated for predictive ability by analyzing 
baseline levels only.
Use of biomarker specimens for predictive biomarker assessment (using the same baseline
samples described above for pharmacodynamic biomarkers):

Archival tumor samples (as well as the fresh tumor biopsy, if available) may be used 
as a source of DNA for evaluating tumor associated alterations in genes of interest 
(e.g. PI3K, KRAS, PTEN, and other genes associated with the pathomechanism of the 
disease). Protein signaling status and levels at baseline (e.g. pAKT, PTEN) and 
baseline RNA profiles may also be assessed for predictive ability.

The plasma samples collected at baseline, during treatment and EOT may also be used 
to identify potentially predictive biomarkers, for example through examination of 
plasma protein levels and/or genetic mutations from circulated tumor DNA. 

In addition to the proteins and genes listed above, other biomarkers deemed relevant to 
gain further knowledge about the pathomechanism of the disease or about the drug 
(i.e. mode of action or safety of the drug) may be measured, based on newly emerging 
data from other ongoing studies of these investigational drugs and / or literature data.
9.8
Appropriateness of procedures / measurements
All parameters, as well as the methods to measure them, are standard variables/methods in 
studies and clinical practice. They are widely used and generally recognized as reliable, 
accurate, and relevant. Parameters and methods not considered standard procedure should be
validated appropriately before their use in this study.
10.
Statistical methods and determination of sample size
10.1
General considerations
Statistical analysis will be performed using SAS version 9.2 or later; the version used will be 
specified in the statistical analysis plan (SAP). In general, continuous variables will be 
summarized using number of non-missing values (n), number of missing values, means, 
standard deviations, medians, maximum, minimum, and interquartile range.
Ordinal variables will be summarized using n, number of missing values, medians, maximum, 
minimum, and interquartile range.
Categorical variables will be summarized using n, number of missing values, and percentages.
Time-to-event variables will be summarized using Kaplan-Meier estimates.
Further details on the statistical analyses will be provided in the SAP.


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10.2
Analysis sets
The statistical analysis sets are defined as follows:
Safety analysis set (SAF): All patients with at least one intake of study drug. The SAF will 
be used for safety evaluations for both Phase I and Phase II.
Full analysis set (FAS): All patients with at least one intake of study drug. This set will be 
used for patient characteristics, demographic, and efficacy evaluations for both Phase I and 
Phase II.
The efficacy variables in Phase I and Phase II will be analyzed in the FAS.
PK analysis set: All patients with at least one intake of study drug and with at least one valid 
measurement for copanlisib after first dosing will be included in the copanlisib PK analysis.
Additional analysis sets, and additional details on analysis sets, may be defined in the SAP.
10.3
Variables and planned statistical analyses
10.3.1
Primary variables
10.3.1.1
Primary safety variable for Phase I
The maximum tolerated dose (MTD): the highest dose level of copanlisib that can be given so 
that not more than 1 out of 6 patients experience a DLT during the DLT evaluation period.
Other primary safety variables also include DLTs, treatment-emergent AEs, SAEs, 
treatment-related AEs.
10.3.1.2
Primary efficacy variable for Phase II
Objective response rate (ORR): A patient is a responder if the patient has a tumor response 
on-study of CR or PR, based on radiological assessments utilizing RECIST 1.1 (see 
Appendix 16.1) for solid tumor patients except for neuroblastoma patients with MIBG-avid 
disease in which SIOPEN or Curie score will be used (see Appendix 16.2 and 16.3). The 
ORR is defined separately in each indication, as the number of responders divided by the 
number of patients in FAS in the indication.  
ORR is the primary efficacy variable in neuroblastoma, Ewing sarcoma and 
rhabdomyosarcoma.
Disease control rate (DCR): A patient has disease control if the patient has a confirmed tumor 
response of CR or PR or a tumor response of SD (post-base line imaging performed within 
7 weeks after the date of baseline tumor evaluation date will not be evaluable for DCR 
analysis of SD in patients with osteosarcoma) as determined per RECIST 1.1 criteria for solid
tumor patients. The DCR is defined as the number of patients with disease control divided by 
the number of patients in FAS in the indication.
DCR is the primary efficacy variable in osteosarcoma.


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For Stage 1 evaluation (in exactly 10 FAS patients per indication), solely the absolute number 
of responders in neuroblastoma, Ewing sarcoma and rhabdomyosarcoma, or number of 
patients with disease control in osteosarcoma will be determined, to make a decision for 
Stage 2.
ORR or DCR will be determined in their respective indication from Stage 1 and (potentially) 
Stage 2 results in FAS patients as unbiased minimum variance unbiased conditional 
(UMVCUE) estimate, using methodology as described in Porcher and Desseaux, 2012 (29).
Progression-free survival (PFS) is defined as the time from first dose of study drug to 
disease progression according to RECIST1.1 for osteosarcoma patients, or death (if death 
occurs before progression is documented). Patients alive without progression will be censored 
at the last tumor assessment. 
PFS is considered as co-primary (descriptively evaluated) variable in patients with 
osteosarcoma.
10.3.2
Secondary variables
10.3.2.1
Efficacy variables
Anti-tumor efficacy of copanlisib in Phase I part, measured as ORR by dose cohort is defined 
as the number of responders divided by the number of patients in FAS in the indication. 
Appropriate response criteria will be used (i.e. either RECIST 1.1 for solid tumors
(Appendix 16.1) or modified Lugano Classification 2014 for lymphoma (Appendix 16.11), or 
SIOPEN or Curie score for neuroblastoma patients with MIBG-avid disease (see 
Appendix 16.2 and 16.3).
The following efficacy endpoints will be measured for Phase II part only, separately for each 
indication reaching Stage 2.
Duration of response (DOR) is defined as the time from the date of first observed tumor 
response (CR or PR) until first subsequent disease progression or until death (if death occurs 
before progression is documented) due to any cause. Patients surviving without disease 
progression will be censored at the last tumor assessment. Duration of response will be 
defined for responders only (i.e. patients with CR or PR)).
PFS in each indication except for osteosarcoma is defined as the time from first dose of 
study drug to disease progression according to RECIST1.1 for solid tumor patients (except 
osteosarcoma) and SIOPEN or Curie score for neuroblastoma patients with MIBG-avid 
disease, or death (if death occurs before progression is documented). Patients alive without 
progression will be censored at the last tumor assessment. 
Overall survival (OS) is defined as the time from first dose of study drug until death from 
any cause or until the last date the patient is known to be alive. 


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10.3.2.2
Safety variables
Safety variables will include treatment-emergent AEs, SAEs, laboratory parameters, ECGs 
and vital signs. The severity of AEs will be graded using the NCI CTCAE v 4.03 dictionary. 
AEs will be classified as related or not related to test drug by the investigator. A treatment-
emergent AE is defined as any event arising or worsening after start of test drug 
administration until 30 days after the last dose of the study drug intake (end of safety follow-
up).
Patients’ ability to manage activities of daily living will be appraised utilizing the 
performance status scale by Lansky/Karnofsky. The patients’ performance score will be 
estimated according to the schedule summarized in Section 9.1.
10.3.2.3
PK variables
Copanlisib maximum drug concentration (Cmax) and area under the curve (AUC(0-168)) on 
Cycle 1 Day 1 and Day 15.
10.3.3
Exploratory variables
10.3.3.1
Biomarker/ pharmacodynamics (PD) variables

pAKT from surrogate tissue (platelet rich plasma) 

Glucose metabolism markers (plasma glucose, insulin, and C-peptide) 

Plasma protein panel

Molecular status (genetic alterations, protein expression and / or activation) of 
biomarkers related to PI3K signaling in tumor tissue. 
10.3.4
Statistical and analytical plans 
A complete description of the planned statistical analyses will be provided in SAPs. 
The primary analysis of the primary efficacy variable for Phase II will be performed on the
data collected up to the last patient of that indication having had the chance to complete 
4 cycles of treatment. The analysis set to be used will be the FAS. Patients who have 
progressive disease prior to 4 cycles will be considered fully evaluable for response and 
included in the efficacy analyses. At that time point, an exploratory analysis of all other 
variables will be performed, as reasonable. The final analyses of all secondary efficacy and 
safety variables and exploratory variables will be performed approximately 2 years after last 
patient completes the treatment (LPLT).
10.3.4.1
Demographic and other baseline characteristics
Demographics and baseline characteristics will be summarized for FAS population by means 
of descriptive statistics and/or frequency tables as appropriate, separately for Phase I and 
Phase II. In Phase II, the results will additionally be split by indication. 


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10.3.4.2
Primary efficacy (Phase II only)
The primary efficacy variable ORR (DCR for osteosarcoma, respectively) for Phase II will be 
summarized including number of patients (N), number of responders, response rate estimate 
(using UMVCUE method), for FAS as primary analysis set. ORR (DCR for osteosarcoma) 
will be reported by each indication independently. For the co-primary endpoint PFS rate at 4 
months (for osteosarcoma), an analyses will be performed only after Stage 2 (see end of this 
section for details). For all indications (except osteosarcoma) reaching Stage 2, the respective 
statistical hypotheses per indication will be:
H0: ORR ≤ 10% vs H1: ORR > 10% will be evaluated based on data cut-off at the day the last 
patient of the respective indication has had the chance to complete 4 cycles of treatment, i.e. 
being part of FAS.
Per indication, ORR ≤ 10% will be statistically rejected for a specific indication in case at 
least 5 responses were measured from the 25 recruited patients.
For osteosarcoma (if Stage 2 is reached), DCR will be tested, with the hypotheses being:
H0: DCR ≤ 10% vs H1: DCR > 10% will be evaluated based on data cut-off at the day the last 
patient with osteosarcoma has completed 4 cycles of treatment, i.e. being part of FAS.
DCR ≤ 10% will be statistically rejected in case at least 5 responses were measured from the 
25 FAS patients with osteosarcoma. In case Stage 2 is reached, per indication, 85% 
confidence intervals as well as p-values according to Porcher & Dessaux, 2012 (29) will be 
provided for ORR (DCR, respectively). Conditional statistical methods should be preferred, 
as applicable. Details will be provided in the SAP.
If Stage 2 is reached for patients in osteosarcoma, the survival rate of PFS at 4 months in 
osteosarcoma will be estimated as co-primary endpoint using the Kaplan-Meier method and 
its two-sided 85% CI will be provided. This analysis will be done for FAS.
10.3.4.3
Secondary efficacy
In the Phase I part, ORR (DCR for osteosarcoma, respectively) will be summarized by cohort
in the FAS only. 
In the Phase II part, for indications reaching Stage 2, Time-to-event variables (PFS, DOR and 
OS) will be evaluated by Kaplan-Meier estimates and plots by indication. Medians with 
Brookmeyer-Crowley confidence intervals using LOGLOG transformation will be provided. 
The efficacy variables will be analyzed in the FAS. Number of patients at risk over time will 
also be provided. Further details will be described in the SAP. For the indication 
osteosarcoma, PFS evaluation will be a co-primary analysis as described in section 10.3.4.2, if 
stage 2 is reached.


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10.3.4.4
Safety
The overall incidences of treatment-emergent AEs will be presented by MedDRA system 
organ class, preferred term, and by the CTCAE v. 4.03 worst grade. Listings of adverse events 
and laboratory toxicities by NCI CTCAE grade will be provided. The incidences of treatment-
emergent AEs will be presented also separately by drug relationship. The number (%) of 
patients who discontinued study drug due to an AE or required a dose reduction or 
interruption caused by an AE will be summarized. Similarily, serious adverse events will be 
evaluated. 
Descriptive summary tables will be presented for other safety variables including laboratory 
changes, abnormal findings in physical examination, changes in performance level by 
Lansky/Karnofsky, changes in vital signs (weight, blood pressure, heart rate and body 
temperature), changes in ECG.
All hematological/biochemical toxicities based on laboratory measurements will be graded by 
CTCAE v4.03 and categorized by MedDRA and will be summarized. 
Patient performance level will be evaluated descriptively, through summary statistics and 
listings.
All safety analyses will be done separately for Phase I by cohort and for Phase II by 
indication. Patients enrolled in the PK group (< 12 years old) will be evaluated with the Phase 
I cohorts.
Individual listing of DLTs will be presented for Phase I by cohort. 
Descriptive summary of safety analyses will be performed for the age group of < 1 year old 
separately.
Additional details will be described in the SAP. 
10.3.4.5
Pharmacodynamics
The change in pAKT relative to total AKT in surrogate tissue (platelet rich plasma) will be 
summarized by cohort for Phase I part and by indication for Phase II part using descriptive 
statistics. The maximum change from baseline of insulin and C-peptide during copanlisib 
treatment will be reported.
10.3.4.6
Biomarkers 
The following variables will be summarized by cohort for Phase I part and by indication for 
Phase II part using descriptive statistics.

Exploration of change from baseline in pAKT from surrogate tissue (platelet rich 
plasma) during copanlisib treatment

Exploration of the time course of glucose metabolism markers (plasma glucose, 
insulin, and C-peptide) during copanlisib treatment

Exploration of change from baseline in plasma protein panel


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
Molecular status (genetic alterations, protein expression and / or activation) of 
biomarkers related to PI3K signaling in tumor tissue. Molecular status at progression 
may be assessed if a fresh tumor is collected at progression (optional).
Further exploratory statistical analyses may be performed and relationships between 
biomarker data and clinical outcome will be evaluated in a separate report. Biomarker 
variables and analyses will be further described in the SAP and/or in a separate document. 
10.3.4.7
Pharmacokinetics (PK)
All copanlisib concentration-time data collected during the study will be listed only.
10.4
Determination of sample size
Phase I part
The purpose of the Phase I part is to determine copanlisib single agent MTD in the pediatric 
population. No formal sample size calculation will be performed. Number of patients will 
depend on observed safety signal with 3-6 patients enrolled per cohort in the Rolling-6 study 
design. Approximately up to 42 patients will be enrolled and treated. A minimum of 50% of 
the enrolled and treated patients will be under the age of 12.
Phase II part
Simon's two-stage optimal design (30) will be used, for each of the four indications for Phase 
II separately. For all the indications, the null hypothesis that the true response rate (disease 
control rate for osteosarcoma) is 10% will be tested against a one-sided alternative. Per 
indication, the first stage will include 10 patients. After these no patients are accrued in that 
indication until decision for Stage 2 in that indication is made. If there is only one or no 
response (for osteosarcoma: one or no response/stable disease) in these 10 patients, the 
respective indication will be stopped (no start of respective Stage 2). Otherwise, 15 additional 
patients will be accrued into Stage 2 for a total of 25. The null hypothesis will be rejected if 5 
or more responses (disease controlled patients for sarcoma, respectively) are observed in 25 
patients. This design yields a per-indication type I error rate of 7.5% and power of 80% when 
the true response rate (disease control rate, respectively) is 30%.
In case of Stage 2 being reached for all four indications, the number of patients across all 
indications is 100 patients. Any over-recruitment, i.e. to more than 25 patients per indication, 
has to be avoided. A minimum of 80% of the enrolled and treated patients will be under the 
age of 18.
10.5
Planned interim analyses
Phase I part
Individual patient’s safety data will be reviewed without formal statistical analysis on an 
ongoing basis and before the dose escalation decision during the dose escalation phase. The 
DLTs, escalation or MTD status, and decision will be documented in a monitoring report.


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Phase II part
According to Simon 2-stage design, after 10 FAS patients per indication (neuroblastoma; 
osteosarcoma; rhabdomyosarcoma; Ewing sarcoma) will have been treated in Stage 1 for at 
least of 4 cycles, recruitment will be paused until decision for go/no-go into Stage 2. To 
support the go/no-go decision into Stage 2, Stage 1 data will be evaluated for ORR or DCR 
for respective indication. The evaluation will be based on a clean database of Stage 1 with 
cut-off date if the last patient of the respective indication has had the chance to complete 4 
cycles of treatment.
11.
Data handling and quality assurance
11.1
Data recording
The data collection tool for this study will be a validated electronic data capture system called 
RAVE. Patient data necessary for analysis and reporting will be entered/transmitted into a 
validated database or data system (CIE/TOSCA; SAS). 
Data required according to this protocol will be recorded by investigational site personnel via 
data entry into the internet based EDC software system RAVE, which Bayer has licensed 
from Medidata Solutions Worldwide. RAVE has been validated by Medidata Solutions 
Worldwide and Bayer for use in its clinical studies. RAVE allows for the application of 
software logic to set-up data entry screens and data checks to ensure the completeness and 
accuracy of the data entered by the site personnel. Bayer extensively applies the logic to 
ensure data are complete and reflect the clinical data requirements of the study. Data queries 
resulting from the application of the software logic are resolved by the site personnel. The 
data are stored at a secure host facility maintained by Medidata Solutions Worldwide and 
transferred on a periodic basis to Bayer's internal computer system via a secure Virtual Private 
Network.
All access to the RAVE system is through a password-protected security system that is part of 
the RAVE software. All internal Bayer and external investigator site personnel seeking access 
must go through a thorough RAVE training process before they are granted access to RAVE 
for use in Bayer's clinical studies. Training records are maintained.
All personnel with access to the RAVE system are supported by a Service Desk staffed with 
trained personnel to answer questions and ensure access is maintained such that data entry can 
proceed in a timely manner.
The RAVE System contains a system-generated audit trail that captures any changes made to 
a data field, including who made the change, why the change was made and the date and time 
it was made. This information is available both at the investigator’s site and at Bayer. Data 
entries made in the RAVE EDC screens are supported by source documents maintained for all 
patients enrolled in this study.


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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 (patient 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: 
o
The SAE itself
o
Concomitant medication
o
Medical history
o
Other information needed for SAE complementary page
11.2
Monitoring
In accordance with applicable regulations, GCP, and sponsor’s procedures, monitors will 
contact the site prior to the start of the study to review with the site staff the protocol, study 
requirements, and their responsibilities to satisfy regulatory, ethical, and sponsor’s 
requirements. When reviewing data collection procedures, the discussion will also include 
identification and documentation of source data items.


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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 pressure readings to support a 
diagnosis of hypertension). 

Safety and rights of patients are being protected

Study is conducted in accordance with the currently approved protocol 
(including study treatment being used in accordance with the protocol)

Any other study agreements, GCP, and all applicable regulatory requirements are met.
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents.
11.3
Data processing
Data will be collected as described in Section 11.1. Clinical data management will be 
performed in accordance with applicable sponsor’s standards and data cleaning procedures. 
This is applicable for data recorded on CRF as well as for data from other sources (e.g. IxRS, 
laboratory, ECG).
For data coding (e.g. AEs, medication), internationally recognized and accepted dictionaries 
will be used.
After its initial release for biometrical analysis, the clinical database is planned to be re-
opened for the inclusion of the following additional data: e.g. pharmacokinetic data, antibody 
data.
11.4
Missing data 
It should be underlined that the discontinuation of study treatment is not the equivalent to
withdrawal of informed consent. Additionally, withdrawal of consent does not withdraw
permission to collect vital status. Withdrawal of this consent must be made separately.
In general, missing data will not be imputed in this study. Every effort should be made to 
collect all data. All missing or partial data will be presented in the patient data listing as they 
are recorded on the Case Report Form (CRF).
11.5
Audit and inspection
To ensure compliance with GCP and regulatory requirements, a member of the sponsor’s (or a 
designated CRO’s) quality assurance unit may arrange to conduct an audit to assess the 
performance of the study at the study site and of the study documents originating there. The 
investigator/institution will be informed of the audit outcome.
In addition, inspections by regulatory health authority representatives and IEC(s)/IRB(s) are 
possible. The investigator should notify the sponsor immediately of any such inspection.


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The investigator/institution agrees to allow the auditor or inspector direct access to all relevant 
documents and allocate his/her time and the time of his/her staff to the auditor/inspector to 
discuss findings and any issues. Audits and inspections may occur at any time during or after 
completion of the study.
11.6
Archiving
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request.
Patient (hospital) files will be archived according to local regulations and in accordance with 
the maximum period of time permitted by the hospital, institution or private practice. Where 
the archiving procedures do not meet the minimum timelines required by the sponsor, 
alternative arrangements must be made to ensure the availability of the source documents for 
the required period.
The investigator/institution notifies the sponsor if the archival arrangements change 
(e.g. relocation or transfer of ownership).
The investigator site file is not to be destroyed without the sponsor’s approval.
The contract with the investigator/institution will contain all regulations relevant for the study 
center.
12.
Premature termination of the study
The sponsor has the right to close this study (or, if applicable, individual segments thereof 
[e.g. treatment arms; dose steps; centers]) at any time, which may be due but not limited to the 
following reasons: 

If risk-benefit ratio becomes unacceptable owing to, for example,
o
Safety findings from this study (e.g. SAEs)
o
Results of any interim analysis
o
Results of parallel clinical studies
o
Results of parallel animal studies 
(on e.g. toxicity, teratogenicity, carcinogenicity or reproduction toxicity).

If the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable time 
frame.
The investigator has the right to close his/her center at any time.


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For any of the above closures, the following applies:

Closures should occur only after consultation between involved parties. Final decision 
on the closure must be in writing.

All affected institutions (e.g. IEC(s)/IRB(s); competent authority(ies); study center; 
head of study center) must be informed as applicable according to local law.

All study materials (except documentation that has to remain stored at site) must be 
returned to the sponsor. The investigator will retain all other documents until 
notification is given by the sponsor for destruction.

In the event of a partial study closure, ongoing patients, including those in post study 
follow-up, must be taken care of in an ethical manner.
Details for individual patient's withdrawal can be found in Section 6.4.1.
13.
Ethical and legal aspects
13.1
Investigator(s) and other study personnel
Sponsor’s Medical Expert 
Name:
 M.D
Address:
100 Bayer Boulevard, P.O. Box 915
Whippany, NJ 07981-0915, USA
Phone:
Email:
Co-ordinating investigator: 
Name:
Margaret Macy, MD
Address: Center for Cancer and Blood Disorders
Children’s Hospital Colorado
13123 East 16th Avenue, Box 115
Aurora, CO 80045, USA
Phone:
Fax: 
Email:
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


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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 principal investigator of each center must sign the protocol signature page and must 
receive all required external approvals (e.g. health authority, ethics committee, sponsor) 
before patient recruitment may start at the respective center. Likewise, all amendments to the 
protocol must be signed by the principal investigator and must have received all required 
external approvals before coming into effect at the respective center.
A complete list of all participating centers and their investigators, as well as all required 
signature documents, will be maintained in the sponsor’s study file.
The global sponsor of this study is identified on the title page of this protocol. If required by 
local law, local co-sponsors will be nominated; they will be identified on the respective 
country-specific signature pages.
External data evaluation bodies
Data Monitoring Committee
A Data Monitoring Committee (DMC) will be established for Phase II of this study 
(according to a separate DMC charter) in order to ensure ongoing safety of study patients.
13.2
Funding and financial disclosure
Funding
This study will be funded by its sponsor.
Financial disclosure 
Each investigator (including principal and/or any sub investigators) who is directly involved 
in the treatment or evaluation of research patients has to provide a financial disclosure 
according to all applicable legal requirements. All relevant documentation will be filed in the 
trial master file.
13.3
Ethical and legal conduct of the study
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigator abide by 
Good Clinical Practice (GCP) guidelines and the guiding principles detailed in the 
Declaration of Helsinki. The study will also be carried out in keeping with applicable local 
law(s) and regulation(s).


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Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating 
centers/countries before start of the study, according to GCP, local laws, regulations and 
organizations. When necessary, an extension, amendment or renewal of the IEC/IRB approval 
must be obtained and also forwarded to the sponsor. The responsible unit (e.g. IEC/IRB, head 
of the study center/medical institution) must supply to the sponsor, upon request, a list of the 
IEC/IRB members involved in the vote and a statement to confirm that the IEC/IRB is 
organized and operates according to GCP and applicable laws and regulations.
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol. 
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties. However, the investigator or the sponsor may 
implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) 
to the trial patients without prior IEC/IRB/sponsor approval/favorable opinion. As soon as 
possible, the implemented deviation or change, the reasons for it and if appropriate the 
proposed protocol amendment should be submitted to the IEC/IRB/head of medical 
institution/sponsor. Any deviations from the protocol must be explained and documented by 
the investigator.
Details on discontinuation of the entire study or parts thereof can be found in Section 12.
13.4
Patient information and consent
All relevant information on the study will be summarized in an integrated patient information 
sheet and informed consent form provided by the sponsor or the study center. Separate patient
information sheets and assent forms for pediatric patients of different age groups will be 
created, taking into consideration local requirements for patient information sheet and 
informed consent/assent. When an adolescent is legally emancipated, i.e. ceases to be a minor, 
or reaches the legal age of consent, informed consent will be sought directly from him/her as 
soon as possible. In addition, patient’s development stage, intellectual capacities and 
life/disease experience will be taken into consideration when obtaining oral or written assent. 
A sample patient information and informed consent form and assent forms are provided as a 
document separate to this protocol.
Based on this patient information sheet, the investigator or designee will explain all relevant 
aspects of the study to each patient and/or parents / legal guardians, prior to his/her entry into 
the study (i.e. before any examinations and procedures associated with the selection for the 
study are performed or any study-specific data is recorded on study-specific forms).
The investigator will also mention that written approval of the IRB/IEC has been obtained.


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Each patient and/or parents / legal guardians will be informed about the following aspects of 
premature withdrawal:
Each patient has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision. 
The patient’s consent covers end-of-study examinations as specified in the visit 
description described in Section 9.2 to be conducted after withdrawal of consent. 
The patient’s data that have been collected until the time of withdrawal will be retained 
and statistically analyzed in accordance with the statistical analysis plan. 
Patient-specific data on the basis of material obtained before withdrawal may be generated 
after withdrawal (e.g. image reading, analysis of biological specimen such as blood, urine 
or tissues); these data would also be retained and statistically analyzed in accordance with 
the statistical analysis plan. The patient and/or parents / legal guardians have the right to 
object to the generation and processing of this post-withdrawal data. The patient’s and/or 
parents/legal guardians oral objection may be documented in the patient’s source data.
Each patient and/or parents / legal guardians will have ample time and opportunity to ask 
questions.
Only if the patient and/or parents / legal guardians voluntarily agrees to sign the informed 
consent form (and assent form, where applicable) and have done so, may the patient enter the 
study. Additionally, the investigator will personally sign and date the form. The patient and/or 
parents / legal guardians will receive a copy of the signed and dated form (and assent form, 
where applicable).
The signed informed consent statement and assent form are to remain in the investigator site 
file or, if locally required, in the patient’s note/file of the medical institution.
In the event that informed consent and assent form are obtained on the date that baseline study 
procedures are performed, the study record or patient´s clinical record must clearly show that 
informed consent and assent form were obtained prior to these procedures.
For minors or adults under legal protection, consent shall be given by the parents / legal 
guardian(s). The assent form of a minor or adult under legal protection shall also be requested 
where such a person is able to express his/her own will. His/her refusal or the withdrawal of 
his/her consent may not be disregarded.
The informed consent form and assent form and any other written information provided to 
patients and/or parents / legal guardians will be revised whenever important new information 
becomes available that may be relevant to the patient’s or parent’s / legal guardian’s consent, 
or there is an amendment to the protocol that necessitates a change to the content of the 
patient information and / or the written informed consent form and assent form. The 
investigator will inform the patient and/or parents / legal guardian of changes in a timely 
manner and will ask the patient and/or parents (or legal guardians) to confirm patient’s 
participation in the study by signing the revised informed consent form (and assent form, 
where applicable). Any revised written informed consent form, assent form and written 
information must receive the IEC/IRB`s approval / favorable opinion in advance of use.


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13.5
Publication policy and use of data
The sponsor has made the information regarding the study protocol publicly available on the 
internet at www.clinicaltrials.gov. 
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. 
13.6
Compensation for health damage of patients / insurance
The sponsor maintains clinical trial insurance coverage for this study in accordance with the 
laws and regulations of the country in which the study is performed.
13.7
Confidentiality
All records identifying the patient will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available.
Patient names will not be supplied to the sponsor. Only the patient number will be recorded in 
the CRF, and if the patient name appears on any other document (e.g. pathologist report), it 
must be obliterated before a copy of the document is supplied to the sponsor. Study findings 
stored on a computer will be stored in accordance with local data protection laws. As part of 
the informed consent process, the patients will be informed in writing that representatives of 
the sponsor, IEC/IRB, or regulatory authorities may inspect their medical records to verify the 
information collected, and that all personal information made available for inspection will be 
handled in strictest confidence and in accordance with local data protection laws.
If the results of the study are published, the patient’s identity will remain confidential.
The investigator will maintain a list to enable patients to be identified.


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14.
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15.
Protocol amendments
15.1
Amendment 1
Amendment 1 is a global amendment dated 04 APR 2019.
15.1.1
Overview of changes
Overall Rationale for the Amendment
The primary driver of this protocol amendment is the amendment to DLT criteria. Under the 
previous version of the protocol, DLTs were not graded based on clinical significance of the 
AE but rather on numerical values (e.g. lab values that were not considered clinically 
significant enough to be considered truly dose-limiting) and both Sponsor and investigators 
considered that it was not reflective of the true safety profile of the study drug.  Therefore, 
this amendment revises the DLT criteria to reflect what would be considered truly dose-
limiting maintaining the safety of the patients but allowing for more flexibility to dose 
patients in this population of high unmet medical need.  Additional changes were made to 
make the dose modification consistent with the updated DLT criteria.  
Protocol Amendment Summary of Changes Table
Section # and Name
Description of Changes
Brief Rationale
5.2 Phase I dose escalation 
design
7.4.1.3 Definition of dose-
limiting toxicities
Clarified which dose level of 
study drug should be used if 
DLT criteria are changed.
When DLT criteria change, it is logical 
to enroll at the previous dose level prior 
to the change since safety profile and 
number of DLTs may be significantly 
different under the new criteria.
Multiple modifications to 
criteria to more accurately 
classify DLTs
To avoid inconsistencies with dose 
modification guidance, to avoid rapidly 
reversible and manageable toxicities be 
categorized as DLTs, and to assure
consistency with dose criteria and 
amended time window allowed before 
mandating omission of study drug dose.
7.4.3.1
Dose-limiting 
hematological and non-
hematological toxicity
6.4.1 Withdrawal
The dose modification tables for 
dose-limiting hematological and 
non-hematological toxicity were 
removed.
To make dose modifications for AEs 
consistent regardless of whether the AEs 
are DLTs or non-DLTs.
6.1 Inclusion criteria
6.2 Exclusion criteria
Changed inclusion criterion for 
duration of agreement to use 
contraception after last 
administration of study drug.
Alignment with updated product label. 
Addition of sub-heading in 
inclusion criterion #4.
For additional clarity on which parts of 
the study this applies to.


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Section # and Name
Description of Changes
Brief Rationale
Inclusion criterion #7:
Addition of maximum glucose 
threshold
Modifications to AST/ALT and 
ALP criteria
Maximum serum glucose threshold 
(based on a generalized ULN for the 
normal population) set to prevent 
patients who are predisposed to 
hyperglycemia issues (e.g. glucose 
intolerance).
To avoid inconsistencies with the DLT 
criteria and to clarify that bone 
metastasis can also elevate ALP levels. 
Addition of neuroblastoma to 
exclusion criterion #7 and 
anemia to exclusion criterion 
#18.
For consistency with the inclusion 
criteria.
6.4.1 Withdrawal
The withdrawal criteria were 
edited. 
Changed the time window of 
30+5 days for reporting deaths 
in the study.
Text was edited to be consistent with 
dose modification guidelines in treatment 
sections and to simplify the protocol. 
The safety data is collected up to 30 days 
after the last dose (not 30 +5 days) 
although the safety FU visit occurs 
during a window of 30+5 days to provide 
flexibility in scheduling a visit.
7.4 Dosage and 
administration
Dosing criteria (lab-based) were 
edited.
Time window for dose delay 
before mandating 
discontinuation of study drug 
was expanded.
Removal of INR from the list of 
laboratory assessments to be 
performed prior to each dose.
To avoid inconsistencies with dose 
modification guidelines and DLT criteria 
(primarily serum glucose, lipase, and 
amylase) and to clarify.   
To add flexibility to deliver doses within 
a cycle in a safe manner while still 
providing a maximum delay in dosing 
(28 days) and to avoid rapidly reversible 
and manageable toxicities to be 
categorized as DLTs since omission of a 
dose is technically dose-limiting.
For consistency with existing text as INR 
will be performed on Day 1 of each
cycle.


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Section # and Name
Description of Changes
Brief Rationale
7.4.3.2 Hematological 
toxicity
7.4.3.3 Non-Hematological 
toxicity
7.4.3.3.3Glucose increases
7.4.4.1
Management of 
transient post-infusion 
glucose increases that can 
occur with study treatment
Various minor edits to dose 
modification tables.
To assure consistency with amended 
dosing criteria and amended time 
window allowed before mandating 
omission of study drug dose.  Most 
notably, the hyperglycemia management 
table was modified to be based on the 
approved FDA label guidance with some 
modifications to reduce inconsistencies 
with the rest of the protocol (dosing 
criteria, DLT criteria).
8.1 Prior and concomitant 
therapy
Added criterion to refrain the 
use of biotin to prohibited 
concomitant therapy.
This addition is in line with FDA Safety 
communication/recommendations on the 
use of biotin. High levels of biotin can 
interfere with the result of the 
immunoassay test.
Clarified when therapeutic anti-
coagulation is permitted
There is no known interaction with any 
of the anticoagulant medications and 
copanlisib. However, any concurrent 
anticoagulant use should be based on 
medical judgement of the treating 
physician considering thrombocytopenia 
has been reported with copanlisib.
9.1 Tabular schedule of 
evaluations, Table 9-1 
9.2.1.1 Screening period
9.4.1 Radiological tumor 
assessments
9.2.1.3 Tumor assessments
9.2.1.4 End-of-treatment 
visit
9.4.1 Radiological tumor 
assessments.
Ewing sarcoma patients are not 
mandated to have a bilateral 
bone marrow biopsy and/or 
bone marrow aspiration.
Agreement with investigators and 
following standard of care in this patient 
population.
Clarified the schedule of bone 
marrow biopsy and/or bone 
marrow aspiration during the 
study treatment.
For additional clarity.
7.4 Dosage and 
administration
7.4.3.3.4 Arterial 
hypertension
9.1 Tabular schedule of 
evaluations, Table 9-1 
9.2.1.2.1 Treatment –
Updated blood pressure 
measurement language to be in 
line with new copanlisib 
hypertension guidance. Added 
guidance for patients > 18 years 
old.
Changes were made to reflect updated 
copanlisib safety information pertaining 
to potential drug-related transient blood 
pressure increases and feedback from 
investigators/lymphoma specialists 
regarding hypertension monitoring and 
management to make the process more 
feasible without compromising patient 
safety.


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Section # and Name
Description of Changes
Brief Rationale
Cycle 1
9.2.1.2.2 Treatment –
Cycle 2 and higher
9.6.3.9
Glucose 
measurement on infusion 
days
9.6.3.4.1 Blood pressure 
measurement on infusion 
days
Clarified glucose measurement 
language and added a time-
window for the pre-dose 
glucose measurement.
For clarity and based on feedback from 
the investigators.
9.1 Tabular schedule of 
evaluations, Table 9-1 
9.2.1.1 Screening period
9.2.1.2.1 Treatment –
Cycle 1
9.2.1.2.2 Treatment –
Cycle 2 and higher
9.2.1.4
End-of-treatment 
visit
9.6.3.5 Electrocardiogram
Added an option to use 15-lead 
ECG.
Addition to reflect standard of care 
procedure in this population.
9.1 Tabular schedule of 
evaluations, Table 9-1 
9.2.1.1
Screening period
9.2.1.5.1 Active follow-up
9.6.3.3
Growth and dental 
exams
Correction of naming of 
procedure which reflects that a 
dentition examination does not 
need to be performed by a 
dentist. Changed the timing of 
this procedure at screening.
To reflect standard of care in this 
population.
9.1 Tabular schedule of 
evaluations, Table 9-1 
9.2.1.1 Screening period
9.2.1.4
End-of-treatment 
visit
Clarified that, for patients > 1 
year and < 6 years old, blood for 
biomarker analysis should be 
collected at -28 day visit.
Corrected inconsistency in the 
plasma sampling at EOT.
For consistency with body protocol text.
9.2.1.1 Screening period
9.4.1. Radiological tumor 
assessments
Removal of the requirement to 
assess all anatomical areas 
specified in all patients.
As per investigator feedback, 
radiological assessment should be 
performed only of the primary tumor 
location area, thus minimizing radiation 
exposure to a vulnerable patient 
population.
9.2.1.1 Screening period
Modified text regarding the 
procedures performed pre-
informed consent in the 
screening period section for 
To allow for results of any procedure 
performed pre-consent as part of 
standard of care patient assessment to be 
used for study screening purposes, if 
performed within the required window / 


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Section # and Name
Description of Changes
Brief Rationale
clarification.
to the required standards.  Also to 
minimize unnecessary blood draws from 
this vulnerable patient population.
9.6.3.8 Laboratory 
examinations
Addition of BUN as alternative 
to urea in chemistry panel.
To allow more flexibility for sites 
assessing at local laboratory facilities.
9.1 Tabular schedule of 
evaluations, Table 9-1 
9.2.1.2.1 Treatment – Cycle 
1
9.2.1.2.2 Treatment – Cycle 
2 and higher
9.6.3.2
Body weight, 
height and BSA calculation
Removal of BSA calculation 
from visits other than C1D1
Dosing not typical to change mid-cycle, 
so BSA calculation is unnecessary.
2 Synopsis
10.2 Analysis sets
10.3.1.2 Primary efficacy 
variable for Phase II
10.3.4 Statistical and 
analytical plans
10.3.4.1 Demographic and 
other baseline characteristics
10.3.4.2 Primary efficacy 
(Phase II only)
10.3.4.3 Secondary efficacy
10.3.4 Statistical and 
analytical plans
Removal of the per protocol set 
(PPS) from planned statistical 
analysis for Phase II efficacy 
endpoints.
Clarification of the primary 
efficacy analysis.
Correction of timing of final 
analysis.
The reason to not use PPS in this study 
from a statistical perspective is that PPS 
is intended to identify a treatment effect 
which would occur under optimal 
conditions without any major protocol 
deviation and non-availability of primary 
endpoint. After the adult study, it is 
unlikely that there will be a major 
difference between the two populations.
In addition, the data following the more 
conservative FAS/ITT concept are
considered more useful for further 
clinical development. Patients who have 
progressive disease prior to 4 cycles will 
be considered fully evaluable for 
response and included in the efficacy 
analyses.
Consistency with related protocol 
sections.
1. Title page 
Signature of the sponsor’s 
medically responsible person
13.1 Investigator(s) and 
other study personnel 
Changes regarding the sponsor’s 
medical expert and sponsor’s 
medically responsible person.
Due to personnel change and 
reorganization of sponsor’s medical team 
information was updated.
3.1.4 Clinical experience
3.3 Benefit-risk assessment
Updated the number of patients 
treated with copanlisib.
Updated information.


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Section # and Name
Description of Changes
Brief Rationale
16.1 Pregnancy information 
form
6.2 Exclusion criteria
Removal of the pregnancy 
information form.
Incorrect version included in error.
Throughout
Minor editorial and document 
formatting revisions
Minor, therefore have not been 
summarized
15.1.2
Changes to the protocol text
Changes to the protocol text are provided in a separate track changes version.
15.2
Amendment 2
Amendment 2 is a global amendment dated 05 MAY 2020.
15.2.1
Overview of changes
Overall Rationale for the Amendment
The primary driver of this protocol amendment is to allow for additional enrollment of 
younger patients (<12 years old), if needed, after MTD and RP2D determination in order to 
assure that there is adequate data to characterize safety and pharmacokinetics in younger 
patients before moving onto phase II. In addition, this will further help to ensure that the 
requirement outlined under Section 10.4 that at least 50% of patients enrolled and treated will 
be under 12 years of age is fulfilled for the Phase I part. Additional changes in this 
amendment include clarifications in the eligibility criteria and allowable washout periods of 
prior therapies, resolution of inconsistencies and technical errors, and editorial updates.
Protocol Amendment Summary of Changes Table
Section # and Name
Description of Changes
Brief Rationale
5.2 Phase I dose escalation 
design
10.4 Determination of 
sample size
Synopsis
Added description for 
enrollment of additional patients 
(< 12 years old) to acquire PK 
data once the MTD or 
recommended Phase 2 dose has 
been defined and updated the 
number of patients.
To ensure that at least 50% of dose 
escalation patients are <12 years old per 
FDA requirement.
6.1 inclusion criteria
Modification of description of 
measurable vs. evaluable 
Clarification of the acceptance of 
measurable vs. evaluable disease in Part I 


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Section # and Name
Description of Changes
Brief Rationale
Synopsis
disease.
and Part II.
6.2 Exclusion criteria
Previous anti-cancer 
immunosuppressive treatment 
defined more specifically as 
exclusion criteria and 
immunotherapy and/or 
chemotherapy removed from 
“Excluded previous therapies”.
To remove the discrepancy that 
chemotherapy washout was listed as “28 
days or 5 half-lives” in one exclusion 
criteria, but as “4 weeks” in another 
exclusion criteria, and to consolidate the 
description of allowable washout periods 
of prior therapies.
7.4.1 Dosage – Phase I part
7.4.3 Dose modifications
8.1 Prior and concomitant 
therapy
Consistency ensured throughout 
the protocol that G-CSF can be 
used when ANC < 500 + sepsis 
or culture-negative sepsis.
Clarification of the use of G-CSF when 
ANC<500.
10.5 Planned interim 
analyses
Removal of language regarding 
the treatment of overrun 
patients.
Language was considered unnecessary in 
regard to conduct of the study and can be 
dealt with in the context of supportive 
documents such as the Statistical 
Analysis Plan (SAP).
10.3.1.2 Primary efficacy 
variable for Phase II 
10.3.2.1 Efficacy variables
The survival time was defined 
to begin from the first intake of 
study drug instead of 
enrollment.
Correction of the definitions of endpoints 
(PFS and OS) for statistical analysis to
align with SAP v1.0.
10.3.4.4 Safety
Specified the safety analysis of 
patients enrolled in the PK 
group.
To clarify that the patients enrolled in the 
PK group are evaluated with Phase I 
cohorts.
9.5 Pharmacokinetics / 
pharmacodynamics
Table 9-2
Corrected a technical error.
Technical error, table continued on the 
next page with a wrong table heading for 
the patients Age < 6 years. Should not
have stated "≥ 6 years", but < 6 years.
Throughout the protocol.
Changed “patients enrolled” 
into “patients enrolled and 
treated” where applicable.
To avoid the misinterpretation that 
enrolled would represent only patients 
who signed informed consent but did not 
go on to be treated.  This would support 
the intent of several regulatory 
documents that use the term “enrolled” 
with the assumption that the vast 
majority, if not all, of enrolled patients 
were treated and had evaluable safety 
and efficacy data.
Signature of the sponsor’s 
medically responsible person
Added a statement about the 
eSignature process.
Administrative change to describe the 
electronic signing of the document.


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15.2.2
Changes to the protocol text
Changes to the protocol text are provided in a separate track changes version. In addition to 
the changes above, other changes were made to update administrative details, and correct 
typographical errors.
16.
Appendices
16.1
RECIST v.1.1
Response and progression will be evaluated in this study using the RECIST, version 1.1. 
Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are 
used.
Measurable disease:
Tumor lesions: Measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) with a minimum size of:
10 mm by CT scan (CT scan slice thickness no greater than 5 mm) or MRI. If scans with slice 
thicknesses greater than 5 mm are used, the minimum size should be twice the slice thickness.
10 mm caliper measurement by clinical examination (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable)
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed.
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components that 
can be evaluated by CT or MRI, can be considered as measurable lesions if the soft tissue 
component meets the definition of measurability.
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). Tumor lesions situated in a previously irradiated area are not considered 
measurable unless there has been demonstrated progression in the lesion.
Non-measurable disease:
All other lesions (or sites of disease), including small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥10 to < 15 mm short axis) are considered non-measurable 
disease. Leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitic 
involvement of skin or lung, abdominal masses/ abdominal organomegaly identified by 
physical examination that is not measurable by reproducible imaging techniques and blastic 
bone lesions are all non-measurable.
Target lesions:
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs should be identified as target lesions and be recorded 
and measured at baseline. These 5 lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs and should be suitable for 


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reproducible repeated measurements. A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters. The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression of the measurable dimension of the disease. If 
there are > 5 measurable lesions, those not selected as target lesions will be considered 
together with non-measurable disease as non-target lesions.
Non-target lesions:
All non-measurable lesions (or sites of disease) plus any measurable lesions over and above 
the 5 listed as target lesions. Measurements are not required but these lesions should be noted 
at baseline and should be followed as “present”, “absent” or in rare cases “unequivocal 
progression”.
Best Response
All patients will have their BEST RESPONSE on study classified as outlined below:
Complete Response (CR): Disappearance of all clinical and radiological evidence of tumor 
(both target and non-target). Any pathological lymph nodes (whether target or non target) 
must have a reduction in short axis to < 10 mm.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions 
taking as reference the baseline sum, no unequivocal progression of existing non target 
lesions and no appearance of new lesions.
Stable Disease: Steady state of disease. Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for progressive disease (PD), no unequivocal progression of 
existing non target lesions and no appearance of new lesions.
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. Unequivocal progression of existing non target lesions 
or the appearance of one or more new lesions will also constitute progressive disease.


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Table 16–1 Response for patients with target and non-target lesions
Target 
lesions
Non-target 
lesions
New lesions
Overall 
response
Best response 
for this category also requires
CR
CR
No
CR
Two objective status determinations of 
CR (not less than 4 weeks apart) 
before progression 
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
Two determinations of PR or better 
(not less than 4 weeks apart) before 
progression, but not qualifying for CR
Stable 
disease
Non-PD or not all 
evaluated
No 
Stable 
disease
Documented at least > 6 weeks from 
baseline
Not all 
evaluated
Non-PD
No 
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR=complete response, NE=not evaluable, PR=partial response, PD=progressive disease
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration”. Every effort should be made to document the objective progression even after 
discontinuation of treatment
Table 16–2 Response for patients with non-target lesions only
Non-target lesions
New lesions
Overall response
CR
No
CR
Non-CR/non-PD
No
Non-CR/Non-PD a
Not evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR=complete response, NE = not evaluable, PD=progressive disease
a Non-CR/non-PD is preferred over “stable disease” for non-target disease.
Method of measurement
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.
Clinical Lesions - Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules, palpable lymph nodes) and ≥10mm diameter as assessed using 
calipers. For the case of skin lesions, documentation by color photography including a ruler to 
estimate the size of the lesion is recommended.


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CT/MRI - CT is the best currently available and reproducible methods to measure target 
lesions selected for response assessment. CT scans should be performed with cuts of 5 mm or 
less in slice thickness. When CT scans have slice thickness greater than 5 mm, the minimum 
size for a measurable lesion should be twice the slice thickness. MRI is also acceptable. This 
applies to the chest, abdomen and pelvis. Head & neck and extremities usually require 
specific protocols.
16.2
SIOPEN scoring method
SIOPEN scoring method for neuroblastoma patients with osteomedullary disease is based on 
the Criteria for Evaluation of Disease Extent by (123)I-metaiodobenzylguanidine Scans in 
Neuroblastoma (27).
Owing to the high specificity and sensitivity in neuroblastoma, 123I-MIBG imaging has 
superseded the use of 99mTc -technetium bone scans for the detection of skeletal metastases 
in the majority of children with neuroblastoma, which take up the tracer in 90% of cases, and 
has been recommended by the last international consensus conference as a standard element 
of staging and response evaluation The SIOPEN score is the current method being used in 
Europe under prospective evaluation in a phase III trial. 
In this method, the skeletal distribution of MIBG was recorded in 12 anatomical body 
segments as follows: skull, thoracic cage, proximal right upper limb, distal right upper limb, 
proximal left upper limb, distal left upper limb, spine, pelvis, proximal right lower limb, distal 
right lower limb, proximal left lower limb and distal left lower limb (Figure 16–1). 
Figure 16–1 123-MIBG scoring SIOPEN-method


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(C) 123I-MIBG scoring SIOPEN-method 3: method 3 divides the skeleton into 12 anatomic 
segments. The extension score for method 3 is graded as: 0, no sites per segment, 1, one 
discrete site per segment; 2, two discrete lesions; 3, three discrete lesions; 4, > 3 discrete foci 
or a single diffuse lesions involving < 50% of a bone; 5, diffuse involvement of > 50–95% 
whole bone; 6, diffuse involvement of the entire bone.
The extent and pattern of skeletal MIBG involvement was scored using a 0–6 scale to 
discriminate between focal discrete lesions and patterns of more diffuse infiltration. Each 
segment is scored as 0, no involvement; 1, one discrete lesion; 2, two discrete lesions; 3, three 
discrete lesions; 4, > 3 discrete foci or a single diffuse lesion involving < 50% of a bone; 
5, diffuse involvement of > 50 to 95% whole bone; 6, diffuse involvement of the entire bone, 
with a maximum score of 72. This method showed 95% concordance in a blinded review by 
six nuclear medicine physicians. 
Response criteria according to the SIOPEN score:
The absolute score is obtained by adding the scores of all the segments. The relative score is 
calculated by dividing the absolute score at each time by the corresponding pretreatment 
overall score. The relative score will be considered for response evaluation:

Complete response: relative score of 0

Partial response: relative score of ≤ 0.5 

Stable disease: relative score > 0.5 to ≤ 1

Progressive disease: relative score > 1 (appearance of new lesions)


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16.3
Curie scoring method
CURIE score is based on the presence of MIBG uptake in multiple anatomic regions. 
Ten different sites are scored, including 9 skeletal sites as follows: the head and the face 
(area 1) the neck and back vertebral column (area 2), the ribs and the sternum (area 3), 
the lumbar and sacral column (area 4), the pelvis (area 5), the arms (area 6), the fore-
arms and the hands (area 7), the thighs (area 8), the legs and the feet (area 9). The tenth 
site is related to any kind of soft-tissue lesions.
Skeletal sites are individually scored from 0 to 3 as follows: 
0, no MIBG involvement;
1, one MIBG-avid lesion present; 
2, more than one MIBG-avid lesion present;
3, MIBG avidity present in > 50% of an individual site. 
Soft-tissue lesions are scored as follows: 
0, no MIBG involvement; 
1, one MIBG-avid soft-tissue lesion present; 
2, more than one MIBG-avid soft-tissue lesion present; 
3, MIBG avidity in a soft-tissue lesion that occupied > 50% of the chest or abdomen.    


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A patient’s Curie score at each time point is calculated as the sum of scores over all individual 
sites, with a maximum score of 30.
MIBG based Response Criteria:

Complete response (CR): MIBG score = 0

Partial response (PR): relative score of ≤ 0.5 - >= 50% reduction in MIBG score

Stable disease (SD): relative score > 0.5 to ≤ 1 – (≤ 50% reduction in score)

Progressive disease (PD): relative score > 1 (appearance of new lesions) – increase in 
score


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16.4
Performance status scales/scores
Table 16–3 Lansky-Play Scale conversion to Karnofsky
Lansky Play Performance Scale
Karnofsky Performance Status
100 
Fully active, normal
100
Normal, no complaints; no evidence of 
disease
90
Minor restrictions in physically 
strenuous activity
90
Able to carry on normal activity; minor 
signs or symptoms of disease
80
Active, but tires more quickly
80
Normal activity with effort, some signs or 
symptoms of disease
70
Both greater restriction of, and less 
time spent in, active play
70
Cares for self but unable to carry on 
normal activity or to do work
60
Up and around, but minimal active 
play; keeps busy with quieter 
activities
60
Requires occasional assistance but is 
able to care for most of personal needs
50
Gets dressed, but lies around much 
of the day; no active play; able to 
participate in all quiet play and 
activities
50
Requires frequent assistance and medical 
care
40
Mostly in bed; participates in quiet 
activities
40
Disabled; requires special care and 
assistance
30
In bed; needs assistance even for 
quiet play
30
Severely disabled; hospitalization is 
indicated although death not imminent
20
Often sleeping; play entirely limited to 
very passive activities
20
Very ill; hospitalization and active 
supportive care necessary
10
No play; does not get out of bed. 
Moribund
10
Moribund, fatal processes progressing 
rapidly
0
Unresponsive. Dead.
0
Unresponsive. Dead. 


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16.5
Blood sampling in pediatric patients
According to the European guideline (28), blood loss should not exceed 3% of total blood 
volume over four weeks, and it should not exceed 1% of total blood volume at any single time. 
The total volume of blood is estimated at 80 to 90 mL/kg body weight; 3% is 2.4 mL blood 
per kg body weight. Table 16–4 shows the acceptable blood volumes for different age ranges. 
Table 16–4 Age ranges and corresponding volume limits for blood sampling
Whole blood 
volume (mL/kg)
Mean body 
weight (kg)
Whole blood 
volume (mL)
3% (mL)
1% (mL)
Infant, 6 months
86
7.85
675
20.3
6.7
Infant, 12 months
80
10.1
808
24.2
8.1
Children, 6 years
80
20.6
1648
49.4
16.5
Children, 10 years
75
32.6
2445
73.4
24.5
Adolescent, 15 years
71
54.3
3855
115.7
38.6


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16.6
Blood pressure levels for children by age and height percentile
Table 16–5 Blood pressure levels for boys by age and height percentile


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Table 16–6 Blood pressure levels for girls by age and height percentile


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Figure 16–2 Age-specific percentiles for blood pressure in boys (a) and girls (b) from birth to 
12 months of age


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16.7
Hypertension
Hypertension is defined as average systolic blood pressure (SBP) and/or diastolic blood 
pressure (DBP) that is greater than or equal to the 95th percentile for sex, age, and height on 
three or more occasions (please refer to Table 16–5 and Table 16–6) for children from 1 to 
17 years old, and Figure 16–2 for infants from birth to 12 months old).
Prehypertension in children is defined as average SBP or DBP levels that are greater than or 
equal to the 90th percentile, but less than the 95th percentile. Any adolescent (≥12 years)
whose blood pressure is greater than 120/80 mmHg is also given this diagnosis, even if the 
blood pressure is below the 90th percentile. 
Table 16–7 Recommended dimensions for blood pressure cuff bladders
Age range
Width (cm)
Length (cm)
Max. arm circumference (cm) a
Newborn
4
8
10
Infant
6
12
15
Child
9
18
22
Small adult
10
24
26
Adult
13
30
34
Large adult
16
38
44
Thigh
20
42
52
a Calculated so that the largest arm would still allow the bladder to encircle arm at least 80%
16.8
NCI-CTCAE
This study will use the NCI-CTCAE version 4.03 for toxicity and AE reporting. A copy can 
be downloaded from the Cancer Therapy Evaluation Program home page 
(http:ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm) 
All appropriate treatment areas should have access to a copy of the NCI-CTCAE version 4.03.


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No.  BAY 80-6946 / 19176
05 MAY 2020
Version: 3.0
Page: 131 of 134
16.9
Modified Ross Heart Failure Classification for Children
Table 16–8 Modified Ross Heart Failure Classification for Children
Class I
Asymptomatic
Class II
Mild tachypnea or diaphoresis with feeding in infants
Dyspnea on exertion in older children
Class III
Marked tachypnea or diaphoresis with feeding in infants
Marked dyspnea on exertion
Prolonged feeding times with growth failure
Class IV
Symptoms such as tachypnea, retractions, grunting, or diaphoresis at rest
Source: (31)
16.10
Serum creatinine based on age/gender
A serum creatinine based on age/gender as follows:
Age
Maximum Serum Creatinine (mg/dL)
Male
Female
6 months to < 1 year
0.5
0.5
1 to < 2 years
0.6
0.6
2 to < 6 years
0.8
0.8
6 to < 10 years
1
1
10 to < 13 years
1.2
1.2
13 to < 16 years
1.5
1.4
≥ 16 years
1.7
1.4
The threshold creatinine values in this Table were derived from the Schwartz 
formula for estimated GFR (32) utilizing child health and stature data 
published by the CDC.


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05 MAY 2020
Version: 3.0
Page: 132 of 134
16.11
Evaluation of tumor response in lymphomas (Phase I part)
In patients with lymphoma, tumor response will be evaluated according to modified
Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and 
Non-Hodgkin Lymphoma: The Lugano Classification (25).
Target lesions
(nodal)
Target lesions
(extranodal)
Non-target
lesions
Spleen
New lesion
Bone marrow
CR
All normal
(LDi ≤ 1.5 cm)
All disappeared
All normal
Normal size for age
No
Normal by 
morphology
If not assessable:
IHC and/or PCR 
negative
PR
Decrease ≥ 50% in the SPD from 
baseline
All normal 
or stable
Spleen must have 
regressed by 50% in 
extent beyond normal at 
baseline 
No
Not relevant
SD
Decrease < 50% in the SPD 
from baseline
No criteria for PD
All normal 
or stable
Normal size for age or 
stable size (not meeting 
criteria for PR or PD)
No
Not relevant
PD
Individual node/lesion:
LDi > 1.5 cm 
AND
Increase ≥ 50% in the PPD from 
nadir 
AND
Increase in LDi or SDi from 
nadir *
≥ 0.5 cm for lesions ≤2 cm 
≥ 1.0 cm for lesions > 2 cm
New 
or increased
New splenomegaly: 
the splenic length must 
increase ≥ 2 cm from 
baseline length
Recurrent 
splenomegaly:
the splenic length must 
increase ≥ 2 cm from 
nadir length 
Progressive 
splenomegaly:
the splenic length must 
increase by > 50% of 
the extent beyond 
normal at baseline  and 
must increase ≥1 cm in 
total vertical length
Yes:
New node > 1.5 cm 
in any axis
New extranodal site 
> 1.0 cm in any axis 
(if < 1.0 cm in any 
axis its presence 
must be unequivocal 
and must be 
attributable to 
lymphoma)
New or recurrent 
involvement
CR = complete response; IHC = Immunohistochemistry; LDi = longest diameter; PD = progressive disease; PPD = product of 
perpendicular diameters; PR = partial response; SD =stable disease; SDi = shortest diameter; SPD = sum of the product of 
the diameters
* If* LDi ≤ 2 cm at nadir, absolute increase required for any diameter (LDi or SDi) will be 0.5 cm; if LDi > 2 cm at nadir, absolute 
increase required for any diameter (LDi or SDi) will be 1.0 cm.
Note: In case the patient has only diffuse spleen involvement with splenomegaly careful evaluation of the spleen should be 
performed as the overall response will be driven by the response for splenomegaly, unless any non-target lesion(s) or a 
target lesion shows progression or a new lesion/new or recurrent involvement of bone marrow is present. 


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Criteria for PET-CT response assessment (for lymphomas)
Target 
Lesions 
(Nodal)
Target lesions 
(Extranodal)
Non target lesions
Spleen
New lesions
Bone marrow
CMR
Score 1, 2, or 3 with or without 
a residual mass on 5PS* 
N/A
N/A
None
No evidence of 
FDG-avid disease 
in marrow
PMR
Score 4 or 5 with reduced 
uptake compared with baseline 
and residual mass(es) of any 
size
At interim, these findings 
suggest responding disease; at 
end of treatment, these findings 
indicate residual disease
N/A
N/A
None
Residual uptake 
higher than uptake 
in normal marrow 
but reduced 
compared with 
baseline (diffuse 
uptake compatible 
with reactive 
changes from 
chemotherapy 
allowed)
NMR 
Score 4 or 5 with no significant 
change in FDG uptake from 
baseline at interim or end of 
treatment
N/A
N/A
None
No change from 
baseline
PMD
Individual target nodes/nodal
masses
Score 4 or 5 with an increase in 
intensity of uptake from baseline 
and/or 
Extranodal lesions
new FDG-avid foci consistent 
with lymphoma at interim or end-
of-treatment assessment 
None
N/A
New FDG-avid foci 
consistent with lymphoma 
rather than another etiology 
(e.g. infection, 
inflammation). If uncertain 
regarding etiology of new 
lesions, biopsy or interval 
scan may be considered
New or recurrent 
FDG-avid foci
CMR= complete metabolic response; FDG = Fluorodeoxyglucose; N/A = not applicable; PMR= partial metabolic 
response; NMR= no metabolic response, equivalent with stable disease; PMD= progressive metabolic 
disease, equivalent with progressive disease
Note: 
• Most avid lesion will determine final score whereas volume/overall uptake and/or intensity of uptake of lesions 
should also be considered for response assessments.
• PET-avid lesions must have a minimum score of 4 at baseline in order to be called “PET positive”.
• Only lesions with a score ≥ 4 can be considered a valid measurable target lesion if CT scan is available. 
• Lesions with score 1, 2 or 3 are considered “PET negative” and do not qualify for target lesion at baseline
• PET negative patients at BL with a positive histology must be followed-up with CT scan only.
For further details refer to the Imaging Manual.
* 5PS= 5 point score for the visual assessment of PET-CT:
Score 1 = no uptake above background
Score 2=uptake ≤ mediastinum
Score 3 =uptake > mediastinum but ≤ liver
Score 4 = uptake moderately > liver
Score 5=uptake markedly higher than liver and/or new lesions 
Score X= new areas of uptake unlikely to be related to NHL


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Response assessment based on CT/MRI and PET-CT scans.
Note: a PET-CT response overrides in most cases the response by CT and/or MRI alone: e.g. 
if PET-CT response = CMR and CT/MRI response = PR, overall response is CR (for further 
details refer to the Imaging Manual).
16.12
CYP3A4 inhibitors and inducers 
A list of strong inhibitors and inducers of CYP3A4 (prohibited) is shown below.
Strong CYP3A4 inhibitors
Boceprevir, clarithromycin, conivaptan, grapefruit juice, 
indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, 
mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, 
saquinavir, telaprevir, telithromycin, voriconazole, atazanavir, 
tipranavir, troleoandomycin, elvitegravir, danoprevir, 
conivaptan, boceprevir, suboxone and cobicistat
Strong CYP3A4 inducers
Avasimibe, carbamazepine, mitotane, phenobarbital, 
phenytoin, rifabutin, rifampin (rifampicin), St. John's wort 
(hypericum perforatum) and enzalutamide
CYP3A4 = Cytochrome P450 isoenzyme 3A4
Source: 33, 34, 35 and 36.

SAP_001.pdf: 
Statistical Analysis Plan
Protocol No.: BAY 80-6946 / 19176
Page: 1 of 24
Title page
A non-randomized, open-label, multi-center, Phase I/II study of PI3K 
inhibitor copanlisib in pediatric patients with relapsed/refractory solid 
tumors or lymphoma
Safety, tolerability, efficacy and pharmacokinetics of copanlisib in pediatric patients
Bayer study drug
BAY 80-6946 / Copanlisib
Study purpose:
Maximum tolerated dose (MTD) finding, safety and activity
Clinical study 
phase:
Phase 1/2
Date:
06 AUG 2019
Study No.:
19176
Version:
1.0
Author:
 
Confidential
The information provided in this document is strictly confidential and is intended solely 
for the guidance of the clinical investigation. Reproduction or disclosure of this document,
whether in part or in full, to parties not associated with the clinical investigation or its use 
for any other purpose without the prior written consent of the sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures.
The approval of the Statistical Analysis Plan is documented in a separate Signature Document.
PPD
PPD


Statistical Analysis Plan
Protocol No.: BAY 80-6946 / 19176
Page: 2 of 24
Table of Contents
Title page................................................................................................................................... 1
Table of tables........................................................................................................................... 3
Table of figures......................................................................................................................... 3
Abbreviations............................................................................................................................ 4
1.
Introduction ....................................................................................................................... 6
2.
Study Objectives................................................................................................................ 6
3.
Study Design ...................................................................................................................... 7
4.
General Statistical Considerations ................................................................................ 11
4.1
General Principles.......................................................................................................... 11
4.2
Handling of Dropouts .................................................................................................... 11
4.3
Handling of Missing Data.............................................................................................. 12
4.4
Interim Analyses and Data Monitoring.......................................................................... 13
4.5
Data Rules...................................................................................................................... 13
4.5.1
Time intervals............................................................................................................. 13
4.5.2
Baseline....................................................................................................................... 13
4.5.3
Repeated measures...................................................................................................... 13
4.5.4
Overall extent of exposure.......................................................................................... 14
4.6
Validity Review ............................................................................................................. 14
5.
Analysis Sets..................................................................................................................... 14
5.1
Assignment of analysis sets ........................................................................................... 14
6.
Statistical Methodology................................................................................................... 15
6.1
Population characteristics .............................................................................................. 15
6.1.1
Disposition.................................................................................................................. 15
6.1.2
Protocol deviations ..................................................................................................... 15
6.1.3
Demographics and other baseline characteristics....................................................... 15
6.1.4
Medical history........................................................................................................... 16
6.1.5
Prior and concomitant medication.............................................................................. 16
6.1.6
Treatment duration and exposure ............................................................................... 16
6.2
Efficacy.......................................................................................................................... 17
6.2.1
Phase I part ................................................................................................................. 17
6.2.2
Phase II part................................................................................................................ 17
6.2.3
Subgroup Analyses ..................................................................................................... 19
6.3
Safety ............................................................................................................................. 19
6.3.1
Adverse Events (AEs)................................................................................................. 19
6.3.2
Deaths and Serious Adverse Events ........................................................................... 20
6.3.3
MTD and RP2D Determination.................................................................................. 20
6.3.4
Pregnancies................................................................................................................. 21
6.3.5
Clinical Laboratory Parameters .................................................................................. 21
6.3.6
Glucose Evaluation..................................................................................................... 22
6.3.7
Further Safety Parameters........................................................................................... 22
6.4
Pharmacokinetics/pharmacodynamics........................................................................... 23
6.5
Biomarker/ pharmacodynamics (PD) evaluation........................................................... 23


Statistical Analysis Plan
Protocol No.: BAY 80-6946 / 19176
Page: 3 of 24
7.
Document history and changes in the planned statistical analysis ............................. 24
8.
References ........................................................................................................................ 24
Table of tables
Table 3–1 Decision rules for dose adjustments in Rolling-6 design.......................................... 9
Table 3–2 Copanlisib dose levels for patients < 1 year............................................................ 10
Table 3–3 Copanlisib dose levels for patients ≥1 year.......................................................... 10
Table 6–1 Censoring rules........................................................................................................ 18
Table 6–2 OS censoring rules .................................................................................................. 19
Table 6–3 Glucose measurement on copanlisib infusion days................................................. 22
Table 6–4 Blood sample collection for copanlisib PK assessment.......................................... 23
Table of figures
Figure 3-1: Study periods........................................................................................................... 8


Statistical Analysis Plan
Protocol No.: BAY 80-6946 / 19176
Page: 4 of 24
Abbreviations
AE
Adverse event
AKT
Protein kinase B
ATC
Anatomical Therapeutic Chemical 
AUC
Area under the curve
BDG
Bayer drug groupings
BRM
Blinded review meeting
BSA
Body surface area
Cmax
Maximum drug concentration
CR
Complete response
CRF
Case report form
CSP
Clinical study protocol
CSR
Clinical study report 
CTCAE
Common Terminology Criteria for Adverse Events
dayfirst
The day of first study drug intake 
daylast
The day of last study drug intake
DCR
Disease control rate
DLT
Dose-limiting toxicity
DOR
Duration of response
ECG
Electrocardiogram
EOT
End of treatment
FAS
Full analysis set
FU
Follow-up
GCP
Good Clinical Practice
HbA1c
Hemoglobin A1c
IxRS
Interactive Voice Response System /Interactive Web Response System
kg
Kilogram
KM
Kaplan-Meier
LPLT
Last patient last treatment
LTFU
Long-term follow-up
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
MTD
Maximum tolerated dose
MUGA
Multiple gated acquisition
NCI
National Cancer Institute
OEE
Overall extent of exposure
ORR
Objective response rate
OS
Overall survival
pAKT
Phosphorylated AKT (protein kinase B [PKB])
PD
Progressive disease
PFS
Progression-free survival
PI3K
Phosphatidylinositol-3-kinase
PID
Patient identification number
PK
Pharmacokinetic(s)
PopPK
Population PK 
PR
Partial response
R2PD
Recommended Phase 2 dose
RECIST
Response Evaluation Criteria in Solid Tumors


Statistical Analysis Plan
Protocol No.: BAY 80-6946 / 19176
Page: 5 of 24
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical Analysis Plan
SFU
Safety follow-up
SOC
Standard of care
TEAE
Treatment-emergent adverse event
UMVCUE
Unbiased minimum variance unbiased conditional
VRM
Validity review meeting 
VRR
Validity Review Report
WHO-DD
World Health Organization Drug Dictionary 


Statistical Analysis Plan
Protocol No.: BAY 80-6946 / 19176
Page: 6 of 24
1.
Introduction
Copanlisib has been evaluated so far only in adults in a number of clinical studies to establish 
efficacy and safety of copanlisib as a single agent and in combination with other treatments in 
various solid and hematologic malignancies. As of 21 JUN 2018 approximately 980 patients 
with advanced cancer have been treated with copanlisib in different studies.
This study is designed to investigate whether the use of copanlisib is safe, feasible and 
beneficial to pediatric patients with solid malignant tumors that are recurrent or refractory to 
standard therapy. 
Based on published data on phosphatidylinositol-3-kinase (PI3K) implication in 
tumorigenesis and the mode of action of copanlisib to potentially block the PI3K/ protein 
kinase B (AKT) pathway activated in high risk pediatric cancers, the following pediatric 
tumors were selected as target pediatric indications for copanlisib: neuroblastoma, 
osteosarcoma, rhabdomyosarcoma and Ewing sarcoma.
Neuroblastoma, osteosarcoma, rhabdomyosarcoma and Ewing sarcoma in children have been 
reported to frequently harbor activated PI3K/AKT pathways (frequency of ≥50%). It is 
therefore hypothesized that inhibition of the PI3K/AKT pathway with copanlisib, a PI3K 
inhibitor that targets all four class I isoforms with predominant activity against α and δ 
isoforms, may have a positive impact on the treatment outcomes in these sub-entities and the 
probability of success of a development in these malignancies could be higher compared to 
other types of neoplasm. 
Even though there have been noticeable improvements in the treatment in recent decades, 
curative therapy remains unattainable for many. Available therapeutic options include highly 
toxic chemotherapeutic agents with some of them having long term toxic effect on 
cardiovascular system (anthracyclines) or reproductive system. Improving and providing new 
therapeutic options for children with recurrent disease remains a high clinical unmet need. 
This Statistical Analysis Plan (SAP) v1.0 is based on the Integrated Clinical Study Protocol 
Version 2.0 (dated 04 APR 2019) for study 19176.
2.
Study Objectives
The objectives of the Phase I (dose escalation) part of the study are provided below:
Primary objective:

To establish the safety, maximum tolerated dose (MTD) and/or recommended Phase 2 
dose (RP2D) of copanlisib in pediatric patients with a relapsed/refractory solid tumor 
or lymphoma 
Secondary objectives:

To characterize the pharmacokinetic(s) (PK) of copanlisib 

To assess the antitumor activity of copanlisib and to identify specific potential tumor 
type(s) for further development


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Page: 7 of 24
Exploratory objectives:

To evaluate pharmacodynamics of copanlisib

To evaluate biomarkers of efficacy, mode-of-action-related effect, and / or the 
pathomechanism of the disease
The objectives for Phase II (extension) part of the study are provided below:
Primary objective:

To determine the objective response rate (ORR) of copanlisib in pediatric patients with 
relapsed/refractory neuroblastoma, rhabdomyosarcoma or Ewing sarcoma. 

To determine the disease control rate (DCR) and progression free survival (PFS) in 
pediatric patients with relapsed/refractory osteosarcoma
Secondary objectives:

To evaluate PFS (in indications other than osteosarcoma), overall survival (OS), and 
duration of response (DOR)

To evaluate safety 
Exploratory objectives:

To characterize population PK of copanlisib

To evaluate pharmacodynamics of copanlisib

To evaluate biomarkers of efficacy, mode-of-action-related effect, and/or the 
pathomechanism of the disease
3.
Study Design
This study 19176 (COG study number ADVL1721) is an open-label, non-controlled, 
dose-escalating trial to evaluate the pharmacokinetics, pharmacodynamics, safety and activity 
of copanlisib in pediatric patients from 6 months to ≤ 21 years of age with a relapsed or 
refractory solid malignant tumor or lymphoma and an extension in pediatric patients from 
6 months to ≤ 21 years with a relapsed or refractory neuroblastoma, osteosarcoma, 
rhabdomyosarcoma or Ewing sarcoma.
The study includes two parts. The Phase I (dose escalation) part will use the Rolling-six 
design with expansion cohort at the maximum tolerated dose (1). The Phase II (extension) 
part will use Simon 2-stage design in arms by tumor type (2).
A schematic of the study periods is presented in Figure 3-1. The following design applies to 
both Phase I and Phase II parts.


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Page: 8 of 24
Figure 3-1: Study periods
On study
Off study
Screening
Treatment
                Active FU a
Long-term 
FU
Informed
consent
First dose of 
study 
treatment 
Last dose of study 
treatment/
End of last cycle
Last protocol-
stipulated 
procedure
a: Mandatory SFU visit and other active follow-up visits, if applicable
The study will comprise on the following periods: screening, treatment, active follow-up 
and long-term follow-up
Screening 
Screening period starts after the patient and/or patient’s parents (or legal guardians) have 
signed the informed consent form (and an assent from the patient is obtained, where 
applicable), and ends just before the start of treatment with copanlisib.
Treatment 
The start of the treatment period is defined by first administration of study drug copanlisib. 
Copanlisib will be administered IV on Days 1, 8 and 15 of each 28-day treatment cycle. 
Treatment will be continued until radiological progressive disease, unacceptable toxicity, 
withdrawal of consent, death or other event specified by the protocol.
An End-of-treatment (EOT) visit will be performed within 7 days after the decision is made to 
discontinue study treatment. 
Active Follow–up (Active FU):
The active follow-up period is the interval from the end of study drug intake to the end of all 
clinical study protocol (CSP)-specified post-treatment interventions. 
All patients who discontinue study treatment for any reason will be followed for safety at a 
mandatory safety follow-up visit except for patients and/or parents (or legal guardians) who 
refuse follow-up data collection. This safety follow-up (SFU) visit will take place 30+5 days 
after the last administration of study drug. 
Patients who discontinue study treatment without radiological progressive disease (PD) will 
be followed for radiological tumor assessments during the active FU until radiological PD is 
documented or until the start of first subsequent anti-cancer therapy, whichever occurs first. 
Long-term follow-up (LTFU):
All patients will be followed up for survival for at least 2 years after the end of the Phase I 
(dose-escalation) and Phase II (extension) parts. 
All patients who discontinue from study treatment or from active follow-up for any reason 
will enter long-term follow-up period during which survival data will be collected except for 
the cases when patients and/or parents (or legal guardians) refuse follow-up data collection. 
Patients’ parents (or legal guardians) will continue to be contacted approximately every 
3 months to determine survival status until death or at least 2 years after the last patient’s last 
treatment in the study. Those patients who reached adult age during the long-term follow-up 
can be contacted directly or via patients’ parents (or legal guardians).


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Page: 9 of 24
Phase I dose escalation design
The Phase I (dose-escalation) part of the study will determine the safety, MTD and/or RP2D 
of copanlisib in a pediatric population by using stepwise dose-escalation design based on 
Rolling-6 rule (see Table 3–1) with expansion cohort at the maximum tolerated dose. The 
sample size was based on feasibility, not formal statistical calculation. Number of patients
will depend on observed safety signal with 3-6 patients enrolled per cohort in the Rolling-6 
study design. Approximately up to 30 patients will be enrolled and treated. A minimum of 
50% of the enrolled patients will be under the age of 12.
In the Rolling-6 study design, up to 6 patients are enrolled concurrently. Accrual to the study 
is suspended when 6 patients are enrolled. Accrual can be stopped earlier in any given 
cohort/dose level once dose-limiting toxicities (DLTs) are established and reviewed. 
Decisions as to whether to enroll a new patient onto the current, at next highest, or next lowest 
dose level will be made based on available data at the time of new patient enrollment. 
Dose level assignment will be based on the number of patients enrolled in the cohort, the 
number of DLTs observed, and the number of patients at risk for developing a DLT (i.e., 
patients enrolled but who are not yet evaluable for toxicity). If the DLT criteria are amended 
for any reason, the next cohort under amended criteria will start at the last dose level assessed 
under the previous DLT criteria.
Table 3–1 Decision rules for dose adjustments in Rolling-6 design
Number of 
patients enrolled
Number of 
patients with DLT
Number of patients with data 
pending
Decision
2
2
-
De-escalate a
0 or 1
-
Same dose level
3
≥ 2
-
De-escalate a
0
0
Escalate b
1
-
Same dose level
4
≥ 2
-
De-escalate a
0
0
Escalate b
1
-
Same dose level
5
≥ 2
-
De-escalate a
0
0
Escalate b
1
-
Same dose level
6
≥ 2
-
De-escalate a
≤ 1
1
Escalate b
0
Escalate b
DLT = Dose-limiting toxicity; MTD = Maximum tolerated dose
a: If 6 patients already entered at the next lower dose level, the MTD has been defined; 
if de-escalation occurs at the lowest dose level (for patients ≥ 1 year old (lowest dose level -1) and 
for patients < 1 year old (lowest dose level -2), please see Table 3–2 and Table 3–3, respectively), 
then the study is discontinued.
b: Dose escalation will take place only after comprehensive review of all collected safety data and 
careful evaluation by the investigators and sponsor.
Copanlisib will be dosed on Day 1, Day 8, and Day 15 of every 28-day cycle. Patients who 
meet the eligibility criteria will receive copanlisib IV infusion with intermittent (3 weeks on / 
1 week off) dosing schedule at the assigned dose level.


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The starting dose for the dose-escalation phase of this study will be 60% for patients < 1 year 
old and 80% for patients ≥1 year old of the dose (60 mg/weekly, 3 weeks on/1 week off) in 
the adult population recommended for copanlisib development. The dosing will be based on 
body surface area (BSA). 
BSA will be calculated at Cycle 1 Day 1 based on either the Mosteller formula or the DuBois 
formula. Mosteller formula is recommended as it combines accurate BSA calculation with 
ease of use. However, the formula that is chosen at Cycle 1 Day 1 must be used throughout 
the study.
Mosteller: BSA (m²) = ([Height(cm) x Weight(kg) ]/ 3600)½
DuBois: BSA (m²) = 0.20247 x Height(m)0.725 x Weight(kg)0.425
The dose levels to be explored are listed in the following tables. In case that a certain cohort 
of pediatric patients reaches the copanlisib plasma exposure of adult patients treated with the 
recommended dose before the pediatric MTD is defined, no higher dose level will be tested. 
The first cohort of patients in this trial will be treated with a dose of 21 mg/m2/week for 
patients < 1 year old and 28 mg/m2/week for patients ≥1 year old by taking in consideration 
the average adult BSA of 1.73 m2. It is estimated that 2 or 3 dose cohorts may be evaluated in 
this part of the study. Please refer to Table 3–2 and Table 3–3 for dose levels of copanlisib for 
patients < 1 year old and ≥1 year old, respectively.
Table 3–2 Copanlisib dose levels for patients < 1 year
Dose level
Copanlisib dose
% of adult dose
mg/m2
-2
40
14
-1
60 a
21
1
80
28
2
100
35
a: Starting dose for patients < 1 year 
       After patients are tested at dose level 1, the population PK (popPK) analysis will determine 
whether the exposure has reached at least 75% of adult exposure.
Table 3–3 Copanlisib dose levels for patients ≥1 year
Dose level
Copanlisib dose
% of adult dose
mg/m2
-1
60
21
1
80 a
28
2
100
35
3 b
120
42
a: Starting dose for patients ≥1 year old 
b: Dose level 3 will only be tested if the geometric mean of the copanlisib plasma exposure in the 
already tested cohorts is less than 75% of the adult plasma exposure of copanlisib of 60 mg. After 
patients are tested at dose level 2, the popPK analysis will determine whether the exposure has 
reached at least 75% of adult exposure.
The recruitment will continue according to the Rolling-6 design, until the MTD is declared or 
copanlisib plasma exposure is assessed as being equivalent to the exposure in adult patients 
receiving the recommended treatment schedule. Once escalation is stopped, the last cohort 


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Protocol No.: BAY 80-6946 / 19176
Page: 11 of 24
will be expanded from 6 up to 12 patients in order to collect more safety and tolerability data 
and establish the RP2D. 
Phase II extension design
The Phase II part (extension) of the study will establish efficacy signal of copanlisib single 
agent treatment in pediatric patients with relapsed/refractory neuroblastoma, osteosarcoma, 
rhabdomyosarcoma or Ewing sarcoma. 
A Simon 2-stage design will be used. According to Simon 2-stage design, after 10 FAS 
patients per indication will have been treated in Stage 1 for at least of 4 cycles, recruitment 
will be paused until decision for go/no-go into Stage 2 (see Section 4.4 for further 
information).
The RP2D as determined in the Phase I part of this study, will be used for the Phase II part of 
the study. This dose will be determined by the investigators and the sponsor after having 
reviewed the data from all evaluated dose levels in Phase I, including PK data, overall 
incidence and intensity of AEs and MTD. 
The number of study participants in the Phase II part: planned 10 pediatric patients per opened 
arm in first stage and, if at least 2 responses occur, in the second stage 15 additional pediatric 
patients in the neuroblastoma, osteosarcoma, rhabdomyosarcoma or Ewing sarcoma arms. Up 
to 25 patients per arm and up to 100 patients could be enrolled. A minimum of 80% of the 
enrolled patients will be under the age of 18.
4.
General Statistical Considerations
4.1
General Principles
The statistical evaluation will be performed by using the software package SAS release 9.2 or 
higher (SAS Institute Inc., Cary, NC, USA). All variables will be analyzed by descriptive 
statistical methods. The number of data available and missing data, mean, standard deviation, 
minimum, quartiles, median, and maximum will be calculated for continuous data. Ordinal 
data will be summarized using n, number of missing values, median, minimum, maximum 
and quartiles. Frequency tables will be generated for categorical data. Time-to-event variables
(in days) will be summarized using Kaplan-Meier (KM) estimates.
4.2
Handling of Dropouts
A patient who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the patient has already been administered at least 1 dose of the study drug 
(copanlisib).
Patients must be withdrawn from the study treatment or the study if any of the pre-specified 
withdrawn criteria is met. See protocol Section 6.4.1 for the pre-specified withdrawn criteria. 
A patient who, for any reason (e.g. failure to satisfy the selection criteria), terminates the 
study before assignment to the study treatment is regarded a “screening failure”. 


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Re-starting the defined set of screening procedures to enable the “screening failure” patient’s 
participation at a later time point is not allowed – with the following exceptions:

The patient had successfully passed the screening procedures, but could not start 
subsequent treatment on schedule.

The in- / exclusion criteria preventing the patient’s initial attempt to participate have 
been changed (via protocol amendment).
Re-screening of patients may only be allowed once after discussion and approval by the 
sponsor. Sponsor approval of re-screening for the patient who has failed screening must be 
documented. The screening failure will be registered in Interactive Voice/Web Response 
System (IxRS) to close the patient identification number (PID), and re-screening will start 
again by signing a new informed consent form and being assigned a new PID.
The number of patients who prematurely discontinue the study and study treatment for any 
reason, as well as the reasons for premature discontinuation of study treatment and the 
completion of the follow-up periods, will be reported.
Replacement
Phase I part
Patients in the Phase I part who discontinue because of a DLT or other related toxicity that led 
to discontinuation of treatment during the DLT evaluation period will not be replaced.
Patients in the Phase I part who discontinue during Cycle 1 because of any reason other than a 
DLT or other treatment-emergent adverse event (TEAE) requiring discontinuation of 
treatment, and patients who were non-compliant in Cycle 1 to the extent that precludes the 
assessment of study objectives according to the sponsor’s decision in consultation with the 
investigator, will be replaced to ensure the required number of evaluable patients per cohort. 
Phase II part
No patients will be replaced in the Phase II part.
4.3
Handling of Missing Data
In general, missing data, except for partially missing dates, will not be imputed in this study. 
In order to achieve the goal of a well conducted clinical trial according to Good Clinical 
Practice (GCP), every effort should be made to resolve incomplete or missing dates during the 
course of the study (i.e. edit checks, data cleaning / monitoring etc.). When only partial dates 
are available, the following replacement rules will be used: if the start date is partially 
missing, the first day of that month will be used when only the day is missing; if the stop date 
is partially missing, the last day of the month will be used when only the day is missing; if 
both the day and the month are missing, the date will be missing. All missing or partial data 
will be presented in the patient data listing as they are recorded on the Case Report Form 
(CRF). 


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4.4
Interim Analyses and Data Monitoring
Phase I part
Individual patient’s safety data will be reviewed without formal statistical analysis on an 
ongoing basis and before the dose escalation decision during the dose escalation phase. The 
DLTs, escalation or MTD status, and decision will be documented in a monitoring report. 
Phase II part
Simon's two-stage optimal design will be used for each of the four indications 
(neuroblastoma; osteosarcoma; rhabdomyosarcoma; Ewing sarcoma) of the Phase II part
separately. For each indication, the null hypothesis is that the background response rate 
(disease control rate for osteosarcoma) of 10% will be tested against a one-sided alternative. 
With type I error rate of 7.5%, power of 80% and the success response rate of 30%, Stage 1 
will include 10 patients. After 10 patients per indication have been treated in Stage 1 for at 
least 4 cycles, recruitment will be paused until decision for go/no-go into Stage 2. To support 
the go/no-go decision into Stage 2, Stage 1 data will be evaluated for ORR or DCR for 
respective indication. The evaluation will be based on a clean database of Stage 1 with cut-off 
date if the last patient of the respective indication has had the chance to complete 4 cycles of 
treatment. If an indication that is not stopped at Stage 1, 15 additional patients will be accrued 
into Stage 2 for a total of 25.
In case of recruitment overrun of Stage 1 (despite plans to pause recruitment), the 10 patients 
for Stage 1 will be determined based on the date/time of signing the informed consent. 
Overrun patients will only stop their treatment in case Stage 2 is not reached and might 
contribute as patients to Stage 2.
The primary analysis of the primary efficacy variable for Phase II will be performed on the 
data collected up to the last patient of that indication having had the chance to complete 
4 cycles of treatment. Patients who have progressive disease prior to 4 cycles will be 
considered fully evaluable for response and included in the efficacy analyses. At that time 
point, an exploratory analysis of all other variables will be performed, as reasonable. The final 
analyses of all secondary efficacy and safety variables and exploratory variables will be 
performed approximately 2 years after last patient last treatment (LPLT).
4.5
Data Rules
4.5.1
Time intervals
If time intervals are to be displayed other than days in statistical evaluations, then one year is 
considered to have 365.24 days (average length of a year, including leap years), one month is 
considered to have 30.44 days (average length of a month, including leap years), one week is 
considered to have 7 days, and one cycle is considered to have 28 days (i.e. 4 weeks).
4.5.2
Baseline
Baseline is defined as the last measurements performed prior to the first study drug 
administration in Cycle 1, unless otherwise specified.
4.5.3
Repeated measures
If there are repeated measurements per time point (e.g. laboratory values, vital signs, etc.), the 
following rules will be used (unless otherwise specified):


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
Before the start of the study drug administration (i.e., for screening and baseline 
value), the latest measurement at scheduled visits will be used. Unscheduled visits will 
be used, if there are no measurements at scheduled visits. If the latter is the case, the 
last unscheduled visit will be used. 

In case of repeated measurements at any post baseline time point, the first 
measurement at scheduled visits will be used. Unscheduled visits will be used, if there 
are no measurements at scheduled visits. If the latter is the case, the first unscheduled 
visit will be used.
4.5.4
Overall extent of exposure
As a general rule, and in accordance with the Oncology Therapeutic Area Standard, leading '0
mg' (prior to the first positive amount of drug) and trailing '0 mg' records (not followed by any 
positive amount of drug), will not be included in the calculation of any drug duration or 
amount. 
Overall extent of exposure (OEE) for study treatment, respectively, is defined as the time 
from first respective study drug intake (dayfirst) until last study drug intake (daylast), including 
7 additional days in order to consider the weekly dosing regimen, and is calculated as:
OEE = daylast - dayfirst + 7
If the respective treatment ends with dose interruptions, the day of the last actual dose will be 
considered to be daylast.
4.6
Validity Review
The results of the validity review meeting (VRM)/ blinded review meeting (BRM) will be 
documented in the Validity Review Report (VRR) and may comprise decisions and details 
relevant for statistical evaluation. Any changes to the statistical analysis prompted by the 
results of the validity review meeting will be documented in an amendment and, if applicable, 
in a supplement to this SAP.
5.
Analysis Sets
5.1
Assignment of analysis sets
Final decisions regarding the assignment of patients to analysis sets will be made during the
review of study data and documented in the final list of important deviations, validity findings 
and assignment to analysis set(s) (see section 4.5.4).
Full analysis set (FAS)
The FAS population is defined as all patients with at least one intake of study drug. This set 
will be used for patient characteristics, demographic, and efficacy evaluations for both Phase I 
and Phase II.
Safety analysis set (SAF)
The SAF population is defined as all patients with at least one intake of study drug. The SAF 
will be used for safety evaluations for both Phase I and Phase II.


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PK analysis set
The popPK is defined as all patients with at least one intake of study drug and with at least 
one valid measurement for copanlisib after first dosing will be included in the copanlisib PK 
analysis.
6.
Statistical Methodology
Statistical analyses in this section will be carried out for Phase I (dose escalation) and Phase II 
(extension) parts, respectively. The analysis methods for Phase II part will be amended based 
on an amended protocol after the completion of the Phase I part, to provide updated 
information on RP2D and other related topics.
6.1
Population characteristics
Population characteristics will be summarized in the FAS, unless otherwise specified. 
6.1.1
Disposition
Disposition at the end of screening will be summarized for all enrolled patients. 
Disposition at the end of treatment and for the follow-up periods will be summarized by 
cohort and overall for Phase I part; and by indication and overall for Phase II part.
6.1.2
Protocol deviations 
Frequency tables of protocol deviations by category and deviation coded term will be 
summarized by cohort and overall for Phase I part, by indication and overall for Phase II part.
6.1.3
Demographics and other baseline characteristics
Demographics variables and baseline characteristics will be summarized by cohort and overall
for Phase I part; and by indication and overall for Phase II part. Summary statistics will be 
presented for continuous variables. Frequency tables will be presented for categorical 
variables.
Demographic variables include age, gender, race, ethnicity. Age will be analyzed as 
continuous variable and in addition, categorized with the following categories: 6 month - < 1
year, 1 year - < 2 years, 2 years - < 6 years, 6 years - < 12 years; 12 years - < 18 years, ≥18
years.
The following additional baseline characteristics will be analyzed:

Date of diagnosis and stage of disease

Tumor site and size, site(s) and date(s) of metastases, type of surgery conducted

Most recent histology of tumor

Most recent staging and grading of tumor

Assessment of baseline toxicity

Karnofsky / Lansky performance status


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6.1.4
Medical history
Medical history findings are defined as the conditions that started before signing of informed 
consent and considered relevant for the patients’ study eligibility. The medical history 
findings will be coded by Medical Dictionary for Regulatory Activities (MedDRA, version 
21.1 or later, if more updated version is available by the time of analysis). Medical history 
will be presented for each MedDRA Primary System Organ Class (SOC) and Preferred Term 
by cohort and overall for Phase I part, and by indication and overall for Phase II part.
6.1.5
Prior and concomitant medication
Prior and concomitant medications will be coded by Anatomical Therapeutic Chemical (ATC) 
classification system according to the World Health Organization Drug Dictionary (WHO-
DD, version 2019MAR or later). Summaries will be provided by ATC class and subclass
separately for Phase I (by cohort and overall) and Phase II (by indication and overall). Note 
that the same medication can appear multiple times in the table as it can have several ATC 
codes.
A medication that has been stopped after first administration of study treatment is considered 
as concomitant and otherwise as prior. Medications with missing start and stop date but 
flagged as being ongoing at end of study will be considered to have started prior to start of 
study medication and end after stop of study medication.
6.1.5.1
Prior anti-cancer therapy
In addition to general prior medications, prior anti-cancer therapy will be further analyzed by 
cohort and overall for Phase I part, as well as by indication and overall for Phase II part for 
the following: 

The minimum, median, and maximum number of prior systemic anti-cancer therapy 
lines 

Number of patients with 1, 2, 3 and ≥  4 lines of therapy

History of prior stem cell transplant

Time since last systemic anti-cancer therapy 

Time between the start day of last course of systemic anti-cancer therapy and the day 
of confirmation of the most recent progression (categorized as ≤ 6 months, > 6 to 12 
months and >12 months)

Prior anti-cancer therapies (displayed by ATC classes, Bayer drug groupings (BDGs)
and preferred drug names, respectively) 

Anti-cancer therapies during follow-up (displayed by ATC classes, BDGs and 
preferred drug names, respectively)
6.1.6
Treatment duration and exposure
Descriptive statistical summaries for the following variables will be provided by cohort for 
Phase I part and by indication for Phase II part: 

Overall extent of exposure (OEE, as defined in section 4.5.4)

Number of cycles 


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
Number of infusions during treatment phase

For patients with dose delay or interruption, the number of dose delays or interruptions 
per patient and their reasons will be summarized.
In addition, the following analyses will be provided by cycle for Phase I part (by cohort) and 
Phase II part (by indication), respectively:

Total amount actually administered

Mean dose intensity (mg/m2)

Percent of planned dose received (i.e., Actual dose [mg] / Planned dose [mg] × 100%).
Copanlisib will be administered IV on Days 1, 8 and 15 of each 28-day treatment 
cycle. Completed cycles therefore have a planned dose of 3 × X mg, where X is the 
planned dose for a patient, depending on the dose level assigned to him/her. For 
incomplete cycles, the planned dose depends on the number of days (d) in that cycle:
o
X mg if 0 < d < 8
o
2 × X mg if 8 ≤d < 15
o
3 × X mg if d ≥ 15
6.2
Efficacy
Tumor assessments will be performed at screening (within 28 days prior to start of treatment), 
during treatment period every 8 weeks (± 7 days) until radiological tumor progression, at EOT 
visit and during active FU period every 12 weeks (± 14 days) until radiological tumor 
progression or start of new anti-cancer therapy, whichever occurs first.
6.2.1
Phase I part
Efficacy analyses of Phase I part will be performed in the FAS by cohort and by indication, 
respectively.
ORR is defined separately in each indication, as the number of responders divided by the 
number of patients of the FAS in the indication. A patient is a responder if the patient has a 
tumor response on-study of complete response (CR) or partial response (PR), based on 
radiological assessments utilizing Response Evaluation Criteria in Solid Tumors (RECIST)
1.1 for solid tumor or modified Lugano Classification 2014 for lymphoma, or SIOPEN or 
Curie score for neuroblastoma patients with MIBG-avid disease. Patients for whom overall 
best response is not CR or PR, as well as patients without any post-baseline tumor assessment 
will be considered non-responders. ORR and 95% Clopper-Pearson exact confidence intervals 
will be computed for each cohort and each indication.
6.2.2
Phase II part
6.2.2.1
Primary Efficacy Analyses

ORR, defined the same as above, is the primary efficacy endpoint in neuroblastoma, 
Ewing sarcoma and rhabdomyosarcoma, while DCR is the primary efficacy endpoints
in osteosarcoma. DCR is defined as the number of patients with disease control 
divided by the number of patients with osteosarcoma in the FAS. A patient has disease 
control if the patient has a confirmed tumor response of CR or PR or a tumor response 
of SD (post-base line imaging performed within 7 weeks after the date of baseline 


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tumor evaluation date will not be evaluable for DCR analysis of SD in patients with 
osteosarcoma) as determined per RECIST 1.1 criteria for solid tumor patients.
ORR or DCR will be determined in their respective indication from Stage 1 and 
(potentially) Stage 2 results in FAS patients as unbiased minimum variance unbiased 
conditional (UMVCUE) estimate, using methodology as described in Porcher and 
Desseaux, 2012 (3).

PFS, considered as the co-primary endpoint for osteosarcoma patients, is defined as 
the time from first intake of study drug to disease progression according to RECIST1.1 
for solid tumor patients or death (if death occurs before progression is documented). 
Censoring rules listed in Table 6–1 will be applied (PFS = End Date – Date of first 
intake of study drug).
PFS will be summarized for patients reaching Stage 2 by KM estimates (4). KM plot 
will be presented with number of subjects at risk and number of events at the bottom. 
Median survival time, as well as 25% and 75% percentiles, with 95% confidence 
intervals will be estimated by product-limit method (5).
Table 6–1 Censoring rules
Situation
End Date
Censored
Reason for Censoring
No baseline or post-baseline 
disease assessment
Treatment start date (i.e., 
censored at day 1)
Yes
No baseline or post-baseline 
disease assessment
PD or death (no more than one 
missing tumor assessment)
Date of the first PD or death No
N/A
PD or death after two or more 
consecutive tumor assessments
Date of the last assessment 
before missing
assessments
Yes
Missed more than one 
disease assessment
Subject discontinued from study 
for reasons other than PD or 
death
Date of the last assessment 
without PD
Yes
Subject discontinued from 
study due to a reason other 
than PD or death
Subject still on study at the time 
of data cutoff without PD
Date of the last assessment 
without PD
Yes
Subjects is still alive without 
PD
New systemic anti-cancer 
therapy started prior to PD
Date of the last assessment 
before starting the new anti-
cancer therapy
Yes
New anti-cancer therapy 
started
6.2.2.2
Secondary Efficacy Analyses
DOR, PFS (except for osteosarcoma) and OS will be considered as secondary endpoints 
for each indication. They will be analyzed separately for each indication reaching Stage 2, 
in the same way as described above for PFS as the co-primary endpoint of osteosarcoma 
patients.

Analyses of DOR will be carried out for responders only (i.e. patients with CR or PR). 
DOR is defined as the time from the date of first observed tumor response until first 
subsequent PD or death (if death occurs before progression is documented) due to any 
cause, with censoring rules in Table 6–1 (for DOR, the first situation does not apply; 
and all situations are referred to as those occurring after the first tumor response. DOR 
= end date – date of first response).

PFS in each indication except for osteosarcoma is defined as the time from first intake 
of study drug to disease progression according to RECIST1.1 for solid tumor patients 


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(except for osteosarcoma) and SIOPEN or Curie score for neuroblastoma patients with 
MIBG-avid disease, or death (if death occurs before progression is documented).
Censoring rules listed in Table 6–1 will be applied.

OS is defined as the time from first intake of study drug until death from any cause, 
with censoring rules listed below in Table 6–2.
Table 6–2 OS censoring rules
Situation
End Date 
Censored
Reason for Censoring
Death on or prior to database 
cutoff date
Date of Death
No
N/A 
Death occurred or subject known 
to be alive after database cutoff 
date
Database cut-off date
Yes
Alive as of data cut-off 
date
Last known alive date is on or prior 
to data cutoff date
Last known alive date 
Yes
The reasons are based 
on the study CRF: e.g., 
subjects lost to follow 
up, withdrew consent 
etc.
6.2.3
Subgroup Analyses
Subgroup analyses will be performed for Phase I and Phase II parts, respectively.
Subgroup levels to be analyzed are:

Age group (< 1 year vs. 1 year - 6 years vs. > 6 years)

Gender (male vs. female)

Race (white vs. others)

Prior lines of therapy (1 vs. >1)

Prior stem cell transplant (Yes vs. No)
6.3
Safety
Safety evaluations will be done at screening, on the first day of study drug administration 
(Cycle 1 Day 1), at each clinic visit during the treatment, at EOT visit and at the SFU visit. 
Safety analyses will be performed by cohort for Phase I part and by indication for Phase II 
part in the SAF. Such safety analyses will also be performed by age group (< 1 year vs. 1 year 
- 6 years vs. > 6 years).
6.3.1
Adverse Events (AEs)
Adverse events will be coded by MedDRA (version 21.1 or later). Severity of AEs and 
hematological/biochemical toxicities based on laboratory measurements will be graded using 
National Cancer Institute (NCI) Common Terminology Criteria Adverse Event (CTCAE, 
version 4.03) dictionary. AEs will be classified by the investigator as related or not related to 
study drug.
All TEAEs
TEAE is defined as any event arising or worsening after start of study drug administration 
until 30 days after the last dose of the study drug intake (end of safety follow-up). In the case 


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where it is not possible to define an AE as treatment-emergent or not, the AE will be 
classified by the worst case; i.e. treatment-emergent. 
An overall summary of TEAEs will be provided. TEAEs, drug-related (copanlisib), 
procedure-related, and/or serious TEAEs will be summarized by MedDRA (SOC and 
preferred term) and worst grade based on CTCAE. The analyses will be repeated by age group 
(< 1 year vs. 1 year - 6 years vs. > 6 years).
TEAEs Leading to Permanent Discontinuation of Study Treatment, Copanlisib 
Interruption and/or Dose Reduction
The number and percentage of patients who discontinued study treatment due to TEAE or 
required a dose reduction or interruption caused by a TEAE will be summarized separately for
each cohort of Phase I part, and for each indication of Phase II part. The incidences of these 
TEAEs will be presented also separately by drug relationship. Patients who discontinued 
study treatment, required a dose reduction or interruption caused by a TEAE will be listed 
separately for each cohort of Phase I part or each indication of Phase II part: patient ID, 
histology, sponsor AE identifier, investigator AE term, MedDRA SOC and preferred term, 
NCI-CTCAE term and toxicity grade, start and stop dates of study drug administration, start 
and stop date of AE, drug related (yes/no), protocol required procedure related (yes/no), 
outcome.
6.3.2
Deaths and Serious Adverse Events
Patients listings will be provided by cohort for Phase I part and by indication for Phase II part, 
respectively:

Patients who died before treatment (only present if any): patient ID, age, sex, race, 
date of inform consent, sponsor AE identifier, date of death, cause of death.

Patients who died during treatment up to 30 days after last dose of study drug intake: 
patient ID, age, sex, race, sponsor AE identifier, start and stop date of study drug, 
relative days to start / stop of study drug, weeks on treatment, date of death, cause of
death, MedDRA SOC and preferred term, reported AE term, toxicity grade, drug 
related (yes/no) and protocol required procedure related (yes/no).

Patients with treatment-emergent serious adverse events (SAE)s: patient ID, age, sex, 
race, sponsor AE identifier, start and stop date of study drug, relative days to start / 
stop of study drug, weeks on treatment, date of death, cause of death, MedDRA SOC 
and preferred term, reported AE term, toxicity grade, drug related (yes/no), protocol 
required procedure related (yes/no), outcome, and action taken.  
6.3.3
MTD and RP2D Determination 
Dose-limiting toxicities 
DLT is defined as any of the following adverse reactions observed during first cycle of 
treatment, and assessed as possibly, probably or definitely related to treatment with copanlisib. 
DLTs include both non-hematological AEs and hematological AEs. The classified DLT 
criteria are listed in the protocol Section 7.4.1.3.
Generally, any AE during cycle 1 that is attributed to copanlisib and results in a missed dose 
or results in delayed start of cycle 2 by > 7 days will be considered a DLT.


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If ≥ 2 patients report DLTs in a cohort size of 3-6, that dose level is declared as toxic dose. If 
6 patients already entered at the next lower dose level, the MTD has been defined. If de-
escalation occurs at the lowest dose level, the study will be discontinued. (See dose 
adjustment in Rolling-6 design in Table 3–1)
Individual listing of DLTs will be presented by cohort. 
Maximum tolerated dose 
MTD for copanlisib will be defined as the highest dose level where 6 patients have been 
treated and ≤ 1 patient experiences a DLT. 

The MTD of copanlisib for patients < 1 year old will be established and analyzed 
separately from the patients ≥1 year old and the results will be provided in a 
descriptive statistical analysis. 
If in the Phase I part of the study the MTD will not be established in patients < 1 year old, the 
MTD determination in patients < 1 year old will continue in parallel with the Phase II part and 
will be stopped when the Phase II part has been closed. Patients < 1 year old may not be 
enrolled in the Phase II part of the study until the MTD and RP2D for that age group has been 
established. However, if in the Phase I part a certain cohort of pediatric patients < 1 year old 
reaches the copanlisib plasma exposure of adult patients treated with the recommended dose 
before the pediatric MTD is defined, no higher dose level will be tested.
Equivalence to adult copanlisib plasma exposure will be defined as the geometric mean of the 
individual area under the curve (AUC)s (i.e., model predicted AUC(0-168) after the third 
infusion of the assigned dose size for each patient) in the cohort with the highest dose level 
being within ± 25% of the adult exposure after dosing recommended for copanlisib 
development. Equivalence will be addressed in a separate modeling and simulation (M&S) 
report.
Recommended Phase II dose 
RP2D for copanlisib therapy will be determined by the investigators and the sponsor after 
having reviewed the data from all dose levels including available PK data, overall incidence 
and intensity of AEs and MTD. The protocol will be amended after completion of the Phase I 
part to update information on RP2D and other related topics (e.g. toxicities management 
guidance).
6.3.4
Pregnancies
The results of pregnancy tests will be listed by cohort of Phase I part and by indication of 
Phase II part, respectively. Any pregnancy will be documented.
6.3.5
Clinical Laboratory Parameters
Results of the clinical laboratory evaluations (coagulation, hematology, chemistry and 
urinalysis) will be summarized by visit and overall with worst grade. Worst grades for 
hematological and biochemical toxicities will be calculated according to CTCAE, version 
4.03 based on laboratory measurements. For tables displaying treatment-emergent laboratory 
abnormalities, patients with specimen collection between start of treatment and 30 days after 
the last dose of the study drug intake will be included.
Summary statistics will also be presented for the change from baseline for each quantitative 
clinical laboratory variable, including quantitative urinalysis variables, at each post-baseline 


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visit. For these variables, the number and percentage of patients with transitions from worst 
grade at baseline to worst grade at post-baseline visits relative to the respective laboratory’s 
reference ranges will be presented by study periods, treatment or safety follow-up. For the 
change in worst grade of hematological toxicities under treatment the latest observation will 
be taken. In case there is more than one observation for the same latest time, the worst grade 
will be taken. In addition to the above summary, specific glucose evaluation will be described 
in the next section.
6.3.6
Glucose Evaluation
Glucose will be displayed by worst CTCAE grade in SAF for pre-dose and post-dose 
measurements on Cycle 1 Day 1 and on subsequent infusion days according to the instructions 
given in Table 6–3.
Table 6–3 Glucose measurement on copanlisib infusion days
Pre-dose glucose 
measurement
Post-dose glucose measurement
Cycle 1 Day 1 a
<1 h prior to start of 
copanlisib infusion
0 h (+ 5 min) after end of infusion (equivalent to 
1h post start of infusion) 
1h (+/- 5 min) after end of infusion (equivalent to 
2h post start of infusion)  
2h (+/- 5 min) after end of infusion (equivalent to 
3h post start of infusion)  
Subsequent infusion 
days a (Cycle 1 Day 8 
onwards)
<1 h prior to start of 
copanlisib infusion
1h (+/- 5 min) after end of infusion (equivalent to 
2h post start of infusion)  
H = Hour; Min = Minute.
a: Additional measurements to be performed at the clinic as clinically indicated.
Changes from respective pre-dose (defined as the first pre-dose glucose measurement in each 
visit) in glucose will be summarized using descriptive statistics at each visit and analysis time 
point by pre-dose fasting status. 
Change in hemoglobin A1c (HbA1c) values by visit and overall (during study treatment) will 
be summarized by descriptive statistics. 
6.3.7
Further Safety Parameters
Results of physical examination, vital signs (including weight, height, BSA, heart rate, 
respiration rate, body temperature, and blood pressure), electrocardiogram (ECG) and Lansky-
Karnofsky performance status score will be summarized with descriptive statistics and/or 
frequency tables. Vital signs and ECG data will be summarized by visit and timepoint, 
including change from baseline where appropriate.
The overall interpretation of the 12-lead (or 15-lead) ECG and the ECG diagnosis, as well as 
the overall interpretation of the echocardiogram and the corresponding diagnosis will be 
summarized by visit. Frequency and shift tables for number of patients by interpretation of 
ECG as abnormal will be performed at all-time points, as well as frequencies and shift tables 
for clinical relevance of ECG. The number of patients with abnormal cardiac function will be 
displayed for echocardiogram and multiple gated acquisition (MUGA) by visit.
The number of patients requiring post dosing antihypertensive treatment (including an 
overview of the maximum blood pressure according to CTCAE grading, medication used and 
outcome after antihypertensive treatment), and patients with non-infectious pneumonitis 


Statistical Analysis Plan
Protocol No.: BAY 80-6946 / 19176
Page: 23 of 24
requiring corticosteroids will be displayed descriptively. The number of patients with 
abnormal blood pressure (according to CTCAE grading) will be displayed by visit and post-
dose hypertension grade.
6.4
Pharmacokinetics/pharmacodynamics
Plasma samples for measurement of copanlisib (BAY 1163877) concentrations will be 
collected from all patients for copanlisib during Cycle 1 (or, optionally, during Cycle 2 if it 
was not done on Cycle 1) on Days 1 and 15 according to Table 6–4.
Table 6–4 Blood sample collection for copanlisib PK assessment
Age ≥6 years
Cycle
Study Day
Time window 
Volume of blood 
(mL)
1
Day 1
pre-infusion (< 30 min prior to start 
infusion)
1.0
1
Day 1
1 – 1.25 hour
1.0
1
Day 1
1.5 – 3 hour
1.0
1
Day 1/2
22 – 24 hour
1.0
1
Day 15
1 – 1.25 hour
1.0
1
Day 15
1.5 – 3 hour
1.0
1
Day 15/16
22 – 24 hour
1.0
Total blood volume to be collected per patient
7 mL
Age < 6 years
Cycle
Study Day
Time window 
Volume of blood 
(mL)
1
Day 1
pre-infusion (< 30 min prior to start 
infusion)
1.0
1
Day 1
1 – 1.25 hour
1.0
1
Day 1/2
22 – 24 hour
1.0
1
Day 15
1 – 1.25 hour
1.0
1
Day 15/16
22 – 24 hour
1.0
Total blood volume to be collected per patient
5 mL
All copanlisib concentration-time data collected during the study will be listed only.
Concentration data of copanlisib from this study will be analyzed separately by cohort for 
Phase I part and by indication for Phase II part in PK analysis set to estimate the individual 
maximum drug concentration (Cmax) and AUC(0-168) on Cycle 1 Day 1 and Day 15. Besides, 
these analyses will also be done by age subgroup (< 1 year, 1 year - 6 years and > 6 years).
Any further statistical analysis will be described in a separate M&S report.
6.5
Biomarker/ pharmacodynamics (PD) evaluation
Biomarker investigations in the current study will include both PD biomarker assessments to 
examine the effect of copanlisib on signaling pathway activity and downstream tumor cell 
processes, as well as potentially predictive biomarkers to determine which molecular subsets 
may respond to treatment. 
The biomarker and pharmacodynamics sampling will be collected from all patients (except 
≤1 year old) at screening, Cycle 1 Day 15 and end of treatment. Biomarker data collected in 
the clinical database will be listed. 


Statistical Analysis Plan
Protocol No.: BAY 80-6946 / 19176
Page: 24 of 24
The following variables will be summarized by cohort for Phase I part and by indication for 
Phase II part, using descriptive statistics. 
PD:

The change in phosphorylated AKT (pAKT) relative to total AKT in surrogate tissue 
(platelet rich plasma) 

The maximum change from baseline of insulin and C-peptide during copanlisib 
treatment 
Biomarker:

Exploration of change from baseline in pAKT from surrogate tissue (platelet rich 
plasma) during copanlisib treatment

Exploration of the time course of glucose metabolism markers (plasma glucose, 
insulin, and C-peptide) during copanlisib treatment

Exploration of change from baseline in plasma protein panel

Molecular status (genetic alterations, protein expression and / or activation) of 
biomarkers related to PI3K signaling in tumor tissue. Molecular status at progression 
may be assessed if a fresh tumor is collected at progression.
Further exploratory statistical analyses may be performed and relationships between 
biomarker data and clinical outcome will be evaluated in a separate report. The biomarker 
results may be reported separately from the main clinical study report (CSR).
7.
Document history and changes in the planned statistical analysis
None.
8.
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Porcher R, Desseaux K. What inference for two-stage Phase II trials? BMC Med Res 
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Kaplan E and Meier P. Nonparametric estimation form incomplete observations. J Amer 
Statist Assn 1958; 53:457–481  
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Brookmeyer R and Crowley J. A confidence interval for the median survival time. 
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