Conditions: Lymphoma, Non-Hodgkin
Keywords: indolent Non-Hodgkin lymphoma rituximab-refractory
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 25
Healthy volunteers: no

Brief summary:
To assess the safety of copanlisib.

Detailed description:

Arms:
arm 1: patients with rituximab-refractory iNHL

Interventions: intervention 1: Copanlisib (BAY 80-6946)
Intervention descriptions: intervention 1: 60 mg of experimental drug in solution administered intravenously on Days 1, 8 and 15 of each 28-day treatment cycle

Protocol document:
Prot_000.pdf: 
Document Type:  
Clinical Study Protocol 
Official Title: 
A randomized, double-blind Phase III study of copanlisib versus placebo 
in patients with rituximab-refractory indolent non-Hodgkin’s lymphoma 
(iNHL) - CHRONOS-2 
NCT Number:  
NCT02369016 
Document Date:  
01 DEC 2017 
 


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Cover page of the integrated protocol
A randomized, double-blind Phase III study of copanlisib versus placebo in patients 
with rituximab-refractory indolent non-Hodgkin’s lymphoma (iNHL) – CHRONOS-2
This protocol version is an integration of the following documents / sections:
Original protocol, Version 1.0, dated 20 MAY 2014
Amendment 01 (global amendment described in Section 13.1)
forming integrated protocol Version 2.0, dated 25 NOV 2014
Amendment 03 (global amendment described in Section 13.2)
forming integrated protocol Version 3.0, dated 16 FEB 2016
Amendment 04 (global amendment described in Section 13.3)
forming integrated protocol Version 4.0, dated 21 JUL 2016
Amendment 05 (global amendment described in Section 13.4)
forming integrated protocol Version 5.0, dated 31 MAR 2017
Amendment 06 (global amendment described in Section 13.5)
forming integrated protocol Version 6.0, dated 01 DEC 2017
Amendments not included in the consecutive numbering of amendments are 
local amendments not forming part of this integrated global protocol. This currently 
includes:
Amendment 02, dated 10 JUN 2015
(local amendment valid for Ireland only)


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Title page
A randomized, double-blind Phase III study of copanlisib versus placebo in patients 
with rituximab-refractory indolent non-Hodgkin’s lymphoma (iNHL) – CHRONOS-2
Phase III copanlisib in rituximab-refractory iNHL
Test drug:
BAY 80-6946 / copanlisib
Study purpose:
Assess the efficacy and safety of copanlisib
Clinical study phase:
III
Date:
01 DEC 2017
EudraCT no.:
2014-000925-19
Version no.: 6.0
Study no.:
BAY 80-6946 / 17322
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 
:
 MD, PhD
Rua Domingos Jorge, 1100 – Bloco 301 - 2º andar 
04779-900, São Paulo, SP Brasil
Telephone: 
(modified by amendment 4, 5 and 6)
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


or DEC 2017 
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Signature of the sponsor's medically responsible person 
The signatory agrees to the content of the final integrated clinical study protocol as presented. 
Responsible person changed by amendment 1 and 5. 
Name: 
 MD 
Role: 
 
Date: 
Signature: 
PPD
PPD
PPD
PPD


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Signature of principal investigator
The signatory agrees to the content of the final integrated 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.


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Synopsis
Title
A randomized, double-blind Phase III study of copanlisib versus 
placebo in patients with rituximab-refractory indolent non-Hodgkin’s 
lymphoma (iNHL) – CHRONOS-2
Short title
Phase III copanlisib in rituximab-refractory iNHL
Clinical study phase
III
Study objectives
(modified by amendment 1, 5
and 6)
The primary objective of this study is:

To assess the safety of copanlisib.
Test drug
Copanlisib
Name of active ingredient
Copanlisib / BAY 80-6946 / phosphatidylinositol 3-kinase (PI3K) 
inhibitor
Dose
Starting dose: 60 mg.
Dose reductions due to toxicities to 45 mg and further to 30 mg are 
allowed.
To be administered on Days 1, 8 and 15 of each 28-day treatment cycle. 
Route of administration
Intravenous (IV) infusion.
Duration of treatment
(modified by amendment 1, 5
and 6)
Treatment will be continued until disease progression (PD) by radiological 
assessments or clinical progression (tumor evaluations will be made at 
intervals that comply with the institution’s standard of care [per 
investigator’s assessment]), unacceptable toxicity, or until another 
criterion is met for withdrawal from the study treatment.
Reference drug
(modified by amendment 5)
Not applicable. 
Indication
Rituximab-refractory iNHL (“asymptomatic” removed by amendment 1).
Diagnosis and main criteria 
for inclusion
Histologically confirmed diagnosis of indolent B-cell NHL, with 
histological subtype limited to the following:

Follicular lymphoma (FL) grade 1-2-3a.

Small lymphocytic lymphoma (SLL) with absolute lymphocyte 
count < 5 x 109/L at the time of diagnosis and at study entry.

Lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia 
(LPL/WM).

Marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal).
Patients must have received two or more prior lines of treatment (changed 
by amendment 1). A previous regimen is defined as one of the following: 
at least two months of single-agent therapy, at least two consecutive cycles 


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of polychemotherapy, autologous transplant, radioimmunotherapy.
Prior therapy must include rituximab and alkylating agent(s). Prior 
exposure to idelalisib or other PI3K inhibitors is acceptable (except to 
copanlisib) provided that there is no resistance (modified by amendment 1
and 3).
Patients must be refractory to the last rituximab-based treatment, defined 
as no response or response lasting < 6 months after completion of 
treatment. Time interval to assess refractoriness will be calculated between 
the end date (last day) of the last rituximab-containing regimen and the 
day of diagnosis confirmation of the subsequent relapse (modified by 
amendment 3).
Patients must have at least one bi-dimensionally measurable lesion (which 
has not been previously irradiated) according to the Recommendations for 
Initial Evaluation, Staging, and Response Assessment of Hodgkin and 
Non-Hodgkin Lymphoma: The Lugano Classification (changed by 
amendment 1).
Patients affected by WM, who do not have at least one bi-dimensionally 
measurable lesion in the baseline radiologic assessment, must have 
measurable disease, defined as presence of immunoglobulin M (IgM) 
paraprotein with a minimum IgM level ≥ 2 x upper limit of normal (ULN)
and positive immunofixation test (changed by amendment 1 and 3). 
Male or female patients ≥ 18 years of age.
ECOG (Eastern Cooperative Oncology Group) performance status ≤ 1.
Life expectancy of at least 3 months.
Availability of fresh (preferred) and/or archival tumor tissue at Screening.
Adequate bone marrow, liver and renal function as assessed within 7 days 
before start of study treatment.
Left ventricular ejection fraction (LVEF) ≥ the lower limit of normal 
(LLN) for the Institution.
Main criteria for exclusion
Histologically confirmed diagnosis of FL grade 3b.
Chronic lymphocytic leukemia (CLL).
Transformed disease (assessed by investigator):

histological confirmation of transformation, or

clinical and laboratory signs: rapid disease progression, high 
standardized uptake value (> 12) by positron emission tomography 
(PET) at baseline if PET scans are performed (optional).
Bulky disease (criterion changed by amendment 1):

Lymph nodes or tumor mass (except spleen) ≥ 7 cm LDi (longest 
diameter).
Known lymphomatous involvement of the central nervous system.
Uncontrolled arterial hypertension despite optimal medical management 
(per investigator’s assessment) (modified and added to synopsis by 


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amendment 3).
Type I or II diabetes mellitus with HbA1c > 8.5% at Screening (modified 
by amendment 3).
Known history of human immunodeficiency virus (HIV) infection.
Hepatitis B (HBV) or hepatitis C (HCV). Patients positive for HBsAg or 
HBcAb will be eligible if they are negative for HBV-DNA. Patients 
positive for HCV immunoglobulin G (IgG) will be eligible if they are 
negative for HCV-RNA.
History or concurrent condition of interstitial lung disease of any severity
and/or severely impaired lung function (clarified by amendment 1).
Documented evidence of resistance to a prior treatment with idelalisib or 
other PI3K inhibitors defined as (exclusion criterion added by 
amendment 1):

No response (response defined as partial response [PR] or complete 
response [CR]) at any time during therapy, or

Progression (PD) after any response (PR/CR) or after stable disease
(SD) within 6 months from the start of the therapy with a PI3K 
inhibitor (modified by amendment 3).
Patients who discontinued treatment due to other reason than 
disease progression, and did not exhibit any signs of PD, will be 
allowed to enroll in this study after discussion with the sponsor.
Prior treatment with copanlisib (added by amendment 3).
Study design
(modified by amendment 1, 5
and 6)
Initially this was a randomized, double-blind, two-arm Phase III study to 
evaluate the efficacy and safety of copanlisib as monotherapy in 
comparison to placebo in patients with rituximab-refractory iNHL.
Following sponsor’s decision to stop enrollment due to lack of feasibility 
to complete this study in reasonable time frame, the study design is 
modified. All patients will be given an opportunity to continue treatment 
with copanlisib. Patients who are on copanlisib treatment at the time of 
unblinding will continue copanlisib treatment. Patients who are on placebo 
at the time of unblinding will be offered to switch to copanlisib treatment
after unblinding procedures are completed.
After individual patient unblinding, patients receiving placebo, who switch 
to copanlisib will have all study assessments reset to the initial schedule of 
study evaluations (i.e. as if the patient was restarted the study at Cycle 1 
Day 1). 
Methodology
(modified by amendment 1, 3, 4, 5
and 6)
The study is composed of the following periods: Screening, Treatment, 
and Safety-follow-up.
By the time the protocol amendment 6 becomes effective, screening 
procedures are no longer applicable as screening for the study ended on 
03 MAR 2017. All screened eligible patients have started treatment.
Patients will receive 60 mg copanlisib IV infusion on Days 1, 8 and 15 of 
each 28-day treatment cycle.
Treatment will be continued until PD, unacceptable toxicity, or until 


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another criterion is met for withdrawal from the study treatment.
An End-of-treatment (EOT) visit will be performed within 7 days after the 
decision is made to discontinue study treatment. Following completion of 
the EOT visit, patients will enter the Safety follow-up. The Safety follow-
up (SFU) visit will take place 30 days (window of +5 days allowed) after 
the last administration of study drug.
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, 
and at the SFU visit.
Tumor assessments (and laboratory/clinical tests for WM patients) will be 
made according to the institution’s standard of care.
Bone marrow biopsy may be performed at the investigator discretion if 
there is clinical suspicion of bone marrow infiltration. Bone marrow 
biopsy will be performed per local standard of care.
Type of control
(modified by amendment 5)
Not applicable.
Number of patients
(modified by amendment 5)
Following sponsor’s decision to stop the study no further patients will be 
enrolled. All patients enrolled in the study by the time the protocol 
amendment 5 is approved will be unblinded.
Primary variable
(modified by amendment 5 and 6)
The primary analysis is safety, which includes treatment-emergent AEs 
(TEAEs) and serious adverse events (SAEs), laboratory parameters, and 
vital signs.
Plan for statistical analysis
(modified by amendment 5 and 6)
Due to the decision of stopping enrollment as protocol amendment 5 
becomes effective, limited number of patients will be included in the 
analyses. Therefore, the statistical analyses included in this study will be 
focused on descriptive statistics on safety variables only.
Two sets of analyses will be performed at the timing when all patients 
have completed the study treatment and Safety follow-up period (if 
applicable):
1)
unblinding cutoff: analyze all data available before the unblinding 
(details in section 6.5); 
2)
final analysis: analyze all data available until all patients have 
completed the copanlisib study treatment and Safety follow-up period. 


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Table of contents
Cover page of the integrated protocol.................................................................................... 1
Title page................................................................................................................................... 2
Signature of the sponsor’s medically responsible person..................................................... 3
Signature of principal investigator......................................................................................... 4
Synopsis..................................................................................................................................... 5
Table of contents....................................................................................................................... 9
Table of tables......................................................................................................................... 20
Table of figures....................................................................................................................... 20
List of abbreviations............................................................................................................... 21
Definitions of terms ................................................................................................................ 25
1.
Introduction..................................................................................................................... 25
1.1
Background.................................................................................................................... 25
1.1.1
Copanlisib (BAY 80-6946) ........................................................................................ 27
1.1.2
Clinical experience ..................................................................................................... 27
1.2
Rationale of the study .................................................................................................... 29
1.3
Benefit-risk assessment.................................................................................................. 29
2.
Study objectives............................................................................................................... 30
3.
Investigator and other study personnel......................................................................... 30
4.
Study design..................................................................................................................... 31
5.
Study population ............................................................................................................. 35
5.1
Eligibility ....................................................................................................................... 35
5.1.1
Inclusion criteria......................................................................................................... 35
5.1.2
Exclusion criteria........................................................................................................ 37
5.1.3
Justification of selection criteria................................................................................. 40
5.2
Withdrawal of patients from study ................................................................................ 40
5.2.1
Withdrawal ................................................................................................................. 40
5.2.1.1
Withdrawal from study treatment ........................................................................... 40
5.2.1.2
Withdrawal from follow-up period ......................................................................... 42
5.2.2
Replacement ............................................................................................................... 42
5.3
Patient identification...................................................................................................... 42
6.
Treatments....................................................................................................................... 43
6.1
Treatments to be administered....................................................................................... 43
6.2
Identity of study treatment............................................................................................. 43
6.3
Treatment assignment.................................................................................................... 44
6.4
Dosage and administration............................................................................................. 44
6.4.1
Dose modification ...................................................................................................... 46


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6.4.1.1
Hematological toxicity............................................................................................ 47
6.4.1.2
Non-hematological toxicity..................................................................................... 48
6.4.2
Treatment of toxicities................................................................................................ 51
6.4.2.1
Management of transient post-infusion glucose increases that can occur with study 
treatment.................................................................................................................. 51
6.4.2.2
Management of hyperlipidemia .............................................................................. 53
6.4.2.3
Treatment of blood pressure increases associated with study treatment................. 53
6.4.2.4
Treatment of vomiting and diarrhea........................................................................ 54
6.4.2.5
Treatment of dermatologic toxicity......................................................................... 54
6.4.2.6
Guidance for monitoring and prophylaxis of opportunistic infection (OI)............. 55
6.5
Blinding ......................................................................................................................... 56
6.6
Drug logistics and accountability................................................................................... 56
6.7
Treatment compliance.................................................................................................... 57
6.8
Post-study therapy.......................................................................................................... 57
6.9
Prior and concomitant therapy....................................................................................... 57
6.9.1
Prohibited concomitant therapy.................................................................................. 57
6.9.2
Permitted concomitant therapy................................................................................... 58
7.
Procedures and variables ............................................................................................... 58
7.1
Schedule of procedures.................................................................................................. 58
7.1.1
Tabulated overview .................................................................................................... 58
7.1.2
Timing of assessments................................................................................................ 64
7.1.2.1
Screening period...................................................................................................... 64
7.1.2.2
Treatment period ..................................................................................................... 66
7.1.2.3
Tumor assessments.................................................................................................. 73
7.1.2.4
End-of-treatment visit ............................................................................................. 73
7.1.2.5
Follow-up periods ................................................................................................... 74
7.2
Population characteristics .............................................................................................. 75
7.2.1
Demographics............................................................................................................. 75
7.2.2
Medical history........................................................................................................... 75
7.2.3
Other baseline characteristics..................................................................................... 76
7.3
Efficacy.......................................................................................................................... 76
7.3.1
Primary efficacy variable............................................................................................ 76
7.3.2
Radiological tumor assessments................................................................................. 76
7.3.3
Tumor assessments in patients with WM................................................................... 77
7.4
Pharmacokinetics / pharmacodynamics......................................................................... 77
7.5
Safety ............................................................................................................................. 78
7.5.1
Adverse events............................................................................................................ 78
7.5.1.1
Definitions............................................................................................................... 78
7.5.1.2
Classifications for adverse event assessment.......................................................... 79
7.5.1.3
Assessments and documentation of adverse events ................................................ 82
7.5.1.4
Reporting of serious adverse events ........................................................................ 82
7.5.1.5
Expected adverse events.......................................................................................... 83
7.5.1.6
Adverse events of special safety interest................................................................. 84
7.5.2
Pregnancies................................................................................................................. 84


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7.5.3
Further safety.............................................................................................................. 84
7.5.3.1
Laboratory............................................................................................................... 84
7.5.3.2
Physical examinations............................................................................................. 86
7.5.3.3
Vital signs................................................................................................................ 87
7.5.3.4
12-lead ECG............................................................................................................ 87
7.5.3.5
Cardiac function...................................................................................................... 88
7.5.3.6
Glucose measurement on infusion days.................................................................. 88
7.6
Other procedures and variables...................................................................................... 88
7.6.1
Biomarker investigations............................................................................................ 88
7.6.2
Quality of life questionnaire....................................................................................... 88
7.6.3
Electronic patient-reported outcomes evaluation ....................................................... 88
7.7
Appropriateness of procedures / measurements ............................................................ 88
8.
Statistical methods and determination of sample size ................................................. 89
8.1
General considerations................................................................................................... 89
8.2
Analysis sets .................................................................................................................. 90
8.3
Variables ........................................................................................................................ 90
8.3.1
Efficacy variables ....................................................................................................... 90
8.3.1.1
Primary efficacy variable ........................................................................................ 90
8.3.1.2
Secondary efficacy variables................................................................................... 90
8.3.1.3
Other efficacy variables .......................................................................................... 90
8.3.2
Safety variables........................................................................................................... 91
8.4
Statistical and analytical plans....................................................................................... 91
8.4.1
Population characteristics........................................................................................... 91
8.4.2
Efficacy....................................................................................................................... 91
8.4.2.1
Primary efficacy analysis ........................................................................................ 91
8.4.2.2
Secondary efficacy analysis .................................................................................... 91
8.4.2.3
Confirmatory statistical testing strategy.................................................................. 91
8.4.2.4
Subgroup analyses................................................................................................... 91
8.4.3
Safety.......................................................................................................................... 91
8.4.4
Pharmacokinetic data.................................................................................................. 92
8.5
Planned interim analyses ............................................................................................... 92
8.6
Determination of sample size......................................................................................... 92
9.
Data handling and quality assurance............................................................................ 92
9.1
Data recording................................................................................................................ 92
9.2
Monitoring ..................................................................................................................... 93
9.3
Data processing.............................................................................................................. 93
9.4
Audit and inspection ...................................................................................................... 94
9.5
Archiving ....................................................................................................................... 94
10. Premature termination of the study.............................................................................. 95
11. Ethical and legal aspects................................................................................................. 95
11.1
Ethical and legal conduct of the study........................................................................... 95
11.2
Patient information and consent .................................................................................... 96
11.3
Publication policy .......................................................................................................... 97


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11.4
Compensation for health damage of patients / insurance .............................................. 98
11.5
Confidentiality ............................................................................................................... 98
12. Reference list.................................................................................................................... 99
13. Protocol amendments.................................................................................................... 102
13.1
Amendment 1............................................................................................................... 102
13.1.1
Overview of changes ................................................................................................ 102
13.1.1.1
Modification 1 – administrative changes .............................................................. 102
13.1.1.2
Modification 2 – introductory information updated.............................................. 102
13.1.1.3
Modification 3 – tumor response criteria updated ................................................ 102
13.1.1.4
Modification 4 – study eligibility criteria updated................................................ 103
13.1.1.5
Modification 5 – time to improvement in DRS-P added as secondary efficacy 
variable.................................................................................................................. 104
13.1.1.6
Modification 6 – PFS2 added as other efficacy variable ...................................... 104
13.1.1.7
Modification 7 – target population for efficacy analysis changed........................ 104
13.1.1.8
Modification 8 – randomization ratio and stratification changed ......................... 105
13.1.1.9
Modification 9 – language on switch to open-label treatment modified............... 105
13.1.1.10 Modification 10 – language on informed consent, re-screening and re-testing 
revised ................................................................................................................... 105
13.1.1.11 Modification 11 – withdrawal criteria updated..................................................... 105
13.1.1.12 Modification 12 – language on study drug reconstitution modified..................... 106
13.1.1.13 Modification 13 – guidelines on management of hyperglycemia updated ........... 106
13.1.1.14 Modification 14 – dose modification rules revised............................................... 106
13.1.1.15 Modification 15 – information on preservation of blinding removed................... 107
13.1.1.16 Modification 16 – prohibited concomitant modification modified....................... 107
13.1.1.17 Modification 17 – laboratory evaluations revised................................................. 107
13.1.1.18 Modification 18 – timing of MUGA/echocardiogram and ECG measurements 
changed.................................................................................................................. 107
13.1.1.19 Modification 19 – clarification of blood pressure and ECG measurements ......... 108
13.1.1.20 Modification 20 – survival sweep language added ............................................... 108
13.1.1.21 Modification 21 – additional language on radiological tumor assessments 
introduced.............................................................................................................. 108
13.1.1.22 Modification 22 – collection of PK samples revised ............................................ 109
13.1.1.23 Modification 23 – collection of tumor tissue/biomarker specimens revised ........ 109
13.1.1.24 Modification 24 – responsible person completing the PRO information sheet 
changed.................................................................................................................. 110
13.1.1.25 Modification 25 – sub-group analysis................................................................... 110
13.1.1.26 Modification 26 – link to GFR calculator added................................................... 110
13.1.1.27 Modification 27 – other clarifications and corrections ......................................... 110
13.1.2
Changes to the protocol text..................................................................................... 112
13.1.2.1
Title page............................................................................................................... 112
13.1.2.2
Signature of the sponsor’s medically responsible person ..................................... 112
13.1.2.3
Synopsis ................................................................................................................ 113
13.1.2.4
Definitions of terms............................................................................................... 122
13.1.2.5
Section 1.1 Background ........................................................................................ 122


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13.1.2.6
Section 1.1.2 Clinical experience.......................................................................... 123
13.1.2.7
Section 1.2 Rationale of the study......................................................................... 124
13.1.2.8
Section 1.3 Benefit-risk assessment...................................................................... 125
13.1.2.9
Section 2 Study objectives .................................................................................... 126
13.1.2.10 Section 3 Investigator and other study personnel.................................................. 127
13.1.2.11 Section 4 Study design.......................................................................................... 127
13.1.2.12 Section 5.1.1 Inclusion criteria.............................................................................. 134
13.1.2.13 Section 5.1.2 Exclusion criteria............................................................................. 135
13.1.2.14 Section 5.2.1 Withdrawal...................................................................................... 137
13.1.2.15 Section 5.2.1.1 Withdrawal from study treatment ................................................ 138
13.1.2.16 Section 5.2.1.2 Withdrawal from follow-up period .............................................. 140
13.1.2.17 Section 5.3 Patient identification .......................................................................... 140
13.1.2.18 Section 6.1 Treatments to be administered ........................................................... 140
13.1.2.19 Section 6.2 Identity of study treatment ................................................................. 140
13.1.2.20 Section 6.3 Treatment assignment ........................................................................ 141
13.1.2.21 Section 6.4 Dosage and administration................................................................. 142
13.1.2.22 Section 6.4.1 Dose modification ........................................................................... 144
13.1.2.23 Section 6.4.1.1 Hematological toxicity................................................................. 145
13.1.2.24 Section 6.4.1.2 Non-hematological toxicity.......................................................... 145
13.1.2.25 Section 6.4.2.1 Management of hyperglycemia that can occur with study 
treatment................................................................................................................ 149
13.1.2.26 Section 6.5 Blinding.............................................................................................. 152
13.1.2.27 Section 6.9.1 Prohibited concomitant therapy ...................................................... 152
13.1.2.28 Section 6.9.2 Permitted concomitant therapy........................................................ 153
13.1.2.29 Section 7.1.1 Tabulated overview......................................................................... 154
13.1.2.30 Section 7.1.2 Timing of assessments .................................................................... 166
13.1.2.31 Section 7.1.2.1 Screening period........................................................................... 166
13.1.2.32 Section 7.1.2.2 Treatment period .......................................................................... 169
13.1.2.33 Section 7.1.2.2.1 Treatment – Cycle 1 .................................................................. 170
13.1.2.34 Section 7.1.2.2.2 Treatment – Cycle 2 and higher ................................................ 175
13.1.2.35 Section 7.1.2.3 Tumor assessments....................................................................... 180
13.1.2.36 Section 7.1.2.4 End-of-treatment visit .................................................................. 181
13.1.2.37 Section 7.1.2.5 Follow-up periods/Safety follow-up ............................................ 183
13.1.2.38 Section 7.1.2.5.3 Survival follow-up..................................................................... 184
13.1.2.39 Section 7.2.2 Medical history................................................................................ 184
13.1.2.40 Section 7.3.2 Radiological tumor assessments...................................................... 185
13.1.2.41 Section 7.4 Pharmacokinetics / pharmacodynamics ............................................. 187
13.1.2.42 Section 7.5.3 Further safety................................................................................... 188
13.1.2.43 Section 7.5.3.1 Laboratory.................................................................................... 189
13.1.2.44 Section 7.5.3.2 Physical examinations.................................................................. 190
13.1.2.45 Section 7.5.3.2.1 Complete physical examination ................................................ 190
13.1.2.46 Section 7.5.3.3 Vital signs..................................................................................... 190
13.1.2.47 Section 7.5.3.4 12-lead ECG................................................................................. 191
13.1.2.48 Section 7.6.1 Biomarker investigations................................................................. 191
13.1.2.49 Section 7.6.2 Quality of life questionnaire............................................................ 194


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13.1.2.50 Section 7.6.3 Electronic patient-reported outcomes evaluation............................ 194
13.1.2.51 Section 7.7 Appropriateness of procedures / measurements................................. 195
13.1.2.52 Section 8.1 General considerations....................................................................... 195
13.1.2.53 Section 8.3.1.2 Secondary efficacy variables........................................................ 196
13.1.2.54 Section 8.3.1.3 Other efficacy variables ............................................................... 197
13.1.2.55 Section 8.4.1 Population characteristics................................................................ 198
13.1.2.56 Section 8.4.2 Efficacy ........................................................................................... 198
13.1.2.57 Section 8.4.2.1 Primary efficacy analysis ............................................................. 198
13.1.2.58 Section 8.4.2.2 Secondary efficacy analysis ......................................................... 200
13.1.2.59 Section 8.4.2.3 Confirmatory statistical testing strategy....................................... 202
13.1.2.60 Section 8.4.2.4 Subgroup analyses........................................................................ 204
13.1.2.61 Section 8.4.3 Safety............................................................................................... 204
13.1.2.62 Section 8.6 Determination of sample size............................................................. 205
13.1.2.63 Section 11.2 Patient information and consent....................................................... 207
13.1.2.64 Section 12 Reference list....................................................................................... 207
13.1.2.65 Section 14.1 Evaluation of tumor response........................................................... 208
13.1.2.66 Section 14.5 Glomerular filtration rate ................................................................. 211
13.2
Amendment 3............................................................................................................... 212
13.2.1
Overview of changes ................................................................................................ 212
13.2.1.1
Modification 1 – update of clinical experience with copanlisib ........................... 212
13.2.1.2
Modification 2 – clarification of rituximab-refractoriness assessment................. 212
13.2.1.3
Modification 3 – clarification of inclusion criterion related to WM patients ....... 212
13.2.1.4
Modification 4 – modification of contraception and pregnancy testing 
requirements.......................................................................................................... 212
13.2.1.5
Modification 5 – modification of inclusion criterion related to laboratory 
requirements.......................................................................................................... 213
13.2.1.6
Modification 6 – modification of exclusion criterion related to arterial 
hypertension .......................................................................................................... 213
13.2.1.7
Modification 7 – exclusion of patients based on plasma glucose levels removed 213
13.2.1.8
Modification 8 – clarification of exclusion criterion related to proteinuria.......... 214
13.2.1.9
Modification 9 – language on corticosteroid therapy clarified ............................. 214
13.2.1.10 Modification 10 – modification of exclusion criterion related to evidence of 
resistance to PI3K inhibitors ................................................................................. 214
13.2.1.11 Modification 11 – prior treatment with copanlisib added to the exclusion criteria.214
13.2.1.12 Modification 12 – detailed instructions on copanlisib handling and PK blood 
sampling removed ................................................................................................. 214
13.2.1.13 Modification 13 – updated guidance for management and monitoring of glucose 
increases ................................................................................................................ 215
13.2.1.14 Modification 14 – updated guidance for management and monitoring of blood 
pressure increases.................................................................................................. 215
13.2.1.15 Modification 15 – fasting requirement for lipid panels revised............................ 216
13.2.1.16 Modification 16 – clarification of laboratory criteria for patients who switch to 
open-label treatment.............................................................................................. 216
13.2.1.17 Modification 17 – dose modification guidance of study treatment for NIP 
modified ................................................................................................................ 216


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13.2.1.18 Modification 18 – clarification of tumor evaluation language.............................. 216
13.2.1.19 Modification 19 – usage of verapamil and diltiazem amended ............................ 217
13.2.1.20 Modification 20 – clarification of AE reporting language.................................... 217
13.2.1.21 Modification 21 – language related to hemoglobin A1c measurements clarified. 218
13.2.1.22 Modification 22 – assessment of hydration status added...................................... 218
13.2.1.23 Modification 23 – paper PRO questionnaire removed.......................................... 218
13.2.1.24 Modification 24 – reference to the Declaration of Objection form removed........ 218
13.2.1.25 Modification 25 – other clarifications and corrections ......................................... 218
13.2.2
Changes to the protocol text..................................................................................... 219
13.2.2.1
Synopsis ................................................................................................................ 220
13.2.2.2
List of abbreviations.............................................................................................. 222
13.2.2.3
Section 1.1.2 Clinical experience.......................................................................... 222
13.2.2.4
Section 1.3 Benefit-risk assessment...................................................................... 225
13.2.2.5
Section 3 Investigator and other study personnel.................................................. 225
13.2.2.6
Section 4 Study design.......................................................................................... 226
13.2.2.7
Section 5.1.1 Inclusion criteria.............................................................................. 227
13.2.2.8
Section 5.1.2 Exclusion criteria............................................................................. 229
13.2.2.9
Section 5.2.1 Withdrawal...................................................................................... 230
13.2.2.10 Section 5.2.1.1 Withdrawal from study treatment ................................................ 231
13.2.2.11 Section 6.2 Identity of study treatment ................................................................. 231
13.2.2.12 Section 6.4 Dosage and administration................................................................. 233
13.2.2.13 Section 6.4.1 Dose modification ........................................................................... 237
13.2.2.14 Section 6.4.1.1 Hematological toxicity................................................................. 238
13.2.2.15 Section 6.4.1.2 Non-hematological toxicity.......................................................... 239
13.2.2.16 Section 6.4.2.1 Management of transient post-infusion glucose increases that can 
occur with study treatment .................................................................................... 243
13.2.2.17 Section 6.4.2.2 Management of hyperlipidemia ................................................... 247
13.2.2.18 Section 6.4.2.3 Treatment of blood pressure increases associated with study 
treatment................................................................................................................ 248
13.2.2.19 Section 6.9.1 Prohibited concomitant therapy ...................................................... 248
13.2.2.20 Section 6.9.2 Permitted concomitant therapy........................................................ 249
13.2.2.21 Section 7.1.1 Tabulated overview......................................................................... 250
13.2.2.22 Section 7.1.2 Timing of assessments .................................................................... 254
13.2.2.23 Section 7.1.2.1 Screening period........................................................................... 254
13.2.2.24 Section 7.1.2.2 Treatment period .......................................................................... 255
13.2.2.25 Section 7.1.2.2.1 Treatment – Cycle 1 .................................................................. 255
13.2.2.26 Section 7.1.2.2.2 Treatment – Cycle 2 and higher ................................................ 259
13.2.2.27 Section 7.1.2.3 Tumor assessments....................................................................... 262
13.2.2.28 Section 7.1.2.4 End-of-treatment visit .................................................................. 262
13.2.2.29 Section 7.3.2 Radiological tumor assessments...................................................... 263
13.2.2.30 Section 7.3.3 Tumor assessments in patients with WM........................................ 265
13.2.2.31 Section 7.4 Pharmacokinetics / pharmacodynamics ............................................. 265
13.2.2.32 Section 7.5.1.3 Assessments and documentation of adverse events ..................... 266
13.2.2.33 Section 7.5.1.4 Reporting of serious adverse events............................................. 266
13.2.2.34 Section 7.5.3 Further safety................................................................................... 266


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13.2.2.35 Section 7.5.3.1 Laboratory.................................................................................... 267
13.2.2.36 Section 7.5.3.2.1 Complete physical examination ................................................ 267
13.2.2.37 Section 7.5.3.2.2 Brief physical examination........................................................ 268
13.2.2.38 Section 7.5.3.3 Vital signs..................................................................................... 268
13.2.2.39 Section 7.5.3.6 Glucose measurement on infusion days....................................... 269
13.2.2.40 Section 7.6.3 Electronic patient-reported outcomes evaluation............................ 269
13.2.2.41 Section 11.2 Patient information and consent....................................................... 270
13.2.2.42 Section 12 Reference list....................................................................................... 270
13.2.2.43 Section 14.1 Evaluation of tumor response........................................................... 271
13.2.2.44 Section 14.7 The average glycemic index of common foods derived from multiple 
studies by different laboratories ............................................................................ 273
13.3
Amendment 4............................................................................................................... 274
13.3.1
Overview of changes ................................................................................................ 274
13.3.1.1
Modification 1 - clarification of bone marrow biopsy sample to be reviewed by 
central pathology................................................................................................... 274
13.3.1.2
Modification 2– update of clinical experience with copanlisib ............................ 274
13.3.1.3
Modification 3– clarification of inclusion criterion related to platelets................ 274
13.3.1.4
Modification 4 – exclusion of patients with Cytomegalovirus (CMV) ................ 274
13.3.1.5
Modification 5 – clarification when a patient withdraws study treatment due to 
CMV infection....................................................................................................... 274
13.3.1.6
Modification 6 – addition of guidance for monitoring and prophylaxis of 
opportunistic infections (OI) ................................................................................. 275
13.3.1.7
Modification 7 – modification to management of hypertension........................... 275
13.3.1.8
Modification 8 – clarification of observation period for adverse events .............. 275
13.3.1.9
Modification 9 – modification to definition of complete response....................... 275
13.3.1.10 Modification 10 – other clarifications and corrections ......................................... 275
13.3.2
Changes to the protocol text..................................................................................... 277
13.3.2.1
Title page............................................................................................................... 277
13.3.2.2
Synopsis ................................................................................................................ 278
13.3.2.3
List of abbreviations.............................................................................................. 279
13.3.2.4
Section 1.1.2 Clinical experience.......................................................................... 279
13.3.2.5
Section 3 Investigator and other study personnel.................................................. 279
13.3.2.6
Section 4 Study design.......................................................................................... 280
13.3.2.7
Section 5.1.1 Inclusion criteria.............................................................................. 280
13.3.2.8
Section 5.1.2 Exclusion criteria............................................................................. 281
13.3.2.9
Section 5.2.1 Withdrawal...................................................................................... 281
13.3.2.10 Section 5.2.1.1 Withdrawal from study treatment ................................................ 282
13.3.2.11 Section 6.4.1.2 Non-hematological toxicity.......................................................... 282
13.3.2.12 Section 6.4.2.6 Guidance for monitoring and prophylaxis of opportunistic 
infection (OI)......................................................................................................... 283
13.3.2.13 Section 7.1.1 Tabulated overview......................................................................... 285
13.3.2.14 Section 7.1.2.1 Screening period........................................................................... 288
13.3.2.15 Section 7.1.2.2 Treatment period .......................................................................... 288
13.3.2.16 Section 7.1.2.2.1 Treatment – Cycle 1 .................................................................. 289
13.3.2.17 Section 7.1.2.2.2 Treatment – Cycle 2 and higher ................................................ 291


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13.3.2.18 Section 7.1.2.3 Tumor assessments....................................................................... 293
13.3.2.19 Section 7.1.2.5.1 Safety follow-up........................................................................ 293
13.3.2.20 Section 7.5.1.3 Assessments and documentation of adverse events ..................... 293
13.3.2.21 Section 7.5.3.1 Laboratory.................................................................................... 294
13.3.2.22 Section 7.5.3.2.1 Complete physical examination ................................................ 295
13.3.2.23 Section 7.5.3.2.2 Brief physical examination........................................................ 295
13.3.2.24 Section 7.6.3 Electronic patient-reported outcomes evaluation............................ 295
13.3.2.25 Section 8.3.2 Safety variables ............................................................................... 296
13.3.2.26 Section 14.1 Evaluation of tumor response........................................................... 296
13.4
Amendment 5............................................................................................................... 297
13.4.1
Overview of changes ................................................................................................ 297
13.4.1.1
Modification 1 - study design revised................................................................... 297
13.4.1.2
Modification 2 – statistical methods and efficacy variables revised..................... 297
13.4.1.3
Modification 3 - Central image evaluation revised............................................... 298
13.4.1.4
Modification 4 - Change in frequency of tumor assessment................................. 298
13.4.1.5
Modification 5 – Survival follow-up revised ........................................................ 298
13.4.1.6
Modification 6 – Bone marrow biopsy revised..................................................... 298
13.4.1.7
Modification 7 – laboratory evaluations revised................................................... 298
13.4.1.8
Modification 8 – ECG and MUGA scan or echocardiogram evaluations revised 299
13.4.1.9
Modification 9 – change in the visits during treatment period ............................. 299
13.4.1.10 Modification 10 – administrative information updated and other clarification .... 299
13.4.2
Changes to the protocol text..................................................................................... 299
13.4.2.1
Title Page............................................................................................................... 300
13.4.2.2
Signature of the sponsor’s medically responsible person ..................................... 301
13.4.2.3
Synopsis ................................................................................................................ 302
13.4.2.4
List of abbreviations.............................................................................................. 308
13.4.2.5
Section 1.2 Rationale of the study......................................................................... 309
13.4.2.6
Section 1.3 Benefit-risk assessment...................................................................... 309
13.4.2.7
Section 2. Study objectives ................................................................................... 310
13.4.2.8
Section 3. Investigator and other study personnel................................................. 311
13.4.2.9
Section 4. Study design......................................................................................... 312
13.4.2.10 Section 5.2.1 Withdrawal...................................................................................... 318
13.4.2.11 Section 5.2.1.1 Withdrawal from study treatment ................................................ 319
13.4.2.12 Section 5.2.1.2 Withdrawal from follow-up period .............................................. 319
13.4.2.13 Section 6.1 Treatments to be administered ........................................................... 320
13.4.2.14 Section 6.2 Identity of study treatment ................................................................. 320
13.4.2.15 Section 6.3 Treatment assignment ........................................................................ 321
13.4.2.16 Section 6.4 Dosage and administration................................................................. 323
13.4.2.17 Section 6.5 Blinding.............................................................................................. 323
13.4.2.18 Section 6.6 Drug logistics and accountability....................................................... 325
13.4.2.19 Section 6.7 Treatment compliance........................................................................ 325
13.4.2.20 Section 7.1.1 Tabulated overview......................................................................... 325
13.4.2.21 Section 7.1.2.1 Screening period........................................................................... 333
13.4.2.22 Section 7.1.2.2 Treatment period .......................................................................... 333
13.4.2.23 Section 7.1.2.2.1 Treatment – Cycle 1 .................................................................. 334


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13.4.2.24 Section 7.1.2.2.2 Treatment – Cycle 2 and higher ................................................ 337
13.4.2.25 Section 7.1.2.3 Tumor assessments....................................................................... 340
13.4.2.26 Section 7.1.2.4 End-of-treatment visit .................................................................. 341
13.4.2.27 Section 7.1.2.5 Follow-up periods ........................................................................ 341
13.4.2.28 Section 7.1.2.5.1 Safety follow-up........................................................................ 341
13.4.2.29 Section 7.1.2.5.2 Active follow-up ....................................................................... 342
13.4.2.30 Section 7.1.2.5.3  Survival follow-up.................................................................... 343
13.4.2.31 Section 7.3.1 Primary efficacy variable ................................................................ 343
13.4.2.32 Section 7.3.2 Radiological tumor assessments...................................................... 344
13.4.2.33 Section 7.3.3 Tumor assessments in patients with WM........................................ 345
13.4.2.34 Section 7.4 Pharmacokinetics / pharmacodynamics ............................................. 346
13.4.2.35 Section 7.5.3 Further safety................................................................................... 346
13.4.2.36 Section 7.6.1 Biomarker investigations................................................................. 347
13.4.2.37 Section 7.6.2 Quality of life questionnaire............................................................ 348
13.4.2.38 Section 7.6.3 Electronic patient-reported outcomes evaluation............................ 349
13.4.2.39 Section 8.1 General considerations....................................................................... 349
13.4.2.40 Section 8.2 Analysis sets....................................................................................... 350
13.4.2.41 Section 8.3.1 Efficacy variables............................................................................ 351
13.4.2.42 Section 8.3.1.1 Primary efficacy variable ............................................................. 351
13.4.2.43 Section 8.3.1.2 Secondary efficacy variables........................................................ 352
13.4.2.44 Section 8.3.1.3 Other efficacy variables ............................................................... 353
13.4.2.45 Section 8.4.1 Population characteristics................................................................ 354
13.4.2.46 Section 8.4.2 Efficacy ........................................................................................... 354
13.4.2.47 Section 8.4.2.1 Primary efficacy analysis ............................................................. 354
13.4.2.48 Section 8.4.2.2 Secondary efficacy analysis ......................................................... 356
13.4.2.49 Section 8.4.2.3 Confirmatory statistical testing strategy....................................... 357
13.4.2.50 Section 8.4.2.4 Subgroup analyses........................................................................ 359
13.4.2.51 Section 8.4.3 Safety............................................................................................... 359
13.4.2.52 Section 8.6 Determination of sample size............................................................. 360
13.4.2.53 Section 9.3 Data processing .................................................................................. 362
13.4.2.54 Section 10. Premature termination of the study.................................................... 362
13.4.2.55 Section 11.2 Patient information and consent....................................................... 363
13.4.2.56 Section 12. Reference list...................................................................................... 363
13.4.2.57 Appendix 14.6 Quality of life questionnaire: NCCN-FACT FLymSI-18 ............ 364
13.5
Amendment 6............................................................................................................... 366
13.5.1
Overview of changes ................................................................................................ 366
13.5.1.1
Modification 1 – Study design revised.................................................................. 366
13.5.1.2
Modification 2 – Change in primary endpoint...................................................... 366
13.5.1.3
Modification 3 – Change in statistical analysis..................................................... 366
13.5.1.4
Modification 4 – Clarification in determination of sample size............................ 367
13.5.1.5
Modification 5 – PK and biomarker analyses removed ........................................ 367
13.5.1.6
Modification 6 – Bone marrow biopsy revised..................................................... 367
13.5.1.7
Modification 7 – Meal timing on infusion days revised ....................................... 367
13.5.1.8
Modification 8 – Home glucose monitoring ......................................................... 367
13.5.1.9
Modification 9 – Clarification and change in withdrawal criteria ........................ 368


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13.5.1.10 Modification 10 – Change in glucose increase dose modification rules............... 368
13.5.1.11 Modification 11 – Change in tumor assessments.................................................. 368
13.5.1.12 Modification 12 – Addition of a clarification note related to hemoglobin test 
results on infusion Days 8 and 15 ......................................................................... 368
13.5.1.13 Modification 13 – Administrative information updated and other clarification ... 368
13.5.2
Changes to the protocol text..................................................................................... 370
13.5.2.1
Title page............................................................................................................... 370
13.5.2.2
Synopsis ................................................................................................................ 371
13.5.2.3
Section 1.1.2 Clinical experience.......................................................................... 375
13.5.2.4
Section 1.2 Rationale of the study......................................................................... 375
13.5.2.5
Section 2. Study objectives ................................................................................... 375
13.5.2.6
Section 3. Investigator and other study personnel................................................. 376
13.5.2.7
Section 4. Study design......................................................................................... 377
13.5.2.8
Section 5.2.1.1 Withdrawal from study treatment ................................................ 382
13.5.2.9
Section 5.2.1.2 Withdrawal from follow-up period .............................................. 383
13.5.2.10 Section 6.4 Dosage and administration................................................................. 384
13.5.2.11 Section 6.4.1 Dose modification ........................................................................... 387
13.5.2.12 Section 6.4.1.2 Non-hematological toxicity.......................................................... 388
13.5.2.13 Section 6.4.2.1 Management of transient post-infusion glucose increases that can 
occur with study treatment .................................................................................... 389
13.5.2.14 Section 7.1.1 Tabulated overview......................................................................... 391
13.5.2.15 Section 7.1.2.1 Screening period........................................................................... 399
13.5.2.16 Section 7.1.2.2.1 Treatment – Cycle 1 .................................................................. 401
13.5.2.17 Section 7.1.2.2.2 Treatment – Cycle 2 and higher ................................................ 404
13.5.2.18 Section 7.1.2.3 Tumor assessments....................................................................... 407
13.5.2.19 Section 7.1.2.4 End-of-treatment visit .................................................................. 408
13.5.2.20 Section 7.1.2.5 Follow-up periods ........................................................................ 409
13.5.2.21 Section 7.1.2.5.2 Active follow-up ....................................................................... 409
13.5.2.22 Section 7.1.2.5.3 Survival follow-up..................................................................... 410
13.5.2.23 Section 7.3.1 Primary efficacy variable ................................................................ 410
13.5.2.24 Section 7.3.2 Radiological tumor assessments...................................................... 411
13.5.2.25 Section 7.3.3 Tumor assessments in patients with WM........................................ 413
13.5.2.26 Section 7.4 Pharmacokinetics / pharmacodynamics ............................................. 413
13.5.2.27 Section 7.5.1.3 Assessments and documentation of adverse events ..................... 414
13.5.2.28 Section 7.5.3.6 Glucose measurement on infusion days....................................... 415
13.5.2.29 Section 7.6.1 Biomarker investigations................................................................. 415
13.5.2.30 Section 7.7 Appropriateness of procedures / measurements................................. 417
13.5.2.31 Section 8.1 General considerations....................................................................... 417
13.5.2.32 Section 8.2 Analysis sets....................................................................................... 419
13.5.2.33 Section 8.3.1 Efficacy variables............................................................................ 420
13.5.2.34 Section 8.3.1.1 Primary efficacy variable ............................................................. 420
13.5.2.35 Section 8.3.1.2 Secondary efficacy variables........................................................ 420
13.5.2.36 Section 8.3.2 Safety variables ............................................................................... 421
13.5.2.37 Section 8.4.2 Efficacy ........................................................................................... 421
13.5.2.38 Section 8.4.3 Safety............................................................................................... 422


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13.5.2.39 Section 8.4.4 Pharmacokinetic data ...................................................................... 422
13.5.2.40 Section 8.6 Determination of sample size............................................................. 422
13.5.2.41 Section 9.1 Data recording.................................................................................... 423
13.5.2.42 Section 10. Premature termination of the study.................................................... 423
13.5.2.43 Section 11.2 Patient information and consent....................................................... 424
13.5.2.44 Section 12. Reference list...................................................................................... 424
13.5.2.45 Section 14.7 The average glycemic index of common foods derived from multiple 
studies by different laboratories ............................................................................ 424
14. Appendices..................................................................................................................... 426
14.1
Evaluation of tumor response ...................................................................................... 426
14.2
A list of CYP3A4 inhibitors and inducers................................................................... 428
14.3
ECOG Performance Status .......................................................................................... 429
14.4
New York Heart Association (NYHA) Functional Classification............................... 429
14.5
Glomerular filtration rate............................................................................................. 430
14.6
Quality of life questionnaire: NCCN-FACT FLymSI-18............................................ 430
14.7
The average glycemic index of common foods derived from multiple studies by 
different laboratories.................................................................................................... 431
Table of tables
Table 6–1 Fasting requirements and pre-dose glucose levels ................................................ 44
Table 6–2 Laboratory test criteria for Day 1 dose of subsequent cycles................................ 46
Table 6–3 Dose levels of study treatment .............................................................................. 47
Table 6–4 Dose modification of study treatment for hematological toxicity......................... 47
Table 6–5 Dose modification of study treatment for non-hematological toxicity (except 
glucose increases, dermatologic toxicity, non-infectious pneumonitis and arterial 
hypertension)......................................................................................................... 48
Table 6–6 Dose modification of study treatment for dermatologic toxicity .......................... 49
Table 6–7 Dose modification of study treatment for non-infectious pneumonitis (NIP)....... 49
Table 6–8 Dose modification of study treatment for arterial hypertension............................ 51
Table 6–9 Management of transient post-infusion glucose increases.................................... 52
Table 6–10 Guidance on treatment of skin toxicities............................................................... 54
Table 7–1 Study flow chart .................................................................................................... 59
Table 8–1 Analysis data cutoffs and treatment group overview............................................ 90
Table of figures
Figure 4–1 Study periods as of amendment 6.......................................................................... 32
Figure 4–2 Overall study design as of amendment 5............................................................... 32


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List of abbreviations
List of abbreviations was updated by amendment 1, 3, 4 and 5.
131I
Iodine-131
90Y
Yttrium-90
β-hCG
β-human chorionic gonadotropin
AE
Adverse event
AG
Joint stock company, Aktiengesellschaft
AKT
Protein kinase B
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration-time curve
AUC(0-25)
AUC from time zero to 25 hours
BP
Blood pressure
BTK
Bruton’s tyrosine kinase
BUN
Blood urea nitrogen
CBC
Complete blood count
CD4
Cluster of differentiation 4
CD8
Cluster of differentiation 8
CD20
B lymphocyte antigen CD20
CHOP
Cyclophosphamide, hydroxydaunorubicin, vincristine, prednisolone
c-KIT
Proto-oncogene cKIT (CD117)
CLL
Chronic lymphocytic leukemia
Cmax
Maximum drug concentration
CMV
Cytomegalovirus
CR
Complete response
CRF
Case report form
CRO
Contract research organization
CRP
C-reactive protein
CRR
Complete response rate
CSP
Clinical study protocol
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CVP
Cyclophosphamide, vincristine, prednisolone
CYP3A4
Cytochrome P450 isoenzyme 3A4
CxDy
Cycle x Day y
D
Day
dL
Deciliter
DLBCL
Diffuse large B-cell lymphoma
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DOR
Duration of response
DPP4
Dipeptidyl peptidase-4
DRS-E
Disease-related symptoms – emotional (subscale)
DRS-P
Disease-related symptoms – physical (subscale)
e.g.
For example, exempli gratia


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ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EGFR
Epidermal growth factor receptor
EMA
European Medicines Agency
EOT
End of treatment
EU
European Union
FAS
Full analysis set
FDA
Food and Drug Administration
FDG
Fluorodeoxyglucose
FFPE
Formalin-fixed paraffin-embedded
FL
Follicular lymphoma
FLIPI
Follicular Lymphoma International Prognostic Index
FLymSI-18
NCCN-FACT Lymphoma Symptom Index-18
FND
Fludarabine, mitoxantrone, dexamethasone
FSH
Follicle stimulating hormone
FU
Follow-up
g
Gram
GCL
Global Clinical Leader
GCP
Good Clinical Practice
GEF
Guanine nucleotide exchange factor
GFR
Glomerular filtration rate
GI
Glycemic index
GMP
Good Manufacturing Practice
GPV
Global Pharmacovigilance
h
Hour(s)
HbA1c
Glycated hemoglobin
HBcAb
Hepatitis B core antibody
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HDL
High-density lipoprotein
HER
Human epidermal growth factor receptor 
HIV
Human immunodeficiency virus
i.e.
That is, id est
IB
Investigator’s Brochure
IC50
Half maximal inhibitory concentration
ICF
Informed consent form
ICH
International Conference on Harmonization
IDMS
Isotope dilution mass spectrometry
IEC
Independent Ethics Committee
IGF-1R
Insulin-like growth factor 1 receptor
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IHC
Immunohistochemistry
iNHL
Indolent non-Hodgkin’s lymphoma
INR
International normalized ratio
IRB
Institutional Review Board
ISO
International Organization for Standardization


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ITT
Intent to treat
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
kg
Kilogram
LDi
Longest diameter
LDH
Lactate dehydrogenase
LDL
Low-density lipoprotein
LLN
Lower limit normal
LPL
Lymphoplasmacytoid lymphoma 
LVEF
Left ventricular ejection fraction
M-1
Metabolite 1
MALT
Marginal-zone lymphoma of mucosa-associated lymphoid tissue
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
Met
Mesenchymal epithelial transition factor
mg
Milligram
min
Minute(s)
mL
Milliliter 
mmHg
Millimeter of mercury
MN
Minnesota
MR
Minor response
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
mTOR
Mammalian target of rapamycin
MUGA
Multiple gated acquisition
MZL
Marginal zone lymphoma
NCCN-FACT
National Comprehensive Cancer Network – Functional Assessment of 
Cancer Therapy
NCI
National Cancer Institute
NCI-CTCAE
National Cancer Institute – Common Terminology Criteria for Adverse 
Events
NHL
Non-Hodgkin’s lymphoma
NIP
Non-infectious pneumonitis
NJ
New Jersey
NK 
Natural killer
nM
Nanomolar
NMZL
Nodal marginal-zone lymphoma
NYHA
New York Heart Association
OI
Opportunistic Infection
ORR
Objective tumor response rate
OS
Overall survival
PCR
Polymerase chain reaction
PD
Progressive disease
PDGFR
Platelet-derived growth factor receptor
PDK-1
3-phosphoinositide-dependent protein kinase-1
PET
Positron emission tomography


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PFS
Progression-free survival
PFS2
Secondary progression-free survival
PH
Pleckstrin homology
PID
Patient identification number
PI3K
Phosphatidylinositol 3-kinase
PI-4,5-P2
Phosphatidylinositol-4,5-bisphosphate
PIK3CA
Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha
PIP3
Phosphatidylinositol-3,4,5-trisphosphate
PK
Pharmacokinetic(s)
PPD
Product of perpendicular diameters
PR
Partial response
PRO
Patient-reported outcome
PT
Prothrombin time
PTEN
Phosphatase and tensin homolog
PTT
Partial thromboplastin time
QA
Quality assurance
QoL
Quality of life
QTcB
QT interval corrected for heart rate – Bazett
QTcF
QT interval corrected for heart rate – Fridericia
RBC
Red blood cell count
RNA
Ribonucleic acid
RR
Response rate
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical analysis plan
SAS
Statistical analysis system
SCR
Serum creatinine
SD
Stable disease
SDi
Shortest diameter
SFU
Safety follow-up
SGLT-2
Sodium/glucose co-transporter 2
SLL
Small lymphocytic lymphoma
SMZL
Splenic marginal-zone lymphoma
SPD
Sum of the product of the diameters
SOC
Standard of care
SUSAR
Suspected, unexpected, serious adverse reaction
TEAE
Treatment-emergent adverse events
ULN
Upper limit of normal
UPCR
Urine protein to creatinine ratio
US, USA
United States (of America)
vs.
As opposed to, versus
VEGF
Vascular endothelial growth factor
VGPR
Very good partial response
WBC
White blood cell count
WHO
World Health Organization
WHO-DD
WHO Drug Dictionary
WM
Waldenström macroglobulinemia
WOCBP
Woman of childbearing potential
WorseDRSP
Worsening of disease-related symptoms – physical


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Definitions of terms
Section changed by amendment 1.
The tumor response assessment will be done according to the Recommendations for Initial 
Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: 
The Lugano Classification (21), henceforth referred to as the Lugano classification.
For patients with WM, response assessment will be done according to the Response 
Assessment in Waldenström macroglobulinemia: update from the VIth International 
Workshop (22), henceforth referred to as the Owen criteria.
1.
Introduction
1.1
Background
Non-Hodgkin’s lymphomas (NHLs) are a heterogeneous group of lymphoproliferative 
malignancies arising either from B lymphocytes (85–90%) or from T/NK lymphocytes. These 
malignancies typically originate in the lymph nodes, but can involve almost any organ 
tissue (1).
It is estimated that worldwide there were around 356,000 new cases of NHLs in 2008 (2). The 
incidence of NHLs is increasing in many regions, but the frequency of specific histologic 
subtypes of lymphoma varies substantially by geographic region. Over two-thirds of patients 
are 60 years and older (1).
NHLs can be divided according to their clinical behavior in two main prognostic groups: 
indolent NHL (iNHL) and aggressive NHL. Aggressive lymphomas are characterized by an 
aggressive clinical course and may evolve into a lethal presentation if not immediately 
treated. However, with modern chemo-immunotherapy regimens and stem cell transplant 
consolidation a definitive cure can be reached in 50-60% of patients. Indolent NHLs have a 
relatively good prognosis with a median survival longer than 10 years, but they are incurable 
with current available therapeutic options, especially in advanced stages. While they are 
highly responsive to standard chemotherapy regimens and to radiotherapy, their natural 
history is characterized by a continuous pattern of relapses, which can be generally treated 
with success, but the time to next relapse progressively decreases, finally evolving into a 
refractory disease or in a transformation into an aggressive histologic type. The risk of 
transformation has been estimated to be 2-3% per year.
Indolent NHLs encompass the following low-grade histologic subtypes of B-cell NHL 
included in the 2008 World Health Organization (WHO) classification of lymphoid neoplasm: 
follicular lymphoma (FL), small lymphocytic lymphoma (SLL), lymphoplasmacytic 
lymphoma (LPL), which is defined as Waldenström’s macroglobulinemia (WM) when 
associated with a monoclonal immunoglobulin M (IgM) component and bone marrow 
involvement, splenic marginal-zone lymphoma (SMZL), nodal marginal-zone lymphoma 
(NMZL) and marginal-zone lymphoma of mucosa-associated lymphoid tissue (MALT) (3). 
FL is the second most common subtype of NHL with 25% of newly diagnosed cases (4), 
followed by MALT lymphoma with 7% of all NHLs, while other subtypes are rather rare, 


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with SLL, LPL, SMZL and NMZL accounting for 3%, 2%, 2% and 1% of NHL patients, 
respectively.
Optimal treatment of advanced stages of iNHL is controversial because of low cure rates with 
the current therapeutic options. The first line standard therapy usually includes rituximab
(anti-CD20 monoclonal antibody), either alone or in combination with purine nucleoside 
analogs such as fludarabine or 2-chlorodeoxyadenosine, alkylating agents (with or without 
steroids), or combination chemotherapy (CVP, CHOP, FND). The recent rediscovery of the 
‘old’ alkylating agent bendamustine has added a new effective and well-tolerated therapeutic 
option in iNHL, both as first line and in relapsed patients.
As patients invariably relapse, further active and well-tolerated agents are needed. In general, 
treatment with standard agents rarely produces a cure in patients whose disease has relapsed. 
Sustained remissions after relapse can often be obtained in patients with indolent lymphomas, 
but relapse will usually ensue. Relapsed patients can often have their disease controlled with 
single agent or combination chemotherapy, rituximab, radiolabeled anti-CD20 monoclonal 
antibodies, or palliative radiation therapy. In recent years a large number of new agents have 
been developed and are under extensive clinical investigations in FL and indolent non-
follicular lymphomas, including new monoclonal antibodies binding CD20 or other surface 
antigens, immunoconjugates, immunomodulatory agents such as lenalidomide and novel 
agents inhibiting intracellular cancer key pathways such as proteasome inhibitors, mammalian 
target of rapamycin (mTOR)/phosphatidylinositol 3-kinase (PI3K) inhibitors and Bruton’s 
tyrosine kinase (BTK) inhibitors (5).
The emergence of refractoriness to rituximab-based therapy represents a turning point in the 
course of disease, as the number of available treatment options sharply decreases. The most 
recent chemotherapeutic agent that has been approved for use in patients with rituximab-
refractory iNHL is the alkylating agent bendamustine, which has become an important 
therapeutic option, although it is not curative (6). Nevertheless, bendamustine is nowadays 
mostly used in combination with rituximab in first or second line, and it is therefore less 
available in later lines of treatment. In addition, chemotherapy-containing regimens are 
associated with long-term toxic effects, including cumulative myelosuppression, neuropathy, 
cardiac toxicity, and secondary cancers (7-10). Radioimmunotherapies (11) such as iodine-
131 (131I)–labeled tositumomab (12) and yttrium-90 (90Y)–labeled ibritumomab (13) are also 
active, but owing to the potential for hematologic toxic effects, their use has been limited to 
patients with adequate marrow function and limited marrow involvement by tumor. The use 
of these agents is further constrained by the complex procedures for their administration. For 
these reasons, 90Y-ibritumomab is used infrequently, and 131I-tositumomab has been 
withdrawn from the market (14). Very recently, idelalisib (Zydelig) was approved for the 
treatment of patients with double-refractory FL after two prior lines of therapy (15) (sentence 
added by amendment 1).
There is a continuing need for additional, active and safe drugs that can be used in the 
refractory setting. 


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1.1.1
Copanlisib (BAY 80-6946)
The PI3K/AKT/mTOR pathway is one of the prominent pathways that promote cellular 
survival and constitutively is activated in many types of cancers (16, 17). Class I PI3K is 
downstream of most cancer-associated tyrosine kinase growth factor receptors (such as 
epidermal growth factor receptor [EGFR]/ human epidermal growth factor receptor [HER], 
insulin-like growth factor 1 receptor [IGF-1R], platelet-derived growth factor receptor 
[PDGFR], vascular endothelial growth factor [VEGF], c-KIT or mesenchymal epithelial 
transition factor [Met]). Once PI3K is activated, it activates Pleckstrin Homology Domain 
(PH-domain) proteins including 3-phosphoinositide-dependent protein kinase-1 (PDK-1) and 
AKT as well as guanine nucleotide exchange factor (GEF) by generation of 
phosphatidylinositol-3,4,5-trisphosphate (PIP3). The tumor suppressor phosphatase and tensin 
homolog (PTEN) antagonizes PI3K by dephosphorylating PIP3, and its activity is frequently 
lost in cancer cells (18). 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 (17), and radiation (17, 19). 
Four of PI3K isoforms (PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ) are categorized as class I enzymes 
because they can use phosphatidylinositol-4,5-bisphosphate (PI-4,5-P2) as a substrate to 
generate PIP3. Elevated PIP3 in cellular membranes drives several hallmarks of the cancer 
phenotype: cell proliferation, survival, metabolic reprogramming, and migration. PI3Kα and 
PI3Kβ are ubiquitous; PI3Kγ and PI3Kδ are expressed mostly in the hematopoietic tissue. 
The clinical relevance of PI3K inhibition has been demonstrated by the activity of idelalisib 
(PI3Kδ-targeted compound) in patients with refractory iNHL (20).
As expected from its pharmacological properties, copanlisib, a small molecule PI3K inhibitor,
showed excellent anti-tumor activity in pre-clinical models with up-regulated PI3Kα pathway. 
However, copanlisib not only inhibits PI3Kα with IC50 of 0.5 nM, but also PI3Kδ with IC50
of 0.7 nM. Copanlisib also potently regulates nuclear localization of the forkhead family 
members resulting in the induction of transcriptional programs that lead to rapid cell death by 
apoptosis. In addition, copanlisib exhibits anti-angiogenesis activity by effectively blocking 
VEG-stimulated endothelial cell proliferation (for further details, see Investigator's 
Brochure (IB) for copanlisib).
1.1.2
Clinical experience
Section updated by amendment 3, 4 and 6.
Copanlisib is currently under investigation in various trials enrolling cancer patients. As of 
21 JUN 2017, approximately 772 patients with advanced cancer have been treated with 
copanlisib in Phase 1, Phase 2, and Phase 3 clinical trials (please refer to IB) as a single agent 
or in combination with other agents.


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As of 10 FEB 2014, a total of 57 cancer patients were treated in the Phase I monotherapy 
study 12871, with 17 patients in the dose escalation cohorts and 34 patients in the maximum 
tolerated dose (MTD) expansion cohorts (two cohorts including 9 patients with NHL and 
25 patients with solid tumors), as well as 6 patients with Type II diabetes mellitus in the 
diabetic expansion cohort at 0.4 mg/kg. In AUG 2013, the enrollment in study 12871 was 
completed. Dose-limiting toxicity was observed at 1.2 mg/kg with MTD established at 
0.8 mg/kg when administered intravenously (IV) over 1 h, on Days 1, 8 and 15 of every 
28 days given as a single agent. The flat dose of 65 mg correlates with 0.8 mg/kg (MTD level) 
dose and was selected in order to control copanlisib exposure in obese patients. 
In the NHL expansion cohort of Study 12871, a total of 6 non-diabetic patients with FL and 
3 patients with diffuse large B-cell lymphoma (DLBCL) were treated, all initially dosed at 
0.8 mg/kg. As of 01 FEB 2014, according to investigator’s assessment, 7 patients (77.8%) with 
NHL experienced partial response (PR) as best overall response and 2 patients (22.2%) had 
progressive disease. Partial responders included 6 patients with FL and 1 patient with DLBCL. 
A retrospective independent review performed in 8 of the 9 NHL patients (excluding the
clinical assessment) concluded that a complete response (CR) was the best overall response in
the 2 FL long-term responders (assessed as partial responders by the investigators).
The most common treatment-emergent adverse events (TEAEs), regardless of seriousness, 
severity, and causality, occurring in ≥20% of the 57 subjects were hyperglycemia (64.9%), 
nausea (52.6%), fatigue (40.4%), diarrhea (33.3%), hypokalemia (31.6%), hemoglobin 
(decreased) and hypertension (29.8% each), rash/desquamation and vomiting (28.1%, each), 
anorexia (26.3%), constipation (24.6%), cough and dehydration (22.8%, each), and 
dyspnea (21.1%).
Pharmacokinetic (PK) results indicate nearly dose proportional increase in maximum 
concentration (Cmax) and area under curve (AUC(0-25)) values in the 0.1 to 1.2 mg/kg dose 
range and lack of significant accumulation after once weekly dosing. At the MTD of 
0.8 mg/kg, the geometric mean half-life, (t1/2) was approximately 36-42 h (preliminary data), 
supporting a once weekly dosage regimen. To date, one metabolite, the morpholinone derivate 
M-1, showing approximately 4 to 16% of the AUC(0-25) of copanlisib has been identified and 
is currently being investigated in clinical studies. Results of a preliminary population PK 
analysis of copanlisib in studies 12871, 15205 (Phase I monotherapy study in Japanese 
subjects) and Phase II study 16349 (part A) showed no correlation between body weight and 
copanlisib clearance, indicating that body weight-based dosing does not reduce between-
subject variability in copanlisib PK (modified by amendment 1). The use of a fixed dose 
regimen for all patients was therefore considered suitable. Using the available data on 
preliminary safety and efficacy of copanlisib monotherapy, a fixed dose of 60 mg copanlisib 
has been defined as the recommended dose for use in all patients in future clinical studies.
As of 28 FEB 2015, a total of 81 patients with various indolent and aggressive lymphomas 
were treated at a starting dose of 0.8 mg/kg in the ongoing study 16349 (part A). The 
objective of the study was to identify activity signals in various histologic NHL subtypes and 
to further explore the safety profile of copanlisib. In the group of patients with iNHL, the 
following histologies were represented: FL (16 patients), CLL/SLL (14 patients), and 
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systemic treatment. As of the cut-off date the median duration of copanlisib treatment was 
6 cycles in the indolent group. The objective response rate (ORR) was 40% in FL, 38% in 
CLL, 100% in SLL and 67% in MZL (paragraph updated by amendment 1 and 3).
The most frequent TEAEs, regardless of relationship to study drug, occurring in > 20% of the 
whole study population were hyperglycemia (59.3%), hypertension (56.8%), diarrhea 
(40.7%), fatigue (35.8%), nausea (32.1%), neutropenia (28.4%) and anemia (27.2%). The two 
most common study drug-related TEAEs were hyperglycemia (56.8%) and hypertension 
(53.1%). At the time of the cut-off, a total of 75 patients (92.6%), 30 with indolent, and 
45 with aggressive lymphomas, had discontinued the study treatment. Altogether 20 patients
(24.7%) stopped treatment because of AEs. No conspicuous cluster of AEs causing treatment 
discontinuation emerged. Overall 17 out of 81 patients received treatment with short-acting 
insulin (paragraph updated by amendment 1 and 3).
Further details can be found in the IB for copanlisib, which contains comprehensive 
information on the test drug.
1.2
Rationale of the study
Section modified by amendment 1, 5 and 6.
The natural history of patients with progressive iNHL refractory to rituximab as per protocol 
is not known. Copanlisib is a targeted agent that works by controlling the signaling pathway 
relevant for the survival and proliferation of iNHL cells. In addition to objective responses, 
copanlisib appears to induce, in a number of patients, tumor regressions that are below 
response level, but can nevertheless have a positive effect on the course of the disease. The 
evaluation of copanlisib’s anticancer activity via a clinical trial design that controls for the 
natural history of tumor growth minimizes investigator bias in assessing treatment outcomes.
Following sponsor’s decision to stop enrollment due to lack of feasibility to complete this 
study in reasonable time frame, the study design is modified. All patients on study treatment 
will be offered to continue treatment with copanlisib after unblinding procedures are 
completed.
1.3
Benefit-risk assessment
Section modified by amendment 1, 3 and 5.
The proposed indication is a serious and, in the long-term, life-threatening disease. Advanced 
iNHL can be controlled with current treatments for a relatively long time, but remains an 
incurable disease of which the patient will ultimately die. While at the early stages of 
advanced iNHL effective treatments are available (e.g. rituximab + CHOP and 
rituximab + bendamustine), the efficacy of subsequent lines of treatment tends to diminish, 
with progressively decreasing response rate and PFS, and increasing residual toxicity. There 
are no guideline recommendations or widely accepted standards of care for patients beyond 
first relapse. The treatment given depends on the patient’s condition, physician’s preference, 
and availability of drugs not already used in previous lines of treatment. There is therefore a 
need for drugs with new targets and mechanisms of action that are effective and have a safety 
profile different from that of drugs used in earlier lines of treatment. 


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Copanlisib has showed activity in patients with iNHL. In the Phase I study 12871 all 
6 patients with FL responded (please see Section 1.1.2). In the Phase II study 16349 (part A), 
response rates in patients with iNHL of various histologies were: 40% in FL, 67% in MZL, 
and 100% in SLL. Responses included complete remissions. Patients with iNHL were heavily 
pretreated, with 82% having received ≥3, and 36% ≥5 lines of treatment prior to study start.
Hyperglycemia and hypertension, the most frequently observed and expected toxicities with 
copanlisib, have been manageable. Toxicities will be carefully monitored during the course of 
the study with a detailed and tailored program of management. 
Considering the existing evidence of the efficacy of copanlisib treatment in patients with 
iNHL and the manageable toxicities, the benefit/risk ratio of the copanlisib treatment is 
assessed as positive.
2.
Study objectives
Section modified by amendment 1, 5 and 6.
The primary objective of this study is:

To assess the safety of copanlisib.
3.
Investigator and other study personnel
Sponsor’s 
(changed by amendment 4, 5 and 6)
Name:
 MD, PhD
Rua Domingos Jorge, 1100 – Bloco 301 - 2º andar 
04779-900, São Paulo, SP Brasil
Telephone: 
Coordinating Investigator (added by amendment 1)
Name: Grzegorz S. Nowakowski, MD
Address: Division of Hematology
Mayo Clinic
200 First Street SW
Rochester, MN 55905, USA
All other study personnel not included in this section are identified in a separate personnel list 
(not part of this clinical study protocol [CSP]) as appropriate. This list will be updated as 
needed; an abbreviated version with personnel relevant for the centers will be available in 
each center’s investigator site file.
Whenever the term ‘investigator’ is noted in the protocol text, it may refer to either the 
principal investigator at the site, or an appropriately qualified, trained and delegated 
individual of the investigational site.
PPD
PPD
PPD


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The principal investigator of each center must sign the protocol signature sheet before patient
recruitment may start at the respective center. Likewise, all protocol amendments/integrated 
protocols must be signed and dated by the principal investigator before coming into effect at 
the respective center.
A complete list of all participating centers and their investigators, as well as all required 
signature documents, will be maintained in the sponsor study file.
The global sponsor of this study is identified on the title page of this protocol. If required by 
local law, local co-sponsors will be nominated; they will be identified on the respective 
country-specific signature pages.
External data evaluation bodies
Data Monitoring Committee
Section modified by amendment 3 and 5.
A Data Monitoring Committee (DMC) will be established for this study (according to a 
separate DMC charter) in order to ensure ongoing safety of study patients. 
The DMC will include at least three members, including an independent Statistician and 
Oncologist. Safety review meetings will be held as per separate DMC charter.
Decisions on trial termination, amendment, or cessation of patient recruitment based on 
risk/benefit assessment will be made after recommendations from the DMC have been 
assessed by the sponsor.
Central radiological evaluation
Section modified by amendment 5.
After study stopped for enrollment and all patients will be unblinded and offered an open 
label study treatment, there will be no central radiological evaluation.
Central pathology review
The confirmation of histopathological diagnosis will be performed centrally.
4.
Study design
Section modified by amendment 1, 3, 4, 5 and 6.
Design overview
Following sponsor’s decision to stop enrollment due to lack of feasibility to complete this 
study in reasonable time frame, the study design is modified. All patients on study treatment 
will be offered to continue treatment with copanlisib after unblinding procedures are 
completed (see Section 6.5).


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By the time the protocol amendment 6 becomes effective, screening procedures are no longer 
applicable as screening for the study ended on 03 MAR 2017. All screened eligible patients 
have started treatment.
Initially this was a randomized, double-blind, two-arm Phase III study to evaluate the efficacy 
and safety of copanlisib as monotherapy in comparison to placebo in patients with rituximab-
refractory iNHL.
The patients have failed at least two previous lines of therapy. Previous treatments must have 
included rituximab and alkylating agent(s); and the patients must have progressed within six 
months of the end of the last previous rituximab-containing regimen.
The overview of study periods updated by amendment 6 is presented in Figure 4–1.
Figure 4–1
Study periods as of amendment 6
Screening
Treatment
Safety follow-up  
Cycle 1
(Day 1 to 28)
Cycle 2 etc.
(Day 1 to 28)
EOT
visit
SFU
visit
Informed
consent
First dose of 
study drug
Last dose of 
study drug/
End of last cycle
Last protocol-
stipulated 
procedure
EOT = End of treatment; SFU = Safety follow-up.
Figure modified by amendment 6.
The start of the study period is defined by signing of the informed consent form (ICF).
A graphical presentation of the study design valid as of amendment 5 is shown in Figure 4–2.
Figure 4–2
Overall study design as of amendment 5
Figure modified by amendment 1 and replaced by amendment 5.


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The start of the treatment period is defined by first administration of study drug (copanlisib). 
Copanlisib will be administered IV over approximately 1 h at starting dose of 60 mg on Days 
1, 8 and 15 of each 28-day treatment cycle. Treatment will be continued until PD by 
radiological assessments or clinical progression (tumor evaluations will be made at intervals 
that comply with the institution’s standard of care [per investigator’s assessment]),
unacceptable toxicity, or until another criterion is met for withdrawal from the study treatment
(see Section 5.2).
All patients, after unblinding procedures are completed, will be offered an opportunity to 
continue this clinical study and receive active treatment with copanlisib. Patients who are on 
copanlisib treatment at the time of unblinding will continue copanlisib treatment. Patients 
who are on placebo at the time of unblinding will switch to copanlisib treatment after 
unblinding procedures are completed. After individual patient unblinding, patients receiving 
placebo, who switch to copanlisib will have all study assessments reset to the initial schedule 
of study evaluations (i.e. as if the patient was restarted the study at Cycle 1 Day 1). Patients
will be treated until disease progression (per investigator’s assessment), unacceptable toxicity, 
or until another criterion is met for withdrawal from the study treatment (see Section 5.2). 
An End-of-treatment (EOT) visit will be performed within 7 days after the decision is made to 
discontinue study treatment. Following completion of the EOT visit, patients will enter the 
Safety follow-up. The Safety follow-up (SFU) visit will take place 30 days (window of 
+5 days allowed) after the last administration of study drug.
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, 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. Doses may be delayed or reduced in the 
event of clinically significant hematological or other toxicities (see Section 6.4.1.1 and
Section 6.4.1.2) that are possibly, probably or definitely related to study treatment. The dose 
modification levels of study drug will follow the pre-defined dose levels outlined in 
Section 6.4.1.
Tumor assessments (and laboratory/clinical tests for WM patients) will be made according to 
the institution’s standard of care.
The response assessment will be done according to the Lugano Classification (21), and for 
patients with WM, according to the Owen criteria (22). Detailed instructions on tumor 
assessment are provided in Appendix 14.1. 
Bone marrow biopsy may be performed at the investigator discretion if there is clinical 
suspicion of bone marrow infiltration. Bone marrow biopsy will be performed as per local 
standard of care. 
All collected blood, plasma and tumor tissue samples may be utilized for biomarker analysis
to contribute to better understanding the mechanism of action and the disease (see 
Section 7.6.1).


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Primary variable
Due to the decision of stopping enrollment, limited number of patients will be included in the 
analyses. Therefore, the statistical analyses included in this study will be focused on 
descriptive statistics for safety only.
Justification of the design
The pre-clinical profile of copanlisib and preliminary efficacy data from Phase I study 12871 
and Phase II study 16349 suggest that copanlisib may improve PFS in patients with 
rituximab-refractory iNHL who have received two or more prior lines of treatment and have 
been exposed to rituximab and alkylating agent(s). The purpose of this study is to evaluate the 
safety of copanlisib treatment.
End of study
For each participating EU country, the end of the study according to the EU Clinical Trial 
Directive will be reached when the last visit or contact of the last patient for all centers in the 
respective country has occurred.
The primary completion date for this study according to the FDA Amendment Act is specified 
in a separate document (not part of this CSP).


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5.
Study population
5.1
Eligibility
5.1.1
Inclusion criteria
1. Ability to understand and willingness to sign written informed consent. Signed 
informed consent must be obtained before any study specific procedure 1 (footnote 
added by amendment 1).
2. Histologically confirmed diagnosis of indolent B-cell NHL, with histological subtype 
limited to the following:
o
Follicular lymphoma (FL) grade 1-2-3a.
o
Small lymphocytic lymphoma (SLL) with absolute lymphocyte count
< 5 x 109/L at the time of diagnosis and at study entry.
o
Lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM).
o
Marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal).
3. Patients must have received two or more prior lines of treatment (changed by 
amendment 1). A previous regimen is defined as one of the following: at least 
two months of single-agent therapy, at least two consecutive cycles of 
polychemotherapy, autologous transplant, radioimmunotherapy.
4. Prior therapy must include rituximab and alkylating agent(s). Prior exposure to
idelalisib or other PI3K inhibitors is acceptable (except to copanlisib) provided that 
there is no resistance (modified by amendment 1 and 3).
5. Patients must be refractory to the last rituximab-based treatment, defined as no 
response or response lasting < 6 months after completion of treatment. Time interval 
to assess refractoriness will be calculated between the end date (last day) of the last 
rituximab-containing regimen and the day of diagnosis confirmation of the subsequent 
relapse (modified by amendment 3).
6. Patients must have at least one bi-dimensionally measurable lesion (which has not 
been previously irradiated) according to the Recommendations for Initial Evaluation, 
Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The 
Lugano Classification (21) (changed by amendment 1).
                                                
1 Certain results from diagnostic testing performed as part of the standard of practice prior to the informed 
consent date and time may be used to fulfill screening criteria. This includes fresh tissue as noted in the protocol 
as well as results from CT/MRI scans, bone marrow sample, MUGA/echocardiogram and hepatitis testing which 
may also be used provided that they fall into the protocol-specified time window. Archival tissue obtained from 
the patients at any time during the course of their iNHL may also be used prior to the informed consent date and 
time if performed as part of the standard of practice. CT/MRI must also meet the quality standards of the 
Imaging Manual (added by amendment 1).


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7. Patients affected by WM, who do not have at least one bi-dimensionally measurable 
lesion in the baseline radiologic assessment, must have measurable disease, defined as 
presence of immunoglobulin M (IgM) paraprotein with a minimum IgM level ≥ 2 x 
upper limit of normal (ULN) and positive immunofixation test (changed by 
amendment 1 and 3). 
8. Male or female patients ≥ 18 years of age.
9. ECOG performance status ≤ 1.
10. Life expectancy of at least 3 months.
11. Availability of fresh (preferred) and/or archival tumor tissue at Screening.
12. Women of childbearing potential (WOCBP) and men must agree to use effective
contraception when sexually active. This applies for the time period between signing 
of the ICF and 3 months after the last administration of study treatment. A woman 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 women not using hormonal contraception or hormonal 
replacement therapy.
o
The investigator or a designated associate is requested to advise the patient how to 
achieve highly effective birth control (failure rate of less than 1%), e.g. 
intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral 
tubal occlusion, vasectomized partner and sexual abstinence. 
o
The use of condoms by male patients is required unless the female partner is 
permanently sterile (criterion 12 modified by amendment 3).
13. Adequate bone marrow, liver and renal function as assessed by the following 
laboratory requirements conducted within 7 days before start of study treatment:
o
Total bilirubin ≤1.5 x ULN
(≤5 x ULN for patients with proven Gilbert-Meulengracht syndrome or
≤3 x ULN for patients with cholestasis due to compressive adenopathies of the 
hepatic hilum) (modified by amendment 3).
o
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
≤2.5 x ULN 
(≤5 x ULN for patients with liver involvement of their lymphoma).
o
Lipase ≤1.5 x the ULN (modified by amendment 3).
o
Glomerular filtration rate (GFR) ≥ 30 ml/min/1.73 m2 according to the 
Modification of Diet in Renal Disease (MDRD) abbreviated formula.


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o
International normalized ratio (INR) ≤1.5 and
partial thromboplastin time (PTT) ≤1.5 x ULN (modified by amendment 3)
Patients who are therapeutically treated with an agent such as warfarin or heparin 
will be allowed to participate provided that no prior evidence of underlying 
abnormality in coagulation parameters exists. Close monitoring is recommended 
according to the local standard of care.
o
Platelet count ≥ 75,000/mm3. For patients with confirmed lymphomatous bone 
marrow infiltration, platelet count ≥ 50,000 /mm3. Platelet transfusion should not 
be given less than 7 days before the exam collection (modified by amendment 4).
o
Hemoglobin (Hb) ≥ 10 g/dL.
o
Absolute neutrophil count (ANC) ≥ 1500/mm3.
o
Requirements related to serum creatinine (SCR), serum lactate dehydrogenase 
(LDH) and serum beta-2-microglobulin levels removed by amendment 1.
14. Left ventricular ejection fraction (LVEF) ≥ the lower limit of normal (LLN) for the 
Institution.
5.1.2
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. 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).
Excluded medical conditions, previous therapies and medications (modified by 
amendment 4)
3. Histologically confirmed diagnosis of FL grade 3b.
4. Chronic lymphocytic leukemia (CLL).
5. Transformed disease (assessed by investigator):
o
histological confirmation of transformation, or
o
clinical and laboratory signs: rapid disease progression, high standardized 
uptake value (> 12) by positron emission tomography (PET) at baseline if PET 
scans are performed (optional).
6. Previous or concurrent cancer that is distinct in primary site or histology from indolent 
B-cell NHL (clarified by amendment 1) within 5 years before start of study treatment
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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7. Criterion 7 removed by amendment 1.
8. Bulky disease (criterion changed by amendment 1):
o
Lymph nodes or tumor mass (except spleen) ≥7 cm LDi (longest diameter).
9. Criterion 9 removed by amendment 1.
10. Criterion 10 removed by amendment 1.
11. Known lymphomatous involvement of the central nervous system.
12. Congestive heart failure > New York Heart Association (NYHA) class 2.
13. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 
3 months). Myocardial infarction less than 6 months before start of study treatment. 
14. Uncontrolled arterial hypertension despite optimal medical management (per 
investigator’s assessment) (modified by amendment 3).
15. Type I or II diabetes mellitus with HbA1c > 8.5% at Screening (modified by 
amendment 3).
16. Arterial or venous thrombotic or embolic events such as cerebrovascular accident 
(including transient ischemic attacks), deep vein thrombosis or pulmonary embolism 
within 6 months before start of study treatment.
17. Non-healing wound, ulcer, or bone fracture.
18. Active clinically serious infections > CTCAE Grade 2.
19. Known history of human immunodeficiency virus (HIV) infection.
20. Hepatitis B (HBV) or hepatitis C (HCV). All patients must be screened for HBV and 
HCV up to 28 days before start of study treatment using the routine hepatitis virus 
laboratory panel. Patients positive for HBsAg or HBcAb will be eligible if they are 
negative for HBV-DNA. Patients positive for HCV immunoglobulin G (IgG) will be 
eligible if they are negative for HCV-RNA.
21. Patients with seizure disorder requiring medication. 
22. Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding 
event ≥ CTCAE Grade 3 within 4 weeks before start of study treatment.
23. Renal failure requiring hemo- or peritoneal dialysis.
24. Proteinuria ≥ CTCAE Grade 3 as assessed by either a 24 h total urine protein 
quantification or a urine protein to creatinine ratio (UPCR) > 3.5 on a random urine 
sample (modified by amendment 3).
25. History or concurrent condition of interstitial lung disease of any severity and/or 
severely impaired lung function (as judged by the investigator) (clarified by 
amendment 1).
26. Concurrent diagnosis of phaeochromocytoma.


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27. Pregnant or breast-feeding patients. Women of childbearing potential must have a 
serum 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. 
28. Unresolved toxicity > CTCAE Grade 1 attributed to any prior therapy/procedure 
excluding alopecia and ≤ CTCAE Grade 2 peripheral neuropathy.
29. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in 
the formulation.
30. Substance abuse, medical, psychological or social conditions that may interfere with 
the patient’s participation in the study or evaluation of the study results.
31. Any illness or medical conditions that are unstable or could jeopardize the safety of 
the patient and his/her compliance in the study.
32. Criterion 32 removed by amendment 1.
33. Treatment with investigational drugs within 28 days before start of study treatment 
(criterion changed by amendment 1).
34. Ongoing immunosuppressive therapy.
35. Radiotherapy or immuno/chemotherapy within 4 weeks before start of study 
treatment.
36. Radioimmunotherapy or autologous transplant within 3 months before start of study 
treatment.
37. Myeloid growth factors within 14 days before start of study treatment.
38. Blood or platelet transfusion within 14 days before start of study treatment.
39. Ongoing systemic corticosteroid therapy at a daily dose higher than 15 mg prednisone 
or equivalent. Previous corticosteroid therapy must be stopped or reduced to the 
allowed dose at least 7 days before performing the screening CT/MRI (modified by 
amendment 3). If a patient is on chronic corticosteroid therapy, corticosteroids should 
be de-escalated to the maximum allowed dose before the Screening. Patients may be 
using topical or inhaled corticosteroids.
40. History of having received an allogeneic bone marrow or organ transplant.
41. Major surgical procedure, or significant traumatic injury (as judged by the 
investigator) within 28 days before start of study treatment; open biopsy within 7 days 
before start of study treatment.
42. Anti-arrhythmic therapy (beta blockers or digoxin are permitted).
43. Use of strong inhibitors of CYP3A4 is prohibited from Day -14 of Cycle 1 until the 
SFU visit.
44. Use of strong inducers of CYP3A4 is prohibited from Day -14 of Cycle 1 until the 
SFU visit.


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45. Documented evidence of resistance to a prior treatment with idelalisib or other PI3K 
inhibitors defined as (exclusion criterion added by amendment 1):
o
No response (response defined as PR or CR) at any time during therapy, or
o
Progression (PD) after any response (PR/CR) or after stable disease (SD)
within 6 months from the start of the therapy with a PI3K inhibitor (modified 
by amendment 3).
Patients who discontinued treatment due to other reason than disease 
progression, and did not exhibit any signs of PD, will be allowed to enroll in 
this study after discussion with the sponsor.
46. Prior treatment with copanlisib (criterion 46 added by amendment 3).
47. Positive cytomegalovirus (CMV) PCR test at baseline (criterion 47 added by 
amendment 4).
For prohibited concomitant therapy please refer to Section 6.9.1.
5.1.3
Justification of selection criteria
The selection criteria are chosen to ensure that patients with specific risks for administration 
of the test drug and/or patients with conditions which may have an impact on the aims of the 
study are excluded.
5.2
Withdrawal of patients from study
5.2.1
Withdrawal
Section modified by amendment 1 and 5.
A patient who, for any reason (e.g. failure to satisfy the selection criteria), terminates the 
study before randomization is regarded a “screening failure”.
A patient who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the patient has already entered treatment.
5.2.1.1
Withdrawal from study treatment
Patients must be withdrawn from the study treatment for the following reasons:

At their own request or at the request of their legally acceptable representative.
At any time during the study and without giving reasons, a patient may decline to 
participate further. The patient will not suffer any disadvantage as a result. (See 
Section 11.2) (modified by amendment 3 and 6).

If, in the investigator’s opinion, continuation of the study treatment would be harmful 
to the patient’s well-being.

Disease progression (PD) as defined in the Lugano Classification (21), and for patients 
with WM, according to the Owen criteria (22) (changed by amendment 1). Detailed 


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instructions on tumor assessment are provided in Appendix 14.1 (modified by 
amendment 5).

The reason related to AEs due to disease-related complications removed by 
amendment 1.

Occurrence of unacceptable toxicity.

CTCAE Grade 4 arterial hypertension.

Persistent occurrence of post-infusion blood glucose > 500 mg/dL based on laboratory 
analysis which occurred at the lowest study drug dose level despite optimal glucose 
lowering therapy (after at least one cycle of treatment). 
Definition of persistent occurrence is based on repeated post-infusion blood glucose 
laboratory analysis taken at different time during the whole cycle of treatment
(criterion changed by amendment 3 and 6).

CTCAE Grade 4 dermatologic toxicity.

CTCAE Grade 4 non-infectious pneumonitis (NIP).

Drug-induced pancreatitis.

Development of a malignancy other than indolent B-cell NHL (clarified by 
amendment 1). New malignancy will be reported as a SAE.

Start of a new anticancer regimen.

Patient does not tolerate study drug dose of at least 30 mg.

Severe allergic reaction to study drug (such as CTCAE Grade 3 or Grade 4 
hypersensitivity reaction).

Patient lost to follow-up.

Substantial non-compliance with the requirements of the study.

Delay in study drug administration due to toxicities for > 21 days (this does not 
include the required 1 week break), a delay of study drug dosing due to reasons other 
than toxicity is not included in this definition (clarified by amendment 1). Except in 
case of delays due to reactivation of CMV where delay could be up to 2 cycles
(modified by amendment 4).

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.

Detection of illicit drugs or other substances that may, in the opinion of the 
investigator, have a reasonable chance of contributing to toxicity or otherwise 
confound results.

Patients with a positive β-human chorionic gonadotropin (β-hCG) test or any other 
sign consistent with pregnancy. Pregnancy will be reported within the same timelines 
as a SAE via the Pregnancy Monitoring Form.


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Patients may be withdrawn from the study for the following reasons:

At the specific request of the sponsor and in liaison with the investigator (e.g. obvious 
non-compliance, safety concerns).

Clinical progression per investigator assessment (added by amendment 6).
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.
For all patients who discontinue due to radiological PD or clinical PD, only date of PD will be 
collected and recorded in eCRF (added by amendment 6). 
For patients who withdraw consent and object to follow-up data collection, no further study-
related procedures will be allowed, and no further data will be collected. The patients will not 
suffer any disadvantage as a result (modified by amendment 6).
Details for the premature termination of the study as a whole (or components thereof [e.g. 
centers, treatment arms, dose steps]) are provided in Section 10.
5.2.1.2
Withdrawal from follow-up period 
Section modified by amendment 1, 5 and 6.
Following completion of the EOT visit, patients will enter the Safety-follow up period.
Reasons for not performing the Safety follow-up include the following: 

Death

Objection to follow-up data collection

Lost to follow-up
5.2.2
Replacement
Patients will not be replaced.
5.3
Patient identification
At Screening upon signing the ICF, each patient will be assigned a unique patient 
identification number (PID) by Interactive Voice Response System (IVRS)/Interactive Web 
Response System (IWRS) for unambiguous identification. The PID will be constructed as 
follows:


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a.
Digits 1 to 2: Unique country code (clarified by amendment 1).
b. Digits 3 to 5: Center code (unique within each country).
c.
Digits 6 to 9: Unique patient code (unique within each center).
Within the unique patient code the first digit (digit 6) represents the study a patient is 
participating in.
Patients participating in study 17322 (this study) have a ‘2’ as the 6th digit. As an example, 
PIDs in this study have the structure ‘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.
6.
Treatments
6.1
Treatments to be administered
Section modified by amendment 1 and 5.
The following treatments will be administered in this study:

Copanlisib (BAY 80-6946) solution for IV infusion (study drug/investigational 
medicinal product)

Placebo solution for IV infusion removed by amendment 5
Eligible patients will receive copanlisib IV infusion at a starting dose of 60 mg as single agent 
on Days 1, 8 and 15 of each 28-day treatment cycle.
In the event of toxicities, dose reductions to 45 mg and further to 30 mg are allowed. The dose 
modifications will follow the pre-defined dose levels outlined in Section 6.4.1. After full 
recovery from toxicity and in the absence of any criteria for further dose reduction or study 
treatment discontinuation, re-escalation will be allowed at the investigator’s discretion. At no 
time should the administered dose exceed the starting dose of 60 mg. Patients who do not 
tolerate the dose of at least 30 mg must discontinue study treatment permanently (see 
Section 5.2).
See Pharmacy Manual for additional details.
6.2
Identity of study treatment
Section modified by amendment 1, 3 and 5.
The 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 ware of the ingredients. Lists linking all numbering levels 
will be maintained by the sponsor’s clinical supplies QA group. 


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A complete record of batch numbers and expiry dates of study treatment as well as the label 
will be maintained in the sponsor study file.
Copanlisib
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 infusions is obtained after reconstitution 
of the lyophilisate with normal saline 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.
6.3
Treatment assignment
Section modified by amendment 1 and 5.
With protocol amendment 5 there will be no randomization. All patients who are on study 
will be offered the opportunity to continue treatment with copanlisib.
The IXRS/IWRS will remain open in order to manage study drug.
6.4
Dosage and administration
Section modified by amendment 1, 3, 5 and 6.
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.
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).
The requirements for fasting and pre-dose glucose levels are presented in Table 6–1.
Table 6–1
Fasting requirements and pre-dose glucose levels
Period
Fasting ≥ 8 h required before 
first glucose measurement
Pre-dose glucose levels 
(first glucose measurement)
Day 1 of
cycle 1
Yes a
≤125 mg/dL (non-diabetic patients)
<160 mg/dL (diabetic patients)
Subsequent infusions after
Cycle 1 Day 1 
No b
<160 mg/dL (fasting)
< 200 mg/dL (non-fasting)
a: Diabetic patients who take insulin treatment at any cycle visit: Timing and content of meal intake will be 
managed by the investigator. Consultation with treating physician or endocrinologist is advised. 
b: The decision regarding meal timing and fasting can be made by the investigator based on glucose 
response patterns during prior treatment days. 
Table added by amendment 1 and modified by amendment 3 and 6.


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
Fasting refers to a ≥ 8 h fast.

Non-fasting status includes any caloric intake such as meals and also juice, snacks, 
and other caloric intake not consistently called a meal.
From Cycle 1 Day 1 onwards, glucose measurements at the site may be done either by 
laboratory analysis or in capillary blood using a handheld glucose meter. If handheld glucose 
meters are chosen, the appropriate calibration of glucose meters will be documented.
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 on infusion days that timing of meal intake and additional glucose testing 
(if applicable) are managed and monitored by the investigators. Consultation with treating 
physician or diabetes specialist (e.g. diabetologist or endocrinologist) is advised.
All glucose measurements done at the site, oral glucose lowering medication and/or insulin 
administration, if applicable, fasting/non-fasting status and meal intake timing on infusion 
days will be collected as part of the clinical source documentation. 

On infusion days at any cycle:
The decision regarding meal timing and fasting can be made by the investigator based 
on glucose response patterns during prior treatment days.

Cycle 1 Day 1:  
Fasting is required before start of infusion. 

Subsequent visits after C1D1 visit:
Fasting is not required before start of infusion.
Dosing criteria
Starting from Cycle 1 Day 8, 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. On Day 
1 of each subsequent cycle, the dose of study drug will be given only if the laboratory test
criteria described in Table 6–2 are met.


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Table 6–2
Laboratory test criteria for Day 1 dose of subsequent cycles
Laboratory Test
Criteria for Day 1 dose (Cycle 2 and higher)
Glucose 
< 160 mg/dL (fasting) or < 200 mg/dL (non-fasting)
Hemoglobin 
≥ 8 g/dLa
ANC
≥ 1,000/mm3
Platelets
≥ 50,000/mm3
ALT
≤ 5 x ULN 
AST
≤ 5 x ULN
Total bilirubin
≤3 x ULN
GFR (MDRD)
≥ 30 mL/min/1.73 m2
ANC = Absolute neutrophil count; ALT = Alanine aminotransferase; AST = Aspartate 
aminotransferase; GFR = Glomerular filtration rate; MDRD = Modification of Diet in Renal 
Disease; ULN = Upper limit of normal.
a: If hemoglobin is < 8 g/dL but ≥ 6 g/dL on the day of planned study drug administration it is 
permissible to give the study drug dose on schedule and transfuse within 48 h after the dose, if 
the patient is hemodynamically stable and in opinion of investigator benefits outweigh risks. 
Rationale and treatment should be recorded in the source documentation and in the eCRF.
Table modified by amendment 1.
A blood count will be performed and assessed prior to infusion on Days 8 and 15 of each 
cycle. The study drug will not be administered if, on the day of scheduled dosing, any of the 
following criteria is met:

CTCAE Grade ≥ 3 neutrophil count decreased (ANC < 1,000/mm3)

CTCAE Grade ≥3 platelet count decreased (platelets < 50,000/mm3)

CTCAE Grade ≥3 anemia (hemoglobin < 8 g/dL)
If hemoglobin is < 8 g/dL but ≥ 6 g/dL on the day of planned study drug administration it 
is permissible to give the study drug dose on schedule and transfuse within 48 h after the 
dose, if the patient is hemodynamically stable and in opinion of investigator benefits 
outweigh risks. Rationale and treatment should be recorded in the source documentation 
and in the eCRF.
Doses scheduled for Days 1 (after Cycle 1 Day 1), 8 and 15 may be delayed by up to 2 days. 
A delay of more than 2 days will be considered a missed dose. Missed doses will not be 
replaced. The minimum interval needed between two infusions of study drugs is 5 days.
6.4.1
Dose modification
Section modified by amendment 1, 3 and 6.
It is recognized that attribution of causality of any AE to the test drug specifically may be
difficult. However, certain toxicities were seen only in relation to copanlisib in Phase I trials: 
e.g., transient increases in glucose and blood pressure. Based on this knowledge the 
investigator may decide on the necessary dose modifications. 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.


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Dose modifications must be done according to the guidelines given in Section 6.4.1.1 and 
Section 6.4.1.2. The investigator may judge a more conservative dose modification 
appropriate. If therefore these guidelines are not followed, the rationale for other measures is 
to be documented in detail in patient’s medical record. Deviations from the guidelines must be 
discussed with the sponsor.
The dose modification levels of study treatment (copanlisib) will follow the pre-defined dose 
levels shown in Table 6–3.
Table 6–3
Dose levels of study treatment
Dose level 1 (starting dose):
60 mg
Dose level -1:
45 mg
Dose level -2:
30 mg
After having fully recovered from toxicity and in the absence of any criteria for further dose 
reduction or study treatment discontinuation, re-escalation from dose level -2 to dose level -1, 
or from dose level -1 to dose level 1 will be allowed at the investigator’s discretion, with the 
exception of NIP.
Patients who do not tolerate the dose of at least 30 mg must discontinue study treatment 
permanently.
6.4.1.1
Hematological toxicity
Neutropenia and febrile neutropenia are listed in the current version of IB as expected adverse 
events. The guidelines for dose modifications in case of hematological toxicity are given 
in Table 6–4 (changed by amendment 1 and modified by amendment 3).
Table 6–4
Dose modification of study treatment for hematological toxicity
Note: This table should not be used to determine patient eligibility for infusion on days 1, 8 and 15. 
Please follow specific guidance given for laboratory test criteria on days 1, 8 and 15 (note added by 
amendment 1)
Hematological toxicity of CTCAE Grade
(any of the following)
Study drug action (for all toxicities)
Grade 4 thrombocytopenia (platelet < 25,000/mm3) 
or Grade 3 (platelet < 50,000/mm3) with bleeding.
Febrile neutropenia.
Grade 4 neutropenia (ANC < 500/mm3).a
INR or PTT of Grade ≥3 with bleeding.
Grade ≥3 anemia (Hb < 8 g/dL).
Delay infusion until criteria displayed in 
Table 6–2 are met.c Patient can be treated 
at one dose level lower at the investigator’s 
discretion.b If more dose reductions are 
required than allowed per protocol, 
discontinue study treatment permanently. 
The lowest dose level is 30 mg.
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, a CBC after 3 days is recommended.
b: After having fully recovered from toxicity and in the absence of any criteria for further dose reduction or study 
drug discontinuation, re-escalation to dose level -1 or 1 will be allowed at the investigator’s discretion.
c: Treatment with transfusion or growth factors is allowed at the investigator’s discretion.
(Table modified by amendment 3)


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6.4.1.2
Non-hematological toxicity
Dose modifications for non-hematologic toxicities except glucose increases, dermatologic 
toxicity, NIP and arterial hypertension are outlined in Table 6–5 (table modified by 
amendment 1 and 3).
Table 6–5
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 3a
1st appearance
Interruption until Grade 2
No change
2nd appearance
Interruption until Grade 2
Decrease by one dose levelb
3rd appearance
Interruption until Grade 2
Decrease by one dose levelb
4th appearance
Permanent discontinuation
–
Grade 4
Any appearance
Permanent discontinuation
–
Toxicity requiring delay for > 21 days
Permanent discontinuation
–
CTCAE = Common Terminology Criteria of Adverse Events.
a: Despite maximum supportive therapy.
b: Not applicable for 30 mg dose level.
A delay > 21 days in study drug administration due to toxicities will cause permanent discontinuation of study 
treatment.
Study treatment must be discontinued if the lowest dose level of 30 mg is not tolerated.
After having fully recovered from toxicity and in the absence of any criteria for further dose reduction or study 
drug discontinuation, re-escalation to dose level -1 or 1 will be allowed at the investigator’s discretion.
Table modified by amendment 1 and 3.
Dermatologic toxicity
The guidelines for dose modifications in case of dermatologic toxicity are given in Table 6–6
(changed by amendment 1).


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Table 6–6
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 2a
1st appearance
Interruption until Grade ≤1
No change
2nd appearance
Interruption until Grade ≤1
Decrease by one dose levelb
3rd appearance
Interruption until Grade ≤1
Decrease by one dose levelb
4th appearance
Permanent discontinuation 
–
Grade 3a
1st appearance
Interruption until Grade ≤1
Decrease by one dose levelb
2nd appearance
Interruption until Grade ≤1
Decrease by one dose levelb
3rd 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 30 mg dose level.
The lowest dose level is 30 mg; if a patient is already on the 30 mg dose level and meets criteria for 
further dose decrease, study treatment will be discontinued permanently.
Table modified by amendment 1.
Non-infectious pneumonitis 
In the event of NIP, an adjustment as described in Table 6–7 must be applied (table modified 
by amendment 3).
Table 6–7
Dose modification of study treatment for non-infectious pneumonitis (NIP)
Study drug action
Suspected or confirmed
NIP of CTCAE
For current course of therapy
Re-initiation of study drug
(if recovered within 14 days)
Grade 1
No change
Not applicable
Grade 2
Interruption
Decrease by one dose levela
Grade 2 re-occurrence
Permanent discontinuation
No
Grade 3
Interruption
Case by case decision (after 
consulting the sponsor)
Grade 3 re-occurrence
Permanent discontinuation
No
Grade 4
Permanent discontinuation
No
NIP = Non-infectious pneumonitis; CTCAE = Common Terminology Criteria for Adverse Events.
a: Not applicable for 30 mg dose level. No re-escalation is allowed after the dose reduction.
The lowest dose level is 30 mg; if a patient is already on the 30 mg dose level and meets criteria for 
further dose decrease, study treatment will be discontinued permanently.
Table modified by amendment 3.
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 


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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” 
(paragraph added by amendment 3).
Glucose increases and arterial hypertension
a)
Glucose increases
Section modified by amendment 1 and further revised by amendment 3 and 6.
Patients who develop transient post-infusion glucose > 250 mg/dL after study drug
administration may continue treatment. However, the next infusion must be delayed until the 
patient’s pre-infusion glucose levels return to < 160 mg/dL (fasting) or < 200 mg/dL (non-
fasting). Guidelines for the management of glucose increases are given in Section 6.4.2.1.

Continuing occurrence of post-infusion blood glucose > 500 mg/dL based on repeated 
laboratory analysis despite optimal glucose lowering therapy after 2 infusions of study 
drug will require dose reduction by one dose level.

Further dose reduction is allowed as long as discontinuation criteria were not met.

Dose re-escalation is allowed when a patient has achieved controlled glucose levels 
per investigator’s judgment.

Persistent occurrence of post-infusion blood glucose > 500 mg/dL based on laboratory 
analysis which occurred at the lowest study drug dose level despite optimal glucose 
lowering therapy (after at least one cycle of treatment) with consultation of a diabetes 
specialist requires permanent discontinuation of the study treatment (see 
Section 5.2.1.1).
b)
Arterial hypertension
The guidelines for dose modifications of study drug in case of arterial hypertension are given 
in Table 6–8 (table added by amendment 3).
No dose should be given if blood pressure is ≥150/90 mmHg. Instructions for blood pressure 
measurement are given in Section 7.5.3.3. Antihypertensive medication may be given to 
control the arterial hypertension. Dosing can proceed on the scheduled day if there are at least 
2 consecutive measurements < 150/90 mmHg. Otherwise dosing must be delayed. 
If drug-related arterial hypertension (post-dose blood pressure of CTCAE Grade 3 or 
160/100 mmHg) is not manageable with optimal antihypertensive treatment, the dose for 
the subsequent study drug administrations may be reduced by 1 or 2 dose levels at the 
investigator’s discretion. Guidelines for the treatment of blood pressure increases are given in 
Section 6.4.2.3. Patients with a blood pressure of CTCAE Grade 4 must permanently 
discontinue the study drug (see Section 5.2.1.1) (paragraph modified by amendment 3).


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Table 6–8
Dose modification of study treatment for arterial hypertension
Toxicity (CTCAE)
Study drug action
Recommendation
Pre-dose measurements
BP ≥150/90 mmHg
No dose should be given until 
recovery to < 150/90 mmHg.
Consider BP lowering medication. Dosing 
can proceed on the scheduled day if after at 
least 2 consecutive measurements BP 
returns to < 150/90 mmHg. If BP doesn’t 
return to < 150/90 mmHg, delay dosing until 
next visit.
During infusion:
CTCAE hypertension of 
grade 3 
or ≥160/100 mmHg
Infusion can be interrupted or 
slowed down and administration 
of BP lowering therapy should 
be initiated.
Infusion may be resumed immediately when 
BP has returned to < 150/90 mmHg or 
skipped otherwise.
Subsequent study drug administrations may 
be reduced by 1 dose level at the 
investigator’s discretion.b
Post-dose:
Drug-related
CTCAE hypertension of 
grade 3
or ≥160/100 mmHga
–
Administration of BP lowering therapy should 
be initiated according to local standard of 
care.  
Additional measurements to be performed as 
clinically indicated until recovery to 
< 150/90 mmHg.
Subsequent study drug administrations may 
be reduced by 1 dose level at the 
investigator’s discretion.b
CTCAE hypertension of 
grade 4
Permanent discontinuation
–
CTCAE = Common Terminology Criteria for Adverse Events; BP = Blood pressure
a: Not manageable despite optimal antihypertensive treatment.
b: The lowest dose level is 30 mg. If a patient is already on the 30 mg dose level and experiences 
post-dose hypertension of CTCAE Grade 3 or ≥160/100 mmHg, consider more intensive 
therapy than previously used.
Table added by amendment 3 and modified by amendment 4.
6.4.2
Treatment of toxicities
Recommendations for the treatment of toxicities described below apply to study treatment.
6.4.2.1
Management of transient post-infusion glucose increases that can occur 
with study treatment
Management of transient post-infusion glucose increases on infusion days
Section modified by amendment 1 and further revised by amendment 3 and 6.
Mild to moderate asymptomatic increases of blood glucose may occur with copanlisib 
infusion, and with larger increases potentially occurring post-prandially.
The guidelines for management of transient post-infusion glucose increases on infusion days 
are given in Table 6–9 (table added by amendment 3).


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Table 6–9
Management of transient post-infusion glucose increases
Criteria 
Recommendation
Suggested Treatment
On infusion days: 
Asymptomatic glucose 
increases ≤ 250 mg/dL
Does not generally require 
treatment with glucose lowering 
medication
None
Asymptomatic glucose 
increases > 250 mg/dL
Should have repeated laboratory 
glucose determination
If the repeated glucose value is 
decreasing, the glucose may be 
followed without glucose lowering 
medication treatment if hydration 
status is normal as clinically 
assessed
Consultation with diabetes 
specialist is recommended
Hydration if appropriate 
When planning next infusion 
consider prophylaxis with oral 
glucose lowering medication
Symptomatic or persisting 
glucose increases 
> 250 mg/dL
Hydration status should be clinically 
assessed
If clinical assessment is consistent 
with dehydration, fluids should be 
given as clinically appropriate 
(orally or IV).
Laboratory test confirming increase 
should be repeated. If the repeated 
glucose value is > 250 mg/dL
and/or patient is symptomatic 
and/or the hydration status indicate 
the need for hydration, glucose 
lowering medication should be 
administered
Prompt input from a diabetes 
specialist should be obtained. 
Hydration if appropriate 
Rapid/short acting insulin may be 
given for glucose persisting at 
> 250 mg/dL, or if the patient is 
symptomatic during the infusion 
day.
Rapid/short acting insulin 
according to the institution sliding 
scale coverage of glucose 
persisting at > 250 mg/dL is 
recommended, with oral or IV 
hydration as clinically appropriate.
When planning next infusion 
consider prophylaxis with oral 
glucose lowering medication
On subsequent days:
Max post-infusion glucose 
> 200 mg/dL noted on 
subsequent days
Oral glucose lowering medication 
recommended on subsequent days
Consultation with diabetes 
specialist is recommended
The use of 
sulphonylurea/metaglinides
insulin secretagogues
medications to manage increased 
glucose levels post drug infusions 
is not recommended.
Treatment with glucose lowering 
medication suggested according 
the local standards of practice. 
Based on mechanisms of action 
and decreased risk of 
hypoglycemia, metformin, SGLT-
2-inhibitor or DPP4-inhibitor might 
be useful treatment options
DPP4 = Dipeptidyl peptidase-4; IV = intravenous; SGLT-2 = Sodium/glucose co-transporter 2
Table added by amendment 3.


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The need for glucose monitoring at home should be determined by the investigator based on 
post-infusion glucose profile and clinical status of the patient.
Monitoring of diabetic patients
Section clarified by amendment 1 and modified by amendment 3 and 6.
If the patient already monitors his/her blood glucose as part of routine antidiabetic care, the 
routine measurements should not be replaced by the study specific measurements. 
6.4.2.2
Management of hyperlipidemia
As lipids are monitored for the duration of this study it is recommended to treat significant 
deviations from normal range with standard interventions and therapy in standard doses 
according to local medical practice. Goals of therapy are to keep fasting triglycerides 
< 300 mg/dL and low-density lipoproteins (LDL) < 190 mg/dL (lower LDL depending on 
cardiovascular risk) in patients with a life expectancy > 1 year. The goals for fasting 
triglycerides can be raised to < 500 mg/dL for patients with life expectancy < 1 year (23). 
Although there is a paucity of data on the effects of hyperlipidemia and cancer outcomes, 
these goals have been chosen to decrease risk of established complications of 
hypertriglyceridemia (pancreatitis) and hypercholesterolemia (cardiovascular events). For 
evaluation of lipid-panels including triglycerides, patients must be fasting prior to sampling 
according to local standards. For patients who cannot adhere to fasting requirements the 
evaluation of lipid-panels including triglycerides is considered as not feasible (changed by 
amendment 3).
6.4.2.3
Treatment of blood pressure increases associated with study treatment
Heading modified by amendment 3.
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 patient, but the experience in Phase I has suggested the benefit of 
dihydropyridine calcium channel blockers (i.e., amlodipine, felodipine). Topical nitrates 
should also be considered. Verapamil and diltiazem (non-dihydropyridine calcium channel 
blockers and moderate inhibitors of CYP3A4) should be used with caution due to a potential 
CYP3A4 interaction (modified by amendment 3). In general, it is advisable for sites to be 
prepared so that antihypertensive medication is readily available in case of need. In the event 
of the occurrence of arterial hypertension ≥ 150/90 mmHg during infusion of study drug on 
any cycle, antihypertensive treatment is suggested as indicated above. In the event of the 
occurrence of CTCAE Grade 3 arterial hypertension (≥160/100 mmHg) during infusion of 
study drug, the infusion should be interrupted and antihypertensive treatment as suggested 
above is administered. Infusion can be resumed when blood pressure has returned 
to < 150/90 mmHg. 


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6.4.2.4
Treatment of vomiting and diarrhea
Adequate hydration through appropriate fluid maintenance is essential in the treatment of 
diarrhea or vomiting. Anti-diarrhea medications may be introduced if symptoms occur. The 
recommended dose of loperamide is 4 mg at first onset, followed by 2 mg every 2 to 4 h until 
diarrhea-free for 12 h; a maximum daily dose of 16 mg is not to be exceeded. If clinically 
indicated, diphenoxylate or Lomotil, which contains diphenoxylate plus atropine might also 
be used. In the event of CTCAE Grade 3 diarrhea with maximal pharmacological support, the 
administration of the study drug should be delayed.
6.4.2.5
Treatment of dermatologic toxicity
If dermatologic changes occur, the patient should be treated quickly and aggressively. Table
6–10 can be used as guidance.
Table 6–10
Guidance on treatment of skin toxicities
MILD (CTCAE Grade 1)
Dry skin/fissures
Emollients – Eucerin or Aquaphor plus gentle soaps 
(Dove, Cetaphil, Basis), use fragrance free detergents
Rash
Topical hydrocortisone 2.5% and/or clindamycin 1% gel plus 
doxycycline 100 mg bid or Minocycline 100 mg bid
Nail changes
Moisturizers
Pruritus
Pramoxine 1% cream or Sarna Ultra Cream
MODERATE (CTCAE Grade 2)
Dry skin/fissures
Emollients and topical as above plus Ammonium lactate or Urea 20%
Rash
Topical hydrocortisone 2.5% and/or clindamycin 1% gel plus
doxycycline 100 mg bid or Minocycline 100 mg bid
Nail changes
Vinegar soaks (dilute 1:1 white vinegar in water) and 
soak fingers for 10 min a day
Pruritus
H1-anti-histamines
SEVERE (CTCAE Grade 3 or 4)
Dry skin/fissures
As above for Moderate
Rash
As above for Moderate plus Medrol dose pack
Nail changes
Topical antibacterials/antifungals (ciclopirox) cream or topical high potency 
steroids (clobetasol ointment) 
Consider dermatology consult for nail avulsion
Pruritus
Pregabalin 50-100 mg bid
CTCAE = Common Terminology Criteria for Adverse Events; bid = Twice daily; min = Minute(s)
Source: (24).


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6.4.2.6
Guidance for monitoring and prophylaxis of opportunistic 
infection (OI) 
Section added by amendment 4
6.4.2.6.1
Monitoring guidelines for OI
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 an examination at each visit prior to infusion.

Laboratory tests: cluster of differentiation 4 (CD4) for patients with signs of infection 
i.e. cough, dyspnea or fever, blood cultures when low ANC of CTCAE Grade 4, PCR 
for CMV (monthly for the first 6 months of study treatment and every 3 months 
thereafter).
o
Note: If PCR test is positive for CMV, treatment should be delayed until 
recovery. Treatment of CMV should be initiated based on local standard of 
care (SOC). Retreatment with copanlisib will be allowed without dose 
reduction once PCR test for CMV is negative.
Enhanced monitoring when prior medical history or laboratory parameters could be associated 
with one of the following risk factors:

Intensive chemotherapy (≥2 lines of myelosuppressive cytotoxic therapy)

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 developed OI on study treatment, 
additional assessments will include:

CD4 and cluster of differentiation 8 (CD8) count and ratio, C-reactive protein (CRP), 
blood cultures

Any additional laboratory and diagnostic methods according to local SOC reported as 
unscheduled laboratory and diagnostic methods of assessment 

Radiological imaging (i.e. chest X-ray or CT scan)
o
Note: Treatment of opportunistic infections should be based on local SOC.


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6.4.2.6.2
Prophylaxis of OI
Mandatory prophylactic therapy is not recommended in all patients:

Review of copanlisib data does not support risk benefit ratio favoring prophylaxis in 
all patients

Mandatory prophylaxis may cause a higher risk of side effects associated with 
supportive treatment where no risk factors are present

Currently implemented schedule of assessments and additional enhancements provide 
frequent monitoring and flexibility for prophylaxis based on local SOC.
Although not mandated in all patients, 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 initiated based on local SOC in patients when high 
risk factors are identified (see protocol Section 6.4.2.6.1). For example: Bactrim or 
equivalent, Acyclovir or equivalent.
6.5
Blinding
Section modified by amendment 5.
Not applicable. 
After individual patient unblinding, patients receiving active study drug will continue 
copanlisib treatment as scheduled. Patients receiving placebo will be offered to switch to 
copanlisib upon discretion of the investigator and patient’s consent.  
6.6
Drug logistics and accountability
Section modified by amendment 5.
All study drugs will be stored at the investigational site in accordance with Good Clinical 
Practice (GCP) and GMP requirements and the instructions given by the clinical supplies 
department of the sponsor (or its affiliate/contract research organization [CRO]), and will be 
inaccessible to unauthorized personnel. Special storage conditions and a complete record of 
batch numbers and expiry dates can be found in the sponsor study file; the site-relevant 
elements of this information will be available in the investigator site file. The responsible site 
personnel will confirm receipt of study drug via IVRS/IWRS and will use the study drug only 
within the framework of this clinical study and in accordance with this protocol. Receipt, 
distribution, return and destruction (if any) of the study drug must be properly documented 
according to the sponsor’s agreed and specified procedures. 
Study drug supply and predictive re-supply will be managed through the IVRS/IWRS. After a 
patient is assigned to treatment, the amount of study drug supply needed at the study site for 
each patient will be calculated. Re-supply of study drug will be performed automatically at 
regular intervals through the IVRS/IWRS based on the expected dosing of the study drug. 


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After closure of the study enrollment, the IxRS will continue to supply copanlisib treatment 
for all patients who remain in the study. When a patient is permanently withdrawn from 
treatment, the study site must notify the Sponsor through the IVRS/IWRS. 
Written instructions on medication destruction will be made available to affected parties as 
applicable.
6.7
Treatment compliance
Section modified by amendment 5.
The administration of IV copanlisib will be performed in the clinic on a weekly basis and 
must be recorded in the eCRF.
6.8
Post-study therapy
After the end of study treatment, further therapy is at the discretion of the investigator.
6.9
Prior and concomitant therapy
For prohibited prior therapy please refer to Section 5.1.2.
6.9.1
Prohibited concomitant therapy

CYP3A4 inhibitors and inducers (see Appendix 14.1). Copanlisib is primarily 
metabolized by CYP3A4. Therefore, concomitant use of strong inhibitors of CYP3A4 
(e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir), and 
inducers of CYP3A4 (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, 
St. John’s Wort) is not permitted from Day -14 of Cycle 1 until the SFU visit. 

Grapefruit and grapefruit juice (CYP3A4 inhibitor) consumption is not permitted 
during the study.

Anti-arrhythmic therapy other than beta blockers or digoxin.

Systemic corticosteroid therapy at a daily dose higher than 15 mg prednisone or 
equivalent. Previous corticosteroid therapy must be stopped or reduced to the allowed 
dose at least 7 days prior to the screening CT/MRI (modified by amendment 3). If a 
patient is on chronic corticosteroid therapy, corticosteroids should be de-escalated to 
the maximum allowed dose before the Screening. Patients may use topical or inhaled 
corticosteroids. Short term systemic corticosteroids above 15 mg prednisolone or 
equivalent will be allowed for the management of acute conditions (e.g. treatment of 
NIP) (changed by amendment 1). The use of corticosteroids as antiemetics prior to 
study drug administration will not be allowed.

Myeloid growth factors within 14 days before start of study treatment.

Ongoing immunosuppressive therapy. 

Concomitant radiotherapy (it is assumed that radiation would be indicated only in case 
of progression, when the patient would come off study treatment anyway).


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6.9.2
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. St John’s Wort is not permitted.

Bisphosphonates.

Patients who are therapeutically treated with an agent such as warfarin or heparin will 
be allowed to participate provided that their medication dose and INR/PTT is stable. 
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.

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.

Palliative and supportive care for the other disease-related symptoms (with the 
exception of radiotherapy) and for toxicity associated with treatment will be offered to 
all patients in this trial. 

Patients may receive palliative and supportive care for any underlying illness (with the 
exception of radiotherapy).

Low-dose aspirin (maximum 100 mg/day) and low-dose heparin are permitted.

Patients taking narrow therapeutic index medications should be monitored proactively, 
if these medications cannot be avoided. These medications may include quinidine and 
digoxin (modified by amendment 3). 
7.
Procedures and variables
7.1
Schedule of procedures
7.1.1
Tabulated overview
Schedule of procedures is presented in Table 7–1.


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Table 7–1
Study flow chart
Screening 
maximum days before 
C1D1
Treatment *
EOT
SFU
Cycle 1
Cycle 2 and higher
Within (days) after
Days
-28 
-14
-7
D1
D8
D15
D1
D8
D15
7
30 + 5
days windowz
Acceptable deviation (in days)
-1 to +2 days
-1 to +2 days
Decision
to stop
Last dose
Screening and enrollment
Patient informed consent (including 
genetic) jj
Xcc,dd
Check in- and exclusion criteria
X
X
X
Medical history a
X
IVRS/IWRS transaction b, dd
X
Xb
X
X
HBsAg, HBcAb, HCV IgG
X
CMV PCR test ff,ii
X
Xff
Xff
Serum pregnancy test (if applicable) c
X
Xc
Xc, ee
UPCR / 24 h total urine protein 
quantification ee
X
GFR dd
X
X
Safety
Toxicity / AE assessment d
X
X
X
X
X
X
X
X
X
Concomitant medication d
X
X
X
X
X
X
X
X
X
Complete physical examination e
X
X
X
X
Brief physical examination f, dd
X
X
X
X
(X)
12-lead ECG g, dd
X
Xg
MUGA scan or echocardiogram h, dd
Xh
Xh
HbA1c i
X
X
Complete blood count j
X
Xx
Xx
Xx
C2 onlyx
C2 onlyx
X
(X)
Hemoglobin, ANC and platelet counts 
(C3)
Xx
Xx
Chemistry panel k
Xk
Xx
Xx
Xk,x
C2 onlyx
C2 onlyx
Xk
(X)
Coagulation panel: PT, INR and PTT
X
Xx
Xx
X
(X)


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Table 7–1
Study flow chart
Screening 
maximum days before 
C1D1
Treatment *
EOT
SFU
Cycle 1
Cycle 2 and higher
Within (days) after
Days
-28 
-14
-7
D1
D8
D15
D1
D8
D15
7
30 + 5
days windowz
Acceptable deviation (in days)
-1 to +2 days
-1 to +2 days
Decision
to stop
Last dose
CD4 (for patients with signs of infection) and 
blood cultures when low ANC of CTCAE 
Grade 4 gg, hh,ii
Urinalysis (dipstick)
X
X
X
Glucose l
X
X
X
X
X
X
Blood pressure n
X
X
X
X
X
X
Bone marrow biopsy o
X
CT/MRI and tumor evaluations and 
laboratory/clinical tests for LPL/WM patientsp
Xp
Xp
Study drug administration
Copanlisib IV infusion
X
X
X
X
X
X
AE = Adverse event; ALP = Alkaline phosphatase; ALT = Alanine aminotransferase; ANC = Absolute neutrophil count; AST = Aspartate 
aminotransferase; BUN = Blood urea nitrogen; CBC = Complete blood count; CD4 = Cluster of differentiation 4; CMV = cytomegalovirus; CT 
= Computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; D = Day; ECG = Electrocardiogram; ECOG = Eastern 
Cooperative Oncology Group; EOT = End of treatment; eCRF= Electronic case report form; FL = Follicular lymphoma; FLIPI = Follicular 
Lymphoma International Prognostic Index; FLymSI-18 = NCCN-FACT Lymphoma Symptom Index-18; GFR = Glomerular filtration rate; h = 
Hour(s); HbA1c = Glycated hemoglobin; HBcAb = Hepatitis B core antibody; HBsAg = Hepatitis B surface antigen; HCV = Hepatitis C virus;
IgG = Immunoglobulin G; iNHL = Indolent non-Hodgkin’s lymphoma; INR = International normalized ratio; IV = Intravenous;
IVRS = Interactive voice response system; IWRS = Interactive web response system; LDH = Lactate dehydrogenase; LDL = Low-density 
lipoprotein; LPL/WM = Lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia; LVEF = Left ventricular ejection fraction; min = 
Minute(s); MRI = Magnetic resonance imaging; MUGA = Multiple gated acquisition; NYHA = New York Heart Association; OI = Opportunistic 
infection; PCR = polymerase chain reaction; PT = Prothrombin time; PTT = Partial thromboplastin time; RBC = Red blood cell count; SCR = 
Serum creatinine; SFU = Safety follow-up; UPCR = Urine protein to creatinine ratio; WBC = White blood cell count (list updated by 
amendment 1 and 5).


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*
NOTE: After individual patient unblinding, patients receiving placebo who switch to copanlisib will have all study assessments reset to the 
initial schedule of study evaluations (i.e. as if the patient was restarting the study at Cycle 1 Day 1). For further information on laboratory 
requirements for patients who switch to open-label treatment, please see Section 7.1.2.2 (clarified by amendment 1 and modified by 
amendment 3 and 5).
a
Demographics, relevant medical history findings, concomitant illnesses, allergy history, prior surgeries, most recent histology of tumor, most 
recent staging and grading of tumor, FLIPI score (for patients with FL), 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 and smoking history (modified by 
amendment 1).
b
IVRS/IWRS transaction to register the patient in the system will be at Screening (modified by amendment 1). IVRS/IWRS transaction will take 
place within 48 h before the first dose of study drug. IVRS/IWRS transactions for medication dispensing will be on Day 1 of each cycle. 
IVRS/IWRS transaction to register end of treatment will be at the EOT visit (modified by amendment 5).
c
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
(changed by amendment 3).
d
After Screening: AE assessment and concomitant medication review must be updated before each dose and all AEs starting within 30 days 
after the last dose of study drug should be collected and recorded in eCRF (modified by amendment 4). After the patient signs the informed 
consent, any new finding discovered not present in the patient’s medical history or a worsening of a prior medical history finding must be 
recorded as an AE. Contrast media does not need to be recorded as concomitant medication unless there is an AE related to its
administration (e.g. allergic reaction) (footnote modified by amendment 6).
e
Complete physical examination to include: ECOG performance status, NYHA classification, height (only at Screening), weight, vital signs 
(temperature, pulse and blood pressure), and a complete review of body systems (changed by amendment 1), including lung examination
(added by amendment 4).
f
Brief physical examination to include: ECOG performance status, vital signs (temperature, pulse and blood pressure), examination of 
pertinent organ systems, and brief interim history (change of symptoms), including lung examination (added by amendment 4).
g
12-lead ECG (including QTcB and QTcF evaluation) will be performed at Screening (within 28 days before Cycle 1 Day 1), EOT and as 
clinically indicated. At the EOT visit, a 12-lead ECG is necessary only if not recorded within the previous 4 weeks. (modified by amendment 5)
h
MUGA scan or echocardiogram to measure LVEF at Screening (within 28 days before Cycle 1 Day 1), EOT and as clinically indicated (if not 
previously done within 4 weeks). The method chosen at Screening must be the same throughout the whole study. (modified by amendment 1 
and 5)
i
HbA1c at Screening and at the EOT visit. The testing is not required if the previous test was performed within 4 weeks preceding EOT visit 
(modified by amendment 3 and 5).


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j
CBC: Hemoglobin, hematocrit, RBC, WBC (with differential to include absolute neutrophil, lymphocyte, monocyte, basophil and eosinophil 
counts and platelet count). From Cycle 2 onwards, only hemoglobin, platelet and ANC counts will be performed on Day 8 and Day 15 prior to 
each infusion. Differential blood count in percentage can be provided when absolute count is not available per standard of care of the local 
lab (modified by amendment 4 and 5).
k
Chemistry panel: calcium, sodium, potassium, chloride, phosphorous, magnesium, bicarbonate (or carbon dioxide, if bicarbonate is not 
routinely measured at the site), total protein, albumin, glucose, BUN (or urea if BUN is not routinely measured at the site), SCR, uric acid, 
total bilirubin, creatine phosphokinase, ALT, AST, LDH, ALP, lipase, amylase (or pancreatic amylase, if total amylase is not routinely 
measured at the site), cholesterol (total and LDL) and triglycerides. Total cholesterol, LDL and triglycerides will be tested only at Screening
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 (modified by amendment 1, 3 and 5).
l
On Cycle 1 Day 1, glucose will be measured at pre-dose and post-dose after the end of study drug infusion (0), 1 h and 2 h. Additional 
measurements to be performed at the clinic as clinically indicated. On subsequent infusions, glucose will be measured prior to and 1 h after
the end of infusion. Deviation of ± 10 min is allowed for glucose measurements, except for the pre-dose measurement. For details on fasting 
requirements and pre-dose glucose levels, see Section 6.4. Glucose is also measured as part of the chemistry panel (footnote changed by 
amendment 1, 3 and 6).
m
Footnote removed by amendment 6.
n
Blood pressure will be measured every 5-10 min prior to infusion of study drug (no more than 4 measurements) until there are 2 consecutive 
results < 150/90 mmHg. If blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention or delaying the infusion of 
study drug. On infusion days, blood pressure will be measured at 0 h (pre-dose), 30 min (mid-infusion), 60 min (end of infusion); and 1 h and 
2 h after the end of infusion. Time window of ± 10 min is allowed for all blood pressure measurements except for 0 h (pre-dose). The patient 
should rest for 5-10 min before blood pressure is recorded (footnote modified by amendment 1 and 3).
o
Bone marrow biopsy may be performed at the investigator discretion if there is clinical suspicion of bone marrow infiltration. Bone marrow 
biopsy will be performed as per local standard of care (clarified by amendment 1 and modified by amendment 4, 5 and 6).
p
Tumor assessments and their frequency as well as laboratory/clinical tests for WM patients will follow the institution’s standard of care
(footnote changed by amendment 1, 3, 5 and 6).
q
Footnote removed by amendment 5. 
r
Footnote removed by amendment 6.
s
Footnote removed by amendment 6.
t
Footnote removed by amendment 6.
u
Footnote removed by amendment 6.
v
Footnote removed by amendment 5.
w
Footnote removed by amendment 6.


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x
Laboratory tests prior to each infusion may be performed either the day before or on the planned date of infusion, with the exception of blood 
glucose (or capillary glucose sampling via glucose meter), which must be performed on the day of infusion (modified by amendment 1). For 
dosing criteria, see Section 6.4.
y
Footnote removed by amendment 5.
z
The post-treatment follow-up 30 days (window of +5 days allowed) after the last administration of study drug can be conducted via telephone 
if the patient is no longer being actively seen at the clinic or has started another therapy. Procedures marked with “(X)” are only to be 
performed, if clinically indicated (modified by amendment 5).
aa Footnote removed by amendment 6.
bb Footnote removed by amendment 6.
cc
Written informed consent must be obtained prior to any study-specific procedures. Certain results from diagnostic testing performed as part of 
the standard of practice prior to the informed consent date and time may be used to fulfill screening criteria. This includes fresh tissue as 
noted in the protocol as well as results from CT/MRI scans, bone marrow sample, MUGA/echocardiogram and hepatitis testing which may 
also be used provided that they fall into the protocol-specified time window. Archival tissue obtained from the patients at any time during the 
course of their iNHL may also be used prior to the informed consent date and time if performed as part of the standard of practice. The 
maximum interval allowed between signature of informed consent and start of treatment is 28 days unless written sponsor authorization has 
been obtained for laboratory re-testing (up to additional 14 days permitted) (footnote added by amendment 1 and modified by amendment 6).
dd Modified by amendment 1.
ee Modified by amendment 3.
ff
Blood test for CMV. Should be performed in all patients prior to IV infusion of copanlisib. Every month for the first 6 months of treatment and 
every 3 months thereafter. If PCR test is positive for CMV, treatment should be delayed until recovery. Treatment of CMV should be initiated 
based on local SOC. Re-treatment with copanlisib will be allowed without dose reduction once PCR test for CMV is negative (footnote added 
by amendment 4).
gg For patients with identified risk factors and those who developed OI on study treatment, additional assessments will include: (1) CD4 and 
CD8 count and ratio, CRP, blood cultures (2) any additional laboratory and diagnostic methods according to local SOC should be reported as 
unscheduled laboratory and diagnostic methods of assessments (3) Radiological imaging (i.e. chest X-ray or CT scans) (Note: Treatment of 
developed OI should be based on local SOC) (footnote added by amendment 4).
hh Blood cultures should be performed as per local SOC if the patient develops low ANC of CTCAE Grade 4. CD4 count should be performed 
for patients with signs of infection (footnote added by amendment 4).
ii
Modified by amendment 4.
jj     As of amendment 5, all patients will be reconsented and need to voluntarily agree to sign the ICF and have to do so, to continue in the study 
(added by amendment 5).


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7.1.2
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 (modified by amendment 1
and 3).
7.1.2.1
Screening period
By the time the protocol amendment 6 becomes effective, screening procedures are no longer 
applicable as screening for the study ended on 03 MAR 2017. All screened eligible patients 
have started treatment (paragraph added by amendment 6).
Screening examinations will be performed after the patient has given written informed 
consent. Certain results from diagnostic testing performed as part of the standard of practice
prior to the informed consent date and time may be used to fulfill screening criteria. This 
includes fresh tissue as noted in the protocol as well as results from CT/MRI scans, bone 
marrow sample, MUGA/echocardiogram and hepatitis testing which may also be used 
provided that they fall into the protocol-specified time window. Archival tissue obtained from 
the patients at any time during the course of their iNHL may also be used prior to the 
informed consent date and time if performed as part of the standard of practice. The 
maximum interval allowed between signature of informed consent and start of treatment is 
28 days unless written sponsor authorization has been obtained for laboratory re-testing (up to 
additional 14 days permitted) (paragraph modified by amendment 1 and 6).
Within 28 days before the first administration of study drug (clarified by amendment 3):

IVRS/IWRS transaction to register the patient in the system.

Blood test for HBV and HCV: HBsAg, HBcAb and HCV IgG. 
(If HBsAg or HBcAb positive also HBV DNA; if HCV IgG positive also HCV RNA).

Blood test for CMV infection per local SOC. Patients who are CMV testpositive at 
baseline will not be eligible (added by amendment 4 and modified by amendment 5).

12-lead ECG including QTcB and QTcF evaluation (added by amendment 1) (see 
Section 7.5.3.4).

Multiple gated acquisition (MUGA) scan or echocardiogram to measure LVEF. The 
method chosen at Screening must be the same throughout the whole study (added by 
amendment 1) (see Section 7.5.3.5).

Bone marrow biopsy: mandatory at Screening. A bone marrow biopsy may be 
performed at the investigator discretion if there is clinical suspicion of bone marrow 
infiltration. Bone marrow biopsy will be performed as per local standard of care 
(clarified by amendment 1and modified by amendment 4, 5 and 6).


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
IV (and oral, if indicated) contrast-enhanced CT/MRI of neck, chest, abdomen and 
pelvis (including WM patients). Corticosteroids must be stopped or reduced to the 
allowed dose (less than 15 mg of prednisone or equivalent) at least 7 days before 
performing the screening CT/MRI (if a patient is on chronic corticosteroid therapy, 
corticosteroids should be de-escalated to the maximum allowed dose before the 
Screening). The method chosen at the baseline must be the same throughout the study
(see Section 7.3.2) (paragraph modified by amendment 1 and 6).

Tumor tissue collection removed by amendment 6.
Within 14 days before the first administration of study drug (clarified by amendment 3):

Check inclusion and exclusion criteria (see Section 5.1).

Complete medical and surgical history including demographics, relevant medical 
history findings, concomitant illnesses, allergy history, prior surgeries, most recent 
histology of tumor, most recent staging and grading of tumor, FLIPI score (for patients 
with FL), 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 and smoking history (modified by amendment 1) (see Section 7.2).

Serum beta-2-microglobulin was changed to be performed only in patients with 
LPL/WM by amendment 1 (see below).

Toxicity/AE assessment: any new findings or worsening of any ongoing medical 
history conditions after the patient has signed the informed consent are to be listed as 
AEs (see Section 7.5.1.3).

Concomitant medication review. Please 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).

Complete physical examination including ECOG performance status (see grading 
definitions in Appendix 14.3), NYHA classification (see Appendix 14.4), height, 
weight, vital signs (temperature, pulse and blood pressure), and a complete review of 
body systems (changed by amendment 1) (see Section 7.5.3.2).

12-lead ECG and MUGA scan/echocardiogram measurements moved to previous 
section (less than 28 days before start of treatment) by amendment 1.

Laboratory/clinical tests for LPL/WM patients removed by amendment 6.
Within 7 days before the first administration of study drug (clarified by amendment 3):

Check inclusion and exclusion criteria (see Section 5.1).

Serum pregnancy test, if applicable (see Section 7.5.3.1).

UPCR/24 h total urine protein quantification (modified by amendment 3) (see 
Section 7.5.3.1).


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
GFR measurement (see Section 7.5.3.1 and Appendix 14.5).

Blood tests for HbA1c, CBC, chemistry and coagulation panels (see Section 7.5.3.1).
Patients must be fasting prior to sampling according to local standards (changed by 
amendment 3). If a patient can’t adhere to fasting requirements, the evaluation of lipid-
panels including triglycerides is considered not feasible.

Urinalysis (dipstick). Microscopy as clinically indicated (see Section 7.5.3.1).

Training on glucose self-monitoring removed by amendment 6.
7.1.2.2
Treatment period
Section modified by amendment 1, 3 and 5.
After all screening assessments have been completed and the patient’s eligibility has been 
confirmed and documented, the patient will be assigned to treatment via IVRS/IWRS. The 
randomization will take place within 48 h before the first dose of study drug.
After individual patient unblinding, patients receiving placebo, who switch to copanlisib will 
have all study assessments reset to the initial schedule of study evaluations (i.e. as if the 
patient was restarted the study at Cycle 1 Day 1). For Day 1 of subsequent cycles, dosing 
criteria outlined in Table 6–2 will apply for patients receiving open-label treatment.
The following assessments should be performed at each visit before receiving study 
treatment (added by amendment 4)

Monitoring for OI (see Section 6.4.2.6): 
In addition to the weekly clinical review and laboratory tests outlined in the schedule 
of assessments, the following should be performed in all patients prior to IV infusion 
of copanlisib:
o
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
o
Laboratory tests: CD4 (for patients with signs of infection), blood cultures if 
low ANC of CTCAE Grade 4, PCR for CMV (monthly for first 6 months of 
treatment and every 3 months thereafter)
Note: If PCR test is positive for CMV, treatment should be delayed until 
recovery. Treatment of CMV should be initiated based on local SOC. Re-
treatment with copanlisib will be allowed without dose reduction once PCR test 
for CMV is negative.
7.1.2.2.1
Treatment – Cycle 1
Cycle 1 Day 1
On Cycle 1 Day 1, patients should be fasting for at least 8 h prior to the pre-dose glucose 
measurement. For details on fasting requirements and pre-dose glucose levels, see Section 6.4
(fasting requirements changed by amendment 1 and 3).


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Patients can stay overnight at the site, if needed, based on the investigator’s decision.

QoL questionnaire removed by amendment 5. 

Check inclusion and exclusion criteria. No patient may receive treatment unless 
adherence to all selection criteria as given in Section 5.1 is established.

IVRS/IWRS transaction will take place within 48 h before the first dose of study drug
(modified by amendment 5).

Toxicity/AE assessment: any new findings or worsening of any ongoing medical 
history conditions after the patient signed the informed consent are to be listed as AEs 
(see Section 7.5.1.3).

Monitoring for OI (see Section 6.4.2.6) (added by amendment 4).

Concomitant medication review. Please 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).

Complete physical examination including ECOG performance status, NYHA 
classification, weight, vital signs (temperature, pulse and blood pressure), and 
complete review of body systems (changed by amendment 1) (see Section 7.5.3.2).

12-lead ECG removed by amendment 5.

Glucose will be measured at pre-dose and post-dose after the end of study drug 
infusion (0), 1 h and 2 h (deviation of 10 min is allowed, except for the pre-dose 
measurement). Additional measurements to be performed at the clinic as clinically 
indicated (see Section 6.4 and Section 7.5.3.6) (changed by amendment 1, 3 and 6).

Home blood glucose monitoring removed by amendment 6.

Blood pressure will be measured every 5-10 min prior to infusion of study drug (no 
more than 4 measurements) until there are 2 consecutive results < 150/90 mmHg. If 
blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention 
or delaying the infusion of study drug. Blood pressure will be measured at 0 h (pre-
dose), 30 min (mid-infusion), 60 min (end of infusion); and 1 h and 2 h after the end 
of infusion. Time window of ± 10 min is allowed for all measurements except for 0 h 
(pre-dose). The patient should rest for 5-10 min before blood pressure is recorded
(modified by amendment 1 and 3).

PK sampling associated with 12-lead ECG removed by amendment 1.

Biomarker sampling removed by amendment 6.
o
Whole blood for genetic biomarker analysis removed by amendment 5.

Study drug IV infusion.


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Cycle 1 Day 4 removed by amendment 5
Cycle 1 Day 8

Toxicity/AE assessment (see Section 7.5.1.3).

Concomitant medication review. Please 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).

Brief physical examination including ECOG performance status, vital signs 
(temperature, pulse and blood pressure), examination of pertinent organ systems, and 
brief interim history (change of symptoms) (see Section 7.5.3.2).

Monitoring for OI (see Section 6.4.2.6) (added by amendment 4). 

Blood tests for CBC and chemistry panel (excluding total cholesterol, LDL and 
triglycerides) (see Section 6.4 and Section 7.5.3.1).

Glucose test prior to study drug infusion and 1 h after the end of study drug infusion
(deviation of 10 min is allowed, except for the pre-dose measurement) (see 
Section 6.4 and Section 7.5.3.6) (changed by amendment 1, 3 and 6).

Review of the blood glucose measurements/meal timing/oral glucose lowering 
medication/insulin administration, if applicable (changed by amendment 1, 3 and 6)
(see Section 6.4.2.1).

Home blood glucose monitoring removed by amendment 6.

Blood pressure will be measured every 5-10 min prior to infusion of study drug (no 
more than 4 measurements) until there are 2 consecutive results < 150/90 mmHg. If 
blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention
or delaying the infusion of study drug. Blood pressure will be measured at 0 h (pre-
dose), 30 min (mid-infusion), 60 min (end of infusion); and 1 h and 2 h after the end 
of infusion. Time window of ± 10 min is allowed for all measurements except for 0 h 
(pre-dose). The patient should rest for 5-10 min before blood pressure is recorded
(modified by amendment 1 and 3).

PK sampling removed by amendment 6.

Biomarker sampling removed by amendment 6.

Study drug IV infusion.
Cycle 1 Day 15

Toxicity/AE assessment (see Section 7.5.1.3).

Concomitant medication review. Please 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).


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
Brief physical examination, including ECOG performance status, vital signs 
(temperature, pulse and blood pressure), examination of pertinent organ systems, and 
brief interim history (change of symptoms) (see Section 7.5.3.2).

Monitoring for OI (see Section 6.4.2.6) (added by amendment 4). 

Blood tests for CBC, chemistry and coagulation panels (excluding total cholesterol, 
LDL and triglycerides) (see Section 6.4 and Section 7.5.3.1).

Glucose test prior to study drug infusion and 1 h after the end of study drug infusion
(deviation of 10 min is allowed, except for the pre-dose measurement) (see 
Section 6.4 and Section 7.5.3.6) (changed by amendment 1, 3 and 6).

Review of the blood glucose measurements/meal timing/oral glucose lowering 
medication/insulin administration, if applicable (changed by amendment 1, 3 and 6) 
(see Section 6.4.2.1).

Home blood glucose monitoring removed by amendment 6.

Blood pressure will be measured every 5-10 min prior to infusion of study drug (no 
more than 4 measurements) until there are 2 consecutive results < 150/90 mmHg. If 
blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention 
or delaying the infusion of study drug. Blood pressure will be measured at 0 h (pre-
dose), 30 min (mid-infusion), 60 min (end of infusion); and 1 h and 2 h after the end 
of infusion. Time window of ± 10 min is allowed for all measurements except for 0 h 
(pre-dose). The patient should rest for 5-10 min before blood pressure is recorded
(modified by amendment 1 and 3).

Biomarker sampling removed by amendment 6.

Study drug IV infusion.
Cycle 1 Day 22 removed by amendment 5
7.1.2.2.2
Treatment – Cycle 2 and higher
Cycle 2 and higher, Day 1
Fasting requirement removed by amendment 6.

QoL questionnaire removed by amendment 5.

IVRS/IWRS 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 (modified by 
amendment 3).

GFR measurement (see Section 7.5.3.1 and Appendix 14.5) (added by amendment 1).

Toxicity/AE assessment (see Section 7.5.1.3).


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
Monitoring for OI (see Section 6.4.2.6) (added by amendment 4). 

Concomitant medication review. Please 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).

Complete physical examination including ECOG performance status, NYHA 
classification, weight, vital signs (temperature, pulse and blood pressure), and 
complete review of body systems (changed by amendment 1) (see Section 7.5.3.2).

12-lead ECG removed by amendment 5.

MUGA scan or echocardiogram removed by amendment 5.

Blood test for HbA1c removed by amendment 5. 

Blood tests for CBC, chemistry and coagulation panels (see Section 6.4 and 
Section 7.5.3.1) (modified by amendment 5).

Urinalysis (dipstick). Microscopy as clinically indicated (see Section 7.5.3.1).

Glucose test prior to study drug infusion and 1 h after the end of study drug infusion
(deviation of 10 min is allowed, except for the pre-dose measurement) (see Section 
6.4 and Section 7.5.3.6) (changed by amendment 1, 3 and 6).

Review of the blood glucose measurements/meal timing/oral glucose lowering 
medication/insulin administration, if applicable (changed by amendment 1, 3 and 6) 
(see Section 6.4.2.1).

Home blood glucose monitoring removed by amendment 6.

Blood pressure will be measured every 5-10 min prior to infusion of study drug (no 
more than 4 measurements) until there are 2 consecutive results < 150/90 mmHg. If 
blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention
or delaying the infusion of study drug. Blood pressure will be measured at 0 h (pre-
dose), 30 min (mid-infusion), 60 min (end of infusion); and 1 h and 2 h after the end 
of infusion. Time window of ± 10 min is allowed for all measurements except for 0 h 
(pre-dose). The patient should rest for 5-10 min before blood pressure is recorded
(modified by amendment 1 and 3).

Biomarker sampling removed by amendment 6.

Study drug IV infusion.

Laboratory/clinical tests for LPL/WM patients removed by amendment 6.


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Cycle 2 and higher, Day 8

Toxicity/AE assessment (see Section 7.5.1.3).

Concomitant medication review. Please 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).

Brief physical examination, including ECOG performance status, vital signs 
(temperature, pulse and blood pressure), examination of pertinent organ systems, and 
brief interim history (change of symptoms) (see Section 7.5.3.2).

Monitoring for OI (see Section 6.4.2.6) (added by amendment 4). 

On Cycle 2, blood tests for CBC and chemistry panel (excluding total cholesterol, 
LDL and triglycerides) will be performed. From Cycle 2 onwards, only hemoglobin, 
platelet and ANC counts will be performed prior to each infusion (see Section 6.4 and 
Section 7.5.3.1) (modified by amendment 5).

Glucose test prior to study drug infusion and 1 h after the end of study drug infusion
(deviation of 10 min is allowed, except for the pre-dose measurement) (see 
Section 6.4 and Section 7.5.3.6) (changed by amendment 1, 3 and 6).

Review of the blood glucose measurements/meal timing/oral glucose lowering 
medication/insulin administration, if applicable (changed by amendment 1, 3 and 6) 
(see Section 6.4.2.1).

Home blood glucose monitoring removed by amendment 6.

Blood pressure will be measured every 5-10 min prior to infusion of study drug (no 
more than 4 measurements) until there are 2 consecutive results < 150/90 mmHg. If 
blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention 
or delaying the infusion of study drug. Blood pressure will be measured at 0 h (pre-
dose), 30 min (mid-infusion), 60 min (end of infusion); and 1 h and 2 h after the end 
of infusion. Time window of ± 10 min is allowed for all measurements except for 0 h 
(pre-dose). The patient should rest for 5-10 min before blood pressure is recorded
(modified by amendment 1 and 3).

Biomarker sampling removed by amendment 6.

Study drug IV infusion.


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Cycle 2 and higher, Day 15

Toxicity/AE assessment (see Section 7.5.1.3).

Concomitant medication review. Please 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).

Brief physical examination, including ECOG performance status, vital signs 
(temperature, pulse and blood pressure), examination of pertinent organ systems, and 
brief interim history (change of symptoms) (see Section 7.5.3.2).

Monitoring for OI (see Section 6.4.2.6) (added by amendment 4).

12-lead ECG removed by amendment 1.

On Cycle 2, blood tests for CBC and chemistry panel (excluding total cholesterol, 
LDL and triglycerides) will be performed. From Cycle 2 onwards, only hemoglobin, 
platelet and ANC counts will be performed prior to each infusion (see Section 6.4 and 
Section 7.5.3.1) (modified by amendment 5).

Glucose test prior to study drug infusion and 1 h after the end of study drug infusion
(deviation of 10 min is allowed, except for the pre-dose measurement) (see 
Section 6.4 and Section 7.5.3.6) (changed by amendment 1, 3 and 6).

Review of the blood glucose measurements/meal timing/oral glucose lowering 
medication/insulin administration, if applicable (changed by amendment 1, 3 and 6) 
(see Section 6.4.2.1).

Home blood glucose monitoring removed by amendment 6.

Blood pressure will be measured every 5-10 min prior to infusion of study drug (no 
more than 4 measurements) until there are 2 consecutive results < 150/90 mmHg. If 
blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention
or delaying the infusion of study drug. Blood pressure will be measured at 0 h (pre-
dose), 30 min (mid-infusion), 60 min (end of infusion); and 1 h and 2 h after the end 
of infusion. Time window of ± 10 min is allowed for all measurements except for 0 h 
(pre-dose). The patient should rest for 5-10 min before blood pressure is recorded
(modified by amendment 1 and 3).

PK sampling associated with 12-lead ECG removed by amendment 1.

Biomarker sampling removed by amendment 6.

Study drug IV infusion.


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Cycle 2 and higher, Day 22 removed by amendment 5
7.1.2.3
Tumor assessments
Section modified by amendment 1, 4, 5 and 6.
After amendment 6 is effective, tumor assessments and their frequency as well as 
laboratory/clinical tests for WM patients will follow the institution’s standard of care.
Bone marrow biopsy may be performed at the investigator discretion if there is clinical 
suspicion of bone marrow infiltration. Biopsy will be performed as per local standard of care.
Physical examination for lymphadenopathy, abdominal masses or organomegaly, and 
collection of B symptoms removed by amendment 1.
7.1.2.4
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:

QoL questionnaire removed by amendment 5.

IVRS/IWRS transaction to register end of treatment.

Serum pregnancy test (if applicable): mandatory for countries where it is required by 
local regulations (see Section 7.5.3.1) (added by amendment 3).

Toxicity/AE assessment (see Section 7.5.1.3).

Concomitant medication review. Please 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).

Complete physical examination including ECOG performance status, NYHA 
classification, weight, vital signs (temperature, pulse and blood pressure), and 
complete review of body systems (changed by amendment 1) (see Section 7.5.3.2).

12-lead ECG including QTcB and QTcF evaluation if not previously done within 
4 weeks (see Section 7.5.3.4).

MUGA scan or echocardiogram to measure LVEF if not previously done within 
4 weeks (clarified by amendment 1). The method chosen at Screening must be the 
same throughout the whole study (see Section 7.5.3.5).

Blood tests for HbA1c, CBC, chemistry and coagulation panels (see Section 7.5.3.1). 
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 (see Section 6.4.2.2).
The testing for HbA1c is not required if the previous test was performed within 
4 weeks preceding EOT visit (bullet point modified by amendment 3).

Urinalysis (dipstick). Microscopy as clinically indicated (see Section 7.5.3.1).


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
Review of the blood glucose measurements/meal timing/oral glucose lowering 
medication/insulin administration, if applicable (modified by amendment 1, 3 and 6) 
(see Section 6.4.2.1).

CT/MRI removed by amendment 6.

Tumor biopsy removed by amendment 6.

Biomarker sampling removed by amendment 6.

Laboratory/clinical tests for LPL/WM patients removed by amendment 6.
7.1.2.5
Follow-up periods
Section removed by amendment 6.
7.1.2.5.1
Safety follow-up
Section modified by amendment 4 and 5.
If a patient discontinues study treatment at any time during the study for any reason (except 
death or lost to follow-up) SFU visit will take place 30 days (window of +5 days allowed) 
after the last administration of study drug. This visit includes:

QoL questionnaire removed by amendment 5.

Toxicity/AE assessment (see Section 7.5.1.3).

Concomitant medication review.
If clinically indicated:

Brief physical examination, including ECOG performance status, vital signs 
(temperature, pulse and blood pressure), examination of pertinent organ systems, and 
brief interim history (change of symptoms) (see Section 7.5.3.2).

CBC (see Section 7.5.3.1).

Chemistry and coagulation panels (see Section 7.5.3.1).
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.
7.1.2.5.2
Active follow-up
Section modified by amendment 6.
As the study design is modified, patients will be followed for safety only. All patients who
have already completed the safety follow-up visit at the time the amendment 6 becomes 
effective will discontinue the study.


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7.1.2.5.3
Survival follow-up
Section modified by amendment 1, 5 and 6.
As the study design is modified, patients will be followed for safety only. All patients who 
have already completed the safety follow-up visit at the time the amendment 6 becomes 
effective will discontinue the study.
7.2
Population characteristics
7.2.1
Demographics
Baseline patient data pertaining to demographic information should be documented on the 
eCRFs including the following:

Year of birth and age

Sex

Race (where legally allowed)

Ethnicity
7.2.2
Medical history
Relevant medical history findings (i.e., relevant previous diagnoses, diseases or surgeries) 
meeting all criteria listed below will be collected:

Not pertaining to the study indication

Start before signing of the informed consent 

Considered relevant to the study
Detailed instructions on the differentiation between (i) medical history and (ii) adverse events 
can be found in Section 7.5.1.1.
Disease history of the study indication will be recorded:

Most recent histology of tumor

Most recent staging and grading of tumor 

FLIPI score for patients affected by FL (FLIPI: Follicular Lymphoma International 
Prognostic Index [25])

History of anticancer treatments (including type of treatment, type of response, date
and duration of response and date of subsequent relapse) (modified by amendment 1)

Assessment of baseline toxicity: any unresolved toxicity > CTCAE Grade 1 attributed 
to any prior therapy/procedure, not due to the underlying disease, excluding alopecia 
and ≤ CTCAE Grade 2 peripheral neuropathy
All medications and significant non-drug therapies taken within 30 days before study entry 
must be recorded on the eCRF, including:


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
Trade name of medication

Reason for medication (indication)

Dose of medication

Start date and end date or if continuing at patient's last visit 
7.2.3
Other baseline characteristics
Information on patient’s history of smoking will be collected and recorded.
7.3
Efficacy
7.3.1
Primary efficacy variable
As study primary endpoint was changed to safety by amendment 6, primary efficacy variable 
was removed.
7.3.2
Radiological tumor assessments
Section changed by amendment 1, 3, 5 and 6.
After amendment 6 is effective, tumor assessments and their frequency as well as 
laboratory/clinical tests for WM patients will follow the institution’s standard of care.
Radiological tumor assessments with IV (and oral, if indicated) contrast-enhanced CT/MRI
will include neck, chest, abdomen and pelvis, and will be evaluated locally at the study site.
The first radiological (IV [and oral, if indicated] contrast-enhanced CT/MRI) tumor 
assessment will be performed at Screening (including WM patients). Corticosteroids must be 
stopped or reduced to the allowed dose (less than 15 mg of prednisone or equivalent) at least 7 
days before performing the screening CT/MRI (if a patient is on chronic corticosteroid 
therapy, corticosteroids should be de-escalated to the maximum allowed dose before the 
Screening). The method chosen at the baseline must be the same throughout the study. MRI 
shall be performed instead of CT when local regulations do not permit the use of CT as 
requested per protocol schedule.
During the treatment phase, radiological (IV [and oral, if indicated] contrast-enhanced 
CT/MRI) tumor assessment will be performed, per local standard of care of the institution
(see Section 7.1.2.3).
For patients switching from placebo to copanlisib therapy after unblinding procedures 
completed CT/MRI scans are not required if the patient had radiological tumor evaluation 
performed and documented in eCRF within 4 weeks preceding the start date of copanlisib 
treatment.
If the patients on placebo treatment had symptoms/signs of clinical progressive disease prior
to switching to copanlisib treatment, it is recommended to have radiological tumor 
assessments before starting copanlisib therapy unless CT/MRI scans performed within 
4 weeks prior to a scheduled date of the first copanlisib infusion. For patients who previously 


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received placebo and will be treated with copanlisib the tumor assessments should be 
continued as the initial schedule.
The response assessment will be done according to the Lugano Classification (21). For 
patients with WM, additional criteria apply (see Section 7.3.3).
Detailed instructions on tumor assessment are provided in Appendix 14.1.
The same technique (e.g., slice thickness, field of view) should be used for all scans during 
the study treatment period. Preferably all scans should be interpreted by the same 
investigator/radiologist during the study whenever possible. CT/MRI scans must be 
performed with contrast agents and must meet the standard of care for imaging of lesions in 
the respective organ system(s). If IV (and oral, if indicated) contrast-enhanced CT is 
medically contraindicated, sites may acquire contrast-enhanced MRI of the neck, abdomen 
and pelvis, and an unenhanced CT of the chest above lung apices to the bottom of the 
adrenals. Chest CT is preferred. Only if a patient develops contra-indication to both CT and 
MRI contrast medium during the treatment phase of the study, the case examinations should 
be continued without contrast. In certain countries MRI should be used based on local 
regulations.
7.3.3
Tumor assessments in patients with WM
Section added by amendment 3 and modified by amendment 5 and 6.
WM patients who do not have radiologically measurable lesion at Screening will not have 
further radiological assessments as per protocol. Their tumor response will be measured only 
by laboratory/clinical tests, and response assessment will be done according to the Owen 
Criteria. However, in cases when WM patients will develop extramedullary disease without 
simultaneous increase in IgM the radiological assessment should be performed to confirm
disease progression (per investigator’s assessment). 
WM patients who have radiologically measurable lesion at Screening will continue having 
radiological assessments and, in addition, will have laboratory tests performed at intervals that 
comply with the institution’s standard of care (see Section 7.1.2.3). 
Detailed instructions on tumor assessment are provided in Appendix 14.1.
7.4
Pharmacokinetics / pharmacodynamics
Section modified by amendment 1, 3, 5 and 6.
No further PK samples will be collected. However, blood samples already collected may be 
used for the PK analysis.


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7.5
Safety
7.5.1
Adverse events
7.5.1.1
Definitions
Definition of adverse event (AE)
In a clinical study, an AE is any untoward medical occurrence (i.e. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a 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 AE (however, the condition for which the surgery is 
required may be an AE).
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal e.g. physical examination findings, symptoms, diseases, laboratory, ECG.

Conditions that started before signing of informed consent and for which no symptoms 
or treatment are present until signing of informed consent are recorded as medical 
history (e.g. seasonal allergy without acute complaints).

Conditions that started before signing of informed consent and for which symptoms or 
treatment are present after signing of informed consent, at unchanged intensity, are 
recorded as medical history (e.g. allergic pollinosis).

Conditions that started or deteriorated after signing of informed consent will be 
documented as adverse events.
Definition of serious adverse event (SAE)
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a – f):
a. Results in death.
b. Is life-threatening.
The term ‘life-threatening’ in the definition refers to an event in which the patient was 
at risk of death at the time of the event, it does not refer to an event which 
hypothetically might have caused death if it were more severe.


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c. Requires inpatient hospitalization or prolongation of existing hospitalization.
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if 
at least one of the following exceptions is met:
o
The admission results in a hospital stay of less than 12 h.
o
The admission is pre-planned 
(i.e. elective or scheduled surgery arranged prior to the start of the study).
o
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 medically important serious event as judged by the investigator.
7.5.1.2
Classifications for adverse event assessment
All AEs will be assessed and documented by the investigator according to the categories 
detailed below. 
7.5.1.2.1
Seriousness
For each AE, the seriousness must be determined according to the criteria given in 
Section 7.5.1.1.
7.5.1.2.2
Intensity
The intensity/severity of an AE will be graded using the NCI CTCAE v. 4.03. For events not 
listed in the NCI CTCAE, the following scale will be used:

Grade 1: Mild

Grade 2: Moderate

Grade 3: Severe

Grade 4: Life-threatening

Grade 5: Fatal


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7.5.1.2.3
Causal relationship 
The assessment of the causal relationship between an AE and the administration of treatment 
is a clinical decision based on all available information at the time of the completion of the 
CRF.
The assessment is based on the question whether there was a “reasonable causal relationship” 
to the study treatment in question.
Possible answers are “yes” or “no”
An assessment of “no” would include:
1. The existence of a clear alternative explanation, e.g. mechanical bleeding at surgical 
site.
or
2. Non-plausibility, e.g. the patient is struck by an automobile when there is no indication 
that the drug caused disorientation that may have caused the event; cancer developing a 
few days after the first drug administration.
An assessment of “yes” indicates that there is a reasonable suspicion that the AE is 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 patient’s response after re-challenge should be 
considered in the view of the usual clinical course of the event in question.

Underlying, concomitant, intercurrent diseases:
Each event should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the 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 may be suspected to cause the event in 
question.

The pharmacology and pharmacokinetics of the study treatment: 
The pharmacokinetic properties (absorption, distribution, metabolism and excretion) 
of the study treatment, coupled with the individual patient’s pharmacodynamics 
should be considered.


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Causal relationship to protocol-required procedure(s)
The assessment of a possible causal relationship between the AE and protocol-required 
procedure(s) is based on the question whether there was a “reasonable causal relationship” to 
protocol-required procedure(s).
Possible answers are “yes” or “no”
7.5.1.2.4
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

Not applicable

Unknown
The study treatment action should be recorded separately for each study treatment as detailed 
in the CRF.
7.5.1.2.5
Other specific treatment(s) of adverse events

None

Remedial drug therapy

Other
7.5.1.2.6
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


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7.5.1.3
Assessments and documentation of adverse events
Section modified by amendment 3, 4 and 6.
AEs observed, mentioned upon open questioning by a member of the investigator team or 
spontaneously reported by the patient will be documented in the patient’s records and the 
appropriate eCRF. AEs will be documented in an event-based manner, using NCI-CTCAE 
v.4.03 guidelines. 
The observation phase for AEs will start with signing the ICF and shall end 30 days after the 
last dose of study drug. The safety follow-up visit shall occur 30 days (window of +5 days 
allowed) after the last dose of study medication. AEs still present at the end of the observation 
phase should be followed until resolution or stabilization unless the condition is unlikely to 
resolve due to the patient’s underlying disease.
AEs to be documented include all AEs that were ongoing at the end of study treatment as well 
as new AEs that, in the opinion of the investigator, could be related to study treatment 
(information may be obtained via phone call). Documentation must be supported by an entry 
in the patient’s file. 
The investigator is responsible for the grading of each category mentioned in Section 7.5.1.2. 
For all SAEs the sponsor is to carry out a separate assessment for expectedness, seriousness 
and causal relationship to the study drug.
If any patient dies during the observation phase for AEs, the investigator will inform the 
sponsor and record the cause of death in detail within 24 h on an SAE form. “Death” should 
generally not be recorded as an AE on the AE page. Instead, “death” should be recorded as 
the outcome of underlying AE(s). If death is reported without any associated AE (s), it should 
be reported as SAE.
A laboratory test abnormality considered clinically relevant, e.g., causing the patient to 
withdraw from the study, requiring treatment or causing apparent clinical manifestations, or 
judged relevant by the investigator, should be reported as an AE. Each event should be 
described in detail along with start and stop dates, intensity, relationship to investigational 
product, action taken and outcome. 
7.5.1.4
Reporting of serious adverse events
The definition of serious adverse events (SAEs) is given in Section 7.5.1.1. Each SAE must 
be followed up until resolution or stabilization by submission of updated reports to the 
designated recipient.
Investigator’s notification of the sponsor
All investigators will be thoroughly instructed and trained on all relevant aspects of the 
investigator’s reporting obligations for SAEs. This information, including all relevant contact 
details, is summarized in the investigator site file. This information will be updated as needed.
All SAEs occurring during the observation period defined in Section 7.5.1.3 must 
immediately (within 24 h of the investigator’s awareness) be reported to the recipient detailed 


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in the manual. An SAE form must also be completed within 24 h of the investigator 
awareness and forwarded to the designated recipient. 
SAEs occurring after the protocol-defined observation period will be processed by the 
sponsor according to all applicable regulations.
If disease progression leads to signs and symptoms that meet the criteria for seriousness (see 
Section 7.5.1.1), the associated signs and symptoms, not the underlying cause, should be 
reported as SAE, (i.e. progressive disease should not be recorded as SAE). In this case, 
disease progression should be clearly mentioned on the SAE form as an “alternative 
explanation” (clarified by amendment 3).
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 report to be faxed 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 7.5.3.1.
Notification of the Independent Ethics Committee / Institutional Review Board
Notification of the Independent Ethics Committees (IECs)/Institutional Review Boards 
(IRBs) about all relevant events (e.g. SAEs, suspected, unexpected, serious adverse reactions 
(SUSARs)) will be performed by the sponsor 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.
7.5.1.5
Expected adverse events
For this study, the applicable reference document is the most current version of the 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.


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7.5.1.6
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 
unexpected AEs, including hypersensitivity reactions.
Based on data from Phase I studies with copanlisib, as soon as there is reasonable suspicion of 
the following AE, the investigator should immediately notify the sponsor as outlined in 
Section 7.5.1.4, regardless of whether the investigator assessed the AE as serious or 
non-serious:

NIP.
7.5.2
Pregnancies
The investigator must report to the sponsor any pregnancy occurring in a study patient during 
the patient’s participation in this study. The report should be submitted within the same 
timelines as an SAE, although a pregnancy per se is not considered an SAE. 
For a study patient, the outcome of the pregnancy should be followed up carefully, and any 
outcome of the mother or the child should be reported.
Bayer usually does not gather information of drug exposure via the father, however, if those 
cases are reported, all efforts should be made to obtain similar information on course and 
outcome, subject to the partner’s consent.
For all reports, the forms provided are to be used.
7.5.3
Further safety
Text was removed by amendment 5.
7.5.3.1
Laboratory
All laboratory analyses will be performed locally according to the schedule summarized in the 
flow chart of Section 7.1.1. Dipsticks should be available for urinalysis (modified by 
amendment 1 and 3).

Complete blood count (CBC): hemoglobin, hematocrit, red blood cell count (RBC), 
and white blood cell count (WBC) with differential to include absolute neutrophil, 
lymphocyte, monocyte, basophil and eosinophil counts, and platelet count. Differential 
blood count in percentage can be provided when absolute count is not available per 
SOC of the local lab (modified by amendment 4).

Complete chemistry panel: calcium, sodium, potassium, chloride, phosphorus, 
magnesium, bicarbonate (or carbon dioxide if bicarbonate is not routinely measured at 
the site), total protein, albumin, glucose, blood urea nitrogen (BUN) (or urea if BUN is 
not routinely measured at the site), serum creatinine (SCR), uric acid, total bilirubin, 
creatine phosphokinase, alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), lipase, amylase (or 


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pancreatic amylase if total amylase is not routinely measured at the site), cholesterol 
(total, low-density lipoprotein [LDL]) and triglycerides (modified by amendment 1). 

Coagulation panel: prothrombin time (PT), international normalized ratio (INR), and 
partial thromboplastin time (PTT).

Urinalysis: blood cells, glucose, ketones, bilirubin, protein, and pH (dipstick).
Additional microscopic examinations will be performed if clinically indicated
(modified by amendment 1).

Quantification of proteinuria by either a 24 h total urine protein quantification or by
UPCR on a random urine sample preferably taken at mid-morning. This should be 
reported as the ratio of concentrations of total urine protein (in mg/dl) to urine 
creatinine (in mg/dl), both done on the same sample. Dipstick analysis is not 
acceptable to assess proteinuria (modified by amendment 3).

Measurement of GFR according to the MDRD abbreviated formula (see 
Appendix 14.5).

Serum pregnancy test in women of childbearing potential. Postmenopausal women 
who have not had periods for more than 1 year or surgically sterilized women will not 
be required to undergo a pregnancy test (this information should be recorded under 
medical history on the eCRF). 

Hemoglobin A1c (bullet point added by amendment 3).

CD4 (for patients with signs of infection), blood cultures when low ANC of CTCAE 
Grade 4, PCR for CMV (bullet point added by amendment 4).
For patients with identified risk factors and those who developed opportunistic 
infections, additional laboratory assessments will include:
o
CD4, CD8 count and ratio, CRP, blood cultures.
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
International Conference on Harmonization (ICH) criteria for an SAE (SAE definition in 
Section 7.5.1.1). All laboratory abnormalities, including CTCAE Grade 4 abnormalities, will 
be documented on the laboratory eCRF and will be reviewed on a regular basis.
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.


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7.5.3.2
Physical examinations
Physical examinations will be performed according to the schedule summarized in the flow 
chart of Section 7.1 (added by amendment 1).
7.5.3.2.1
Complete physical examination
Complete physical examination includes ECOG performance status assessment (see grading 
definitions in Appendix 14.3), NYHA classification (see Appendix 14.4), height (only at 
Screening), weight, vital signs (see Section 7.5.3.3), and complete review of body systems
(changed by amendment 1).
All clinical signs and regions that can be brought in context with the underlying disease, with 
the anticancer treatment to be administered or with relevant accompanying diseases (if 
present) should be clinically assessed.
At minimum the following aspects/regions need to be assessed as well:

General appearance

Skin (paleness, jaundice, redness/rash, acneiforme changes) including clinical 
assessment of hydration status via hand extensor surface skin turgor (modified by 
amendment 3)

Hand and feet (signs of hand-foot-skin-syndrome/hand-foot skin reaction)

Eyes (accommodation, double images, abnormal sensitivity to light, jaundice)

Ears, nose, throat (presence of petechial bleeding, gingival bleeding) including 
inspection of oral mucosa for hydration status (modified by amendment 3)

Head and neck

Lungs: evaluation of new onset or worsening of pulmonary symptoms, and lung 
examination (modified by amendment 4).

Heart

Abdomen (pain, tenderness, peristaltic, ascites, organomegaly)

Lymph nodes

Musculoskeletal system and spine

Lower legs (petechial bleedings, ulcer, signs of thrombosis)

Neurologic findings
7.5.3.2.2
Brief physical examination
Brief physical examination includes ECOG performance status (see Appendix 14.3), vital 
signs (see Section 7.5.3.3), examination of pertinent organ systems, and brief interim history 
(change of symptoms).


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The examination of pertinent organ systems should investigate at minimum:

Skin (paleness, jaundice, redness/rash, acneiforme changes) including clinical 
assessment of hydration status via hand extensor surface skin turgor (modified by 
amendment 3)

Hand and feet (signs of hand-foot-skin-syndrome)

Throat (presence of petechial bleeding, gingival bleeding) including inspection of oral 
mucosa for hydration status (modified by amendment 3)

Lungs: evaluation of new onset or worsening of pulmonary symptoms, and lung 
examination (modified by amendment 4)

Abdomen (pain, tenderness, peristaltic, ascites, organomegaly)

Neurologic findings
Other clinical signs and regions might be investigated as well, if clinically indicated.
7.5.3.3
Vital signs
Pulse, blood pressure and temperature will be assessed according to the schedule summarized 
in the flow chart of Section 7.1. If clinically indicated, it is at the investigator’s discretion to 
perform these measurements more frequently. 
Blood pressure measurement on infusion days
Blood pressure will be measured every 5-10 min prior to infusion of study drug (no more than 
4 measurements) until there are 2 consecutive results < 150/90 mmHg. If blood pressure is 
≥150/90 mmHg, the investigator can consider a medical intervention or delaying the infusion 
of study drug. The patient should rest for 5-10 min before blood pressure is recorded
(modified by amendment 1).

On infusion days: blood pressure will be measured at 0 h (pre-dose), 30 min (mid-
infusion), 60 min (end of infusion); and 1 h and 2 h after the end of infusion.

Note: time window of ± 10 min is allowed for all blood pressure measurements except 
for 0 h (pre-dose) (changed by amendment 3)
For details on the management of arterial hypertension, see also Section 6.4.1 and 
Section 6.4.2.3.
7.5.3.4
12-lead ECG
12-lead ECGs will be performed according to the schedule summarized in the flowchart in 
Section 7.1. The study number, patient number, visit and the date of the ECG will be noted on 
every ECG.
The patient should rest for 10 min before the ECG is recorded (modified by amendment 1).
The overall interpretation of the ECG (normal/abnormal, clinical relevance) and the ECG 
findings will be recorded in the source documentation and in the eCRF.


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7.5.3.5
Cardiac function
Cardiac function test: MUGA scan or echocardiogram. The method chosen at Screening (i.e. 
either MUGA scan or echocardiogram) must be used throughout the whole study (see 
flowchart in Table 7–1). Additional cardiac function tests are required if any signs or 
symptoms of cardiac dysfunction occur.
MUGA scan or echocardiogram scan should be performed for determination of LVEF. 
The study number, patient number, visit and the date of the MUGA scan/echocardiogram are 
noted on every MUGA scan/echocardiogram.
The overall interpretation of the MUGA scan/echocardiogram and findings will be recorded 
in the source documentation and in the eCRF. 
7.5.3.6
Glucose measurement on infusion days
Section added by amendment 3 and modified by amendment 6.

On Cycle 1 Day 1: glucose will be measured at pre-dose and post-dose after the end of 
study drug infusion (0), 1 h and 2 h. Additional measurements to be performed at the 
clinic as clinically indicated.

On subsequent infusion days: glucose will be measured prior to study drug infusion
and 1 h after the end of study drug infusion. 

On all infusion days: time window of ± 10 min is allowed for glucose measurements, 
except for the pre-dose measurement. 
7.6
Other procedures and variables
7.6.1
Biomarker investigations
Section modified by amendment 1, 5 and 6.
No further biomarker samples will be collected. However tumor tissue, plasma and whole 
blood (if consented) samples collected may be used for the biomarker analysis.
7.6.2
Quality of life questionnaire
Section removed by amendment 5.
7.6.3
Electronic patient-reported outcomes evaluation 
Section removed by amendment 5.
7.7
Appropriateness of procedures / measurements
Section modified by amendment 1 and 6.
The tumor assessments used in this study include those considered standard of care to 
evaluate objective tumor response rate in patients with iNHL. Although the recently published 
Lugano Classification (21) strongly support the use of PET-CT for staging and response 


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assessment of routinely FDG-avid histologies, especially in clinical trials, it was decided to 
use in this study only a CT-based response. CT/MRI-based response remains in fact preferred 
for histologies with low or variable FDG avidity and in regions of the world where PET-CT is 
unavailable. Moreover, in trials exploring new agent in multiply relapsed disease where data 
are lacking regarding PET-CT and where assessment of disease control is more important 
than likelihood of cure, CT/MRI-based response may also be more relevant.
The safety assessments are appropriate and standard to monitor safety and assess toxicity.
8.
Statistical methods and determination of sample size
8.1
General considerations
Section modified by amendment 1, 5 and 6.
Statistical analyses will be conducted by or under the supervision of the sponsor’s Study 
Statistician, except for the analysis of biomarker data, which will be performed by or under 
the direction of the sponsor’s Genomics and Biomarker Statistical Expert. Statistical analyses 
will be performed using Statistical Analysis System (SAS); the version used will be specified 
in the statistical analysis plan (SAP). 
Further details on the statistical analyses including handling of missing data will be provided 
in the SAP that will be approved before database release.
Due to the decision of stopping enrollment as protocol amendment 5 becomes effective, 
limited number of patients will be included in the analyses. Therefore, the statistical analyses 
included in this study will be focused on descriptive statistics on safety variables only.
Two sets of analyses will be performed at the primary analysis timing when all patients have 
completed the study treatment and Safety follow-up period (if applicable). 
1) unblinding cutoff: analyze all data available before the unblinding (details in 
section 6.5); 
2) final analysis: analyze all data available until all patients have completed the
copanlisib study treatment and Safety follow-up period.
The data cutoffs and treatment groups included for each analysis are summarized in the 
following table. 


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Table 8–1
Analysis data cutoffs and treatment group overview
Analysis cutoff on the 
date of unblinding
Final analysis cutoff2
Patients randomized to Copanlisib1


Placebo Patients: Period 1 
(before their PD)

Not shown
Placebo Patients: Period 2 
(after PD period 2)
Not shown

Placebo Patients: switching to 
Copanlisib per protocol amend 5
NA

1 All patients randomized/assigned into Copanlisib arm 
2 When all patients have completed the study treatment and Safety follow-up period.
Table modified by amendment 6.
8.2
Analysis sets
Section modified by amendment 5 and 6.
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 analyzed as treated.
All patients with valid PK data may be included in the evaluation of PK concentrations and 
parameters. 
The SAF will be used for the analyses of the safety variables. 
8.3
Variables
8.3.1
Efficacy variables 
Section modified by amendment 5 and 6.
Due to the limited number of patients enrolled in this study, the study efficacy objectives and 
analyses were removed and the efficacy variables, including but not limited to date of 
progression, time to progression, and best response will be listed descriptively.
8.3.1.1
Primary efficacy variable 
Section removed by amendment 6.
8.3.1.2
Secondary efficacy variables
Section removed by amendment 6.
8.3.1.3
Other efficacy variables
Section removed by amendment 5.


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8.3.2
Safety variables 
Safety variables will include treatment-emergent AEs (TEAEs), SAEs, laboratory parameters, 
and vital signs. The severity of AEs will be graded using the CTCAE v 4.03 dictionary. AEs 
will be classified by the investigator as related or not related to study drug. TEAE is defined 
as any event arising or worsening after start of study drug administration until 30 days after 
the last study drug intake (end of Safety follow-up). For TEAE summaries based on placebo 
randomized patients switching to copanlisib (see Table 8–1), the baseline reference period 
will be defined in the SAP (modified by amendment 4 and 6).
8.4
Statistical and analytical plans
8.4.1
Population characteristics
Section modified by amendment 5.
Demographics and baseline characteristics will be summarized by treatment and total 
population, using descriptive statistics and frequency tables as appropriate.
8.4.2
Efficacy
Section modified by amendment 5 and 6.
Due to the limited number of patients enrolled in this study, the study efficacy objectives and 
analyses were removed and the efficacy variables, including but not limited to date of 
progression, time to progression, and best response will be listed descriptively.
8.4.2.1
Primary efficacy analysis
Section removed by amendment 5.
8.4.2.2
Secondary efficacy analysis
Section removed by amendment 5.
8.4.2.3
Confirmatory statistical testing strategy
Section removed by amendment 5.
8.4.2.4
Subgroup analyses
Section removed by amendment 5.
8.4.3
Safety 
Section modified by amendments 1, 5 and 6.
Safety variables will be summarized by means of descriptive statistics and/or frequency tables 
as appropriate. Summaries will be given by treatment group and total. As clarified in 
section 8.1, safety data analyses will be provided based on two sets of data, unblinding cutoff
and final data cutoff.


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All AEs, treatment-emergent and hematological/biochemical toxicities based on laboratory 
measurements, as well as drug related AEs and SAEs, will be summarized by CTCAE v. 4.03 
category and worst grade. 
In addition, results of physical examination, vital signs, and ECG will be summarized in 
accordance with SAP.
8.4.4
Pharmacokinetic data 
Section modified by amendment 6.
Individual concentration-time data of copanlisib and M-1 may be provided in a clinical study 
report appendix. Sparse copanlisib concentration data from this study, which might be 
augmented with PK data from other studies, may be analyzed to evaluate the variability of the 
copanlisib PK in this Phase III population. The possible effect of relevant covariates on the 
PK of copanlisib might also be evaluated. A population pharmacokinetic approach will be 
applied for these evaluations, which will be described in detail in a separate Modeling & 
Simulation (M&S) Plan if the results will be reported separately in the M&S Report.
8.5
Planned interim analyses
No interim efficacy analyses are planned for this study.
8.6
Determination of sample size
Section modified by amendments 1, 5 and 6.
Determination of sample size has not been applicable since amendment 5 became effective. 
9.
Data handling and quality assurance
9.1
Data recording
Section modified by amendment 6. 
It is the expectation of the sponsor that all data entered into the CRF has source 
documentation available at the site. The site must implement processes to ensure this happens. 
A source document checklist will be used at the site to identify the source data for all data 
points collected and the monitor will work with the site to complete this.
Data recorded from “only screened patients (screening failures)”
Data of 'only screened patients' will be recorded at least as source data, as far as the reason for 
the premature discontinuation is identifiable. At minimum, data to be recorded in the CRF are 
demographic information (patient number, year of birth/age, sex, race and ethnicity), the 
reason for premature discontinuation and date of last visit. These data will be transferred to 
the respective database.


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For screening failures with an SAE, the following additional data should be collected in the 
CRF, in addition to demographic information, primary reason for discontinuation and date of 
last visit:

All information about the SAE.

All information related to the SAE such as: 
o
Concomitant medication.
o
Medical history.
o
Other information needed for SAE complementary page.
9.2
Monitoring
In accordance with applicable regulations, GCP, and sponsor’s/CRO’s procedures, monitors 
will contact the site prior to the start of the study to review with the site staff the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and sponsor’s 
requirements. When reviewing data collection procedures, the discussion will also include 
identification and documentation of source data items.
The sponsor/designee will monitor the site activity to verify that the:

Data are authentic, accurate and complete.

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.
9.3
Data processing
Section modified by amendment 5.
The data collection tool for this study will be a validated electronic system called RAVE. 
Patient data necessary for analysis and reporting will be entered/transmitted into a validated 
database or data system (e.g. TOSCA; SAS). 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. IVRS, 
laboratory).
Clinical data will be entered into Rave by clinical site staff and will be transferred from Rave
into SAS datasets. Data review will be performed by sponsor on an ongoing basis to ensure
data is accurate, consistent and complete. Data for, external supplier sources will be checked
by sponsor. Data corrections will be made under the supervision of clinical site staff.


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For data coding (e.g. AEs, medication), internationally recognized and accepted dictionaries 
will be used. Medical Dictionary for Regulatory Activities (MedDRA) will be used for AEs 
and medical history, and WHO-Drug Dictionary (WHO-DD) for concomitant medications. 
The SAS datasets to be used for descriptive statistical analysis to be included in the clinical 
study report will remain unmodified after the data is declared clean and ready for analysis.
9.4
Audit and inspection
To ensure compliance with GCP and regulatory requirements, a member of the sponsor’s (or a 
designated CRO’s) quality assurance unit may arrange to conduct an audit to assess the 
performance of the study at the study site and of the study documents originating there. The 
investigator/institution will be informed of the audit outcome.
In addition, inspections by regulatory health authority representatives and IEC(s)/IRB(s) are 
possible. The investigator should notify the sponsor immediately of any such inspection.
The investigator/institution agrees to allow the auditor or inspector direct access to all relevant 
documents and allocate his/her time and the time of his/her staff to the auditor/inspector to 
discuss findings and any issues. Audits and inspections may occur at any time during or after 
completion of the study.
9.5
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 must notify 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.


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10.
Premature termination of the study
Section modified by amendment 5 and 6.
The sponsor has the right to close this study (or, if applicable, individual segments thereof 
[e.g. centers, treatment arms; dose steps]) 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 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.
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 given by the sponsor for destruction.

In case of a partial study closure, ongoing patients, including those in post study 
follow-up, must be taken care of in an ethical manner.
The sponsor’s decision was to stop enrollment due to lack of feasibility to complete this study 
in reasonable time frame. Therefore, the study design is modified. All patients on study 
treatment will be offered the possibility to continue treatment with copanlisib after unblinding 
procedures are completed.
Details for individual patient's withdrawal can be found in Section 5.2.1.
11.
Ethical and legal aspects
11.1
Ethical and legal conduct of the study
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigator abide by 
Good Clinical Practice (GCP) guidelines and under the guiding principles detailed in the 


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Declaration of Helsinki. The study will also be carried out in keeping with applicable local 
law(s) and regulation(s).
Documented approval from appropriate IECs/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 10.
11.2
Patient information and consent
Section modified by amendments 1, 3, 5 and 6.
All relevant information on the study will be summarized in an integrated patient information 
sheet and ICF provided by the sponsor or the study center. Genetic biomarker research of
whole blood requires separate ‘genetic’ research consent (optional testing for research). A 
sample patient information and ICF is provided as a document separate to this protocol.
Based on this patient information sheet, the investigator or designee will explain all relevant 
aspects of the study to each patient prior to his/her entry into the study (i.e. before any 
examinations and procedures associated with the selection for the study are performed or any 
study-specific data is recorded on study-specific forms).
The investigator will also mention that written approval of the IEC/IRB has been obtained.
Each patient 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 data that have been collected until the time of withdrawal will be 
retained and statistically analyzed in accordance with the SAP.


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
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 SAP. The patient has the right to object to the generation and 
processing of this post-withdrawal data. The patient’s oral objection may be 
documented in the patient’s source data.
Each patient will have ample time and opportunity to ask questions.
As of amendment 5, all patients will be reconsented and need to voluntarily agree to sign the 
ICF and have to do so, to continue in the study. Additionally, the investigator and other 
information provider (if any) will personally sign and date the form. The patient will receive a 
copy of the signed and dated form. Documentation of the informed consent process should be 
recorded in the patient’s medical record.
The signed informed consent statement is to remain in the investigator site file or, if locally 
required, in the patient’s note/file of the medical institution.
In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or patient’s clinical record must clearly show that informed 
consent was obtained prior to these procedures. Certain results from diagnostic testing 
performed as part of the standard of practice prior to the informed consent date and time may 
be used to fulfill screening criteria. This includes fresh tissue as noted in the protocol as well 
as results from CT/MRI scans, bone marrow sample, MUGA/echocardiogram and hepatitis 
testing which may also be used provided that they fall into the protocol-specified time 
window. Archival tissue obtained from the patients at any time during the course of their 
iNHL may also be used prior to the informed consent date and time if performed as part of the 
standard of practice. CT/MRI must also meet the quality per local standards.
The ICF and any other written information provided to patients will be revised whenever 
important new information becomes available that may be relevant to the patient’s consent, or 
there is an amendment to the protocol that necessitates a change to the content of the patient
information and/or the written ICF. The investigator will inform the patient of changes in a 
timely manner and will ask the patient to confirm his/her participation in the study by signing 
the revised ICF. Any revised written ICF and written information must receive the IEC/IRB’s 
approval/favorable opinion in advance of use.
11.3
Publication policy
The sponsor is interested in the publication of the results of every study it performs. 
All relevant aspects regarding publication will be part of the contract between the sponsor and 
the investigator/institution.
The sponsor has made the information regarding the study protocol publicly available on the 
internet at www.clinicaltrials.gov.


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11.4
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.
11.5
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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12.
Reference list 
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Shankland KR, Armitage JO, Hancock BW. Non-Hodgkin lymphoma. Lancet. 
2012;380(9844):848-57.
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Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. GLOBOCAN 2008 v1.2, 
Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 2010. Available 
from: http://globocan.iarc.fr.
3.
Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO 
classification of lymphoid neoplasms and beyond: evolving concepts and practical 
applications. Blood. 2011;117:5019-32.
4.
A clinical evaluation of the International Lymphoma Study Group classification of non-
Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood. 
1997;89:3909-18.
5.
Merli M, Ferrario A, Basilico C, Maffioli M, Caramazza D, Appio L, et al. Novel agents 
in indolent lymphomas. Therapeutic advances in hematology. 2013;4:133-48.
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Cheson BD, Rummel MJ. Bendamustine: rebirth of an old drug. J Clin Oncol. 
2009;27:1492-501.
7.
Lunning MA, Vose JM. Management of indolent lymphoma: where are we now and 
where are we going. Blood Rev. 2012;26:279-88.
8.
Gribben JG. How I treat indolent lymphoma. Blood. 2007;109:4617-26.
9.
Leonard JP, Gregory SA, Maloney DG, Vose JM, Younes A, Zelenetz AD. Optimizing 
the treatment of patients with rituximab-pretreated recurrent indolent non-Hodgkin 
lymphoma. Clin Adv Hematol Oncol. 2008;6:437-45.
10. National Comprehensive Cancer Network. Treatment guidelines for lymphoma. 2013 
(http://www.nccn.org/professionals/physician_gls/f_guidelines.asp).
11. Tomblyn M. Radioimmunotherapy for B-cell non-Hodgkin lymphomas. Cancer Control.
2012;19:196-203.
12. William BM, Bierman PJ. I-131 tositumomab. Expert Opin Biol Ther. 2010;10:1271-8.
13. Johnston PB, Bondly C, Micallef IN. Ibritumomab tiuxetan for non-Hodgkin’s 
lymphoma. Expert Rev Anticancer Ther. 2006;6:861-9.
14. GSK to discontinue manufacture and sale of the BEXXAR therapeutic regimen 
(tositumomab and iodine I-131 tositumomab). GSK press release of GlaxoSmithKline, 
Brentford, Middlesex, United Kingdom, August 7, 2013.
15. FDA approves Zydelig for three types of blood cancers. FDA news release, Silver Spring, 
MD, USA, July 23, 2014 (added by amendment 1).
16. Ihle NT, Powis G. Take your PIK: phosphatidylinositol 3 kinase inhibitors race through 
the clinic and toward cancer therapy. Mol Cancer Ther. 2009;8:1-9.


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17. Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. 
Oncogene. 2008;27:5497-510.
18. Saal LH, Johansson P, Holm K, Gruvberger Saal SK, She QB, Maurer M, et al. Poor 
prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN 
tumor suppressor pathway activity. Proc Natl Acad Sci U S A. 2007;104:7564-9.
19. Prevo R, Deutsch E, Sampson O, Diplexcito J, Cengel K, Harper J, et al. Class I PI3
kinase inhibition by the pyridinylfuranopyrimidine inhibitor PI 103 enhances tumor
radiosensitivity. Cancer Res. 2008;68:5915-23.
20. Gopal AK, Kahl BS, de Vos S, Wagner-Johnston ND, Schuster SJ, Jurczak WJ, et al. 
PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J 
Med. 2014;370:1008-1018.
21. Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. 
Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin 
and Non-Hodgkin Lymphoma: The Lugano Classification. J Clin Oncol. 2014 (added by 
amendment 1).
22. Owen RG, Kyle RA, Stone MJ, Rawstron AC, Leblond V, Merlini G, et al. Response 
assessment in Waldenström macroglobulinaemia: update from the VIth International 
Workshop. British journal of haematology. 2013;160:171-6.
23. Busaidy NL, Farooki A, Dowlati A, Perentesis JP, Dancey JE, Doyle LA, et al. 
Management of metabolic effects associated with anticancer agents targeting the PI3K-
Akt-mTOR pathway. J Clin Oncol. 2012;30:2919-28.
24. Lacouture ME, Wu S, Robert C, Atkins MB, Kong HH, Guitart J, et al. Evolving 
strategies for the management of hand-foot skin reaction associated with the 
multitargeted kinase inhibitors sorafenib and sunitinib. Oncologist. 2008;13:1001-11.
25. Solal-Celigny P, Roy P, Colombat P, White J, Armitage JO, Arranz-Saez R, et al. 
Follicular lymphoma international prognostic index. Blood. 2004;104:1258-65.
26. Removed by amendment 5
27. Removed by amendment 5
28. Removed by amendment 5
29. Removed by amendment 5
30. Removed by amendment 5
31. Removed by amendment 5
32. Removed by amendment 5
33. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana 
University School of Medicine 2007 [cited 2013 9 October]. Available from: 
http://medicine.iupui.edu/clinpharm/ddis/clinical-table.


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34. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9 
ed: Boston: Little Brown & Co; 1994.
35. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to 
estimate glomerular filtration rate from serum creatinine: a new prediction equation. 
Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999; 30:461-70.
36. Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, et al. Chronic 
Kidney Disease Epidemiology Collaboration. Using standardized serum creatinine values 
in the modification of diet in renal disease study equation for estimating glomerular 
filtration rate. Ann Intern Med. 2006;145:247-54.
37. National Kidney Foundation: K/DOQI clinical practice guidelines for chronic kidney 
disease: Evaluation, classification, and stratification. Part 4. Definition and classification 
of stages of chronic kidney disease. Am J Kidney Dis. 2002;39:S46-S75.
38. Removed by amendment 6.


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13.
Protocol amendments
13.1
Amendment 1
Amendment 1 is a global amendment dated 25 NOV 2014.
13.1.1
Overview of changes
13.1.1.1
Modification 1 – administrative changes
The trial name “CHRONOS-2” was added.
The sponsor’s medically responsible person (GCL) was changed.
The contact details of Coordinating Investigator were added.
Sections affected by this modification: Title page, Signature of the sponsor’s medically 
responsible person and 3 Investigator and other study personnel.
13.1.1.2
Modification 2 – introductory information updated
Introductory information on study 16349 (part A) was updated based on most recent data.
Wording regarding population PK analysis was updated accordingly.
Approval of idelalisib was referenced.
Sections affected by this modification: 1.1 Background, 1.1.2 Clinical experience, 
1.3 Benefit-risk assessment and 12 Reference list.
13.1.1.3
Modification 3 – tumor response criteria updated
Criteria for assessing tumor response were updated following the most recent publication by 
Cheson et al. (21). Assessment of response and disease progression will be done according to 
the Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin 
and Non-Hodgkin Lymphoma: The Lugano Classification. According to the new criteria 
organomegaly is only defined by CT imaging, therefore splenomegaly/hepatomegaly will no 
longer be checked at physical examinations. Ann Arbor terminology will no longer use 
suffixes A and B for symptoms related to NHL (they will only be included for Hodgkin 
Lymphomas), therefore B symptoms will not be collected. The change in CT-based criteria 
resulted in an updated table for tumor response definitions (Appendix 14.1). However, even 
though PET CT was formally incorporated into standard staging for FDG-avid lymphomas, 
the current study will only use CT scan for response assessment (see Section 7.7).
The change to the Lugano Classification aligns the criteria for assessing tumor response with 
the most recent guidelines published by a panel of experts in this field. The addition of criteria 
for assessing WM patients according to the Response Assessment in Waldenström 
Macroglobulinemia will expand the eligible study population by allowing WM patients to be 
included on the basis of IgM levels alone if they do not have radiographically measurable 
disease.


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Sections affected by this modification: Synopsis, Definitions of terms, 4 Study design, 
5.1.1 Inclusion criteria, 5.2.1.1 Withdrawal from study treatment, 7.1.1 Tabulated overview, 
7.1.2.1 Screening period, 7.1.2.2.1 Treatment – Cycle 1, 7.1.2.2.2 Treatment – Cycle 2 and
higher, 7.1.2.2.2 Tumor assessments,7.1.2.4 End-of-treatment visit, 7.3.2 Radiological tumor 
assessments, 7.5.3.2 Physical examinations, 7.7 Appropriateness of procedures / 
measurements, 8.3.1.2 Secondary efficacy variables, 12 Reference list and 14.1 Evaluation of 
tumor response.
13.1.1.4
Modification 4 – study eligibility criteria updated
Study eligibility criteria were modified to include also patients with symptomatic rituximab-
refractory iNHL based on feedback from experts in the treatment of iNHL and sponsor’s
additional internal review. Rationale was to maximize the number of patients eligible for 
treatment in this placebo controlled study:

The required number of prior lines of treatment was changed from “one or more” to 
“two or more” to be consistent with the new study population.

Exclusion criteria related to disease symptoms and node size were removed because 
the patient population was aligned with the pivotal study 16349 (part B). 

Bulky disease was added as an exclusion criterion to allow placebo control.
After consultation with regulatory authorities, prior exposure to PI3K inhibitors was removed
from exclusion criteria. Prior treatment with PI3K inhibitors will be allowed if the patient 
does not have documented evidence of resistance to idelalisib or other PI3K inhibitors. This 
change will allow patients who have previously received a PI3K inhibitor, but could not 
tolerate it, to receive active therapy. Consequently, prior treatment with PI3K inhibitor was 
added as a new stratification factor (see Section 13.1.1.8).
Exclusion criterion regarding interstitial lung disease was modified for clarity.
Inclusion criteria were clarified to include patients who have previously been exposed to
either one or more than one alkylating agent.
Inclusion criteria related to laboratory values of serum beta-2-microglobulin and LDH were 
removed. Subsequently, serum beta-2-microglobulin measurement was changed to be 
performed only in patients with LPL/WM instead of total study population.
Inclusion criterion for SCR was removed as assessment of renal function for eligibility will be 
covered by GFR instead. Subsequently, GFR will also be used instead of creatinine as one of 
the dosing criteria on Day 1 of Cycle 2 and higher. It is considered that monitoring renal 
function by using GFR is more precise than creatinine.
Sections affected by this modification: Synopsis, 1.2 Rationale of the study, 2 Study 
objectives, 4 Study design, 5.1.1 Inclusion criteria, 5.1.2 Exclusion criteria, 6.4 Dosage and 
administration, 7.1.1 Tabulated overview, 7.1.2.1 Screening period and 7.1.2.2.2 Treatment –
Cycle 2 and higher.


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13.1.1.5
Modification 5 – time to improvement in DRS-P added as secondary 
efficacy variable 
Time to improvement in disease-related symptoms - physical (DRS-P) was added as an 
additional secondary efficacy variable, to be measured for patients with a baseline DRS-P 
score of 30 points or less (i.e. patients who still have room for improvement in symptoms). 
This was due to a change in the patient population to include both symptomatic and 
asymptomatic patients. Consequently, study objectives and fixed sequence test hierarchy were 
updated. 
Censoring rules for time to deterioration in DRS-P were modified to be in alignment with PFS 
and time to improvement in DRS-P endpoints.
Sections affected by this modification: Synopsis, 2 Study objectives, 7.6.2 Quality of life 
questionnaire, 8.3.1.2 Secondary efficacy variables and 8.4.2 Efficacy.
13.1.1.6
Modification 6 – PFS2 added as other efficacy variable
Secondary PFS (PFS2) was introduced as efficacy variable by the request from European 
Medicines Agency (EMA). PFS2 will be evaluated only in placebo-treated patients who 
switch to open-label copanlisib treatment.
Sections affected by this modification: Synopsis, 2 Study objectives, 8.3.1.3 Other efficacy 
variables and 8.4.2 Efficacy.
13.1.1.7
Modification 7 – target population for efficacy analysis changed
Following advice received by regulatory authorities, the study target population for efficacy 
analysis was changed from iNHL patients to FL patients, with a possibility to also recruit 
other iNHL patients. However, the study will be powered for FL patients. Consequently, the 
number of PFS events and the number of patients to be screened and randomized were re-
calculated, with patients divided into FL and other iNHL groups. 
Likewise, the confirmatory statistical test strategy was revised to include separate tests in the 
FL subgroup and total population, respectively. In accordance with the target population of 
FL patients, the study-wise alpha is initially split with 80% to the primary analysis in the FL 
subgroup. Furthermore, any potential alpha propagation is initially done within the FL 
subgroup or from the total population to the FL subgroup as well.
Sections affected by this modification: Synopsis, 2 Study objectives, 4 Study design, 
8.4.1 Population characteristics, 8.4.2 Efficacy, 8.4.2.1 Primary efficacy analysis, 
8.4.2.2, Secondary efficacy analysis, 8.4.2.3 Confirmatory statistical testing strategy, 
8.4.3 Safety, 8.6 Determination of sample size and 12 Reference list.


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13.1.1.8
Modification 8 – randomization ratio and stratification changed
Randomization ratio in the double-blinded treatment arms, copanlisib monotherapy or 
placebo, was changed from 1:1 to 2:1, respectively. The reason for the change was to allow 
more patients to be on active treatment from onset of the study. 
The number of stratification factors changed from two to three as prior treatment with PI3K 
inhibitors was added as a new factor. This change was done in order have the possibility to 
determine if prior treatment with another agent in the same drug class affects response to 
copanlisib.
Sections affected by this modification: Synopsis, 1.2 Rationale of the study, 4 Study design, 
6.3 Treatment assignment and 8.4.2.1 Primary efficacy analysis.
13.1.1.9
Modification 9 – language on switch to open-label treatment modified
Additional language on laboratory measurements that are required to be completed within 
7 days prior to the first dose of open-label copanlisib was added and reference to laboratory 
test criteria in Table 6–2 was added. A patient who switches and starts open-label treatment 
with copanlisib must have certain laboratory evaluations to ensure that the patient has 
adequate bone marrow, renal and liver function to receive study drug.
Text was modified to specify that patients who switch to open-label treatment will be treated 
until further disease progression or they meet other criterion for withdrawal from the
treatment. It was also clarified that further progression needs to be assessed centrally.
Sections affected by this modification: 4 Study design, 6.4 Dosage and administration, 
7.1.1 Tabulated overview, 7.1.2.2 Treatment period and 7.5.3 Further safety.
13.1.1.10 Modification 10 – language on informed consent, re-screening and re-
testing revised
Language related to informed consent was modified. Certain results from diagnostic testing 
performed as part of the standard of practice prior to the informed consent date and time may 
be used to fulfill screening criteria provided that they fall into the protocol-specified time 
window. 
In addition, changes were made to the language regarding re-screening and re-testing to 
clarify the parameters and guidelines for this study.
Sections affected by this modification: 5.1.1 Inclusion criteria, 5.2.1 Withdrawal, 
7.1.1 Tabulated overview, 7.1.2.1 Screening period and 11.2 Patient information and consent.
13.1.1.11 Modification 11 – withdrawal criteria updated
The reason for withdrawal “AEs due to disease-related complications” was removed because 
AEs due to disease complications need to be considered individually in the context of the 
patient’s overall condition and the risk vs. benefit of continuing therapy. This decision should 
be at the discretion of the investigator and not dictated by the protocol.


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Explanation was added that required 1 week break is not included in the calculation of delay 
time of study drug.
Sections affected by this modification: 5.2.1.1 Withdrawal from study treatment.
13.1.1.12
Modification 12 – language on study drug reconstitution modified
The volume of copanlisib/placebo solution was removed and reference to Pharmacy Manual 
was added to avoid discrepancies between the protocol and the Pharmacy Manual.
Statement on cytotoxicity of copanlisib was removed. Based on mechanism of action of 
copanlisib, it is not considered as cytotoxic agent.
Sections affected by this modification: 6.1 Treatments to be administered, 6.2 Identity of 
study treatment and 6.4 Dosage and administration.
13.1.1.13 Modification 13 – guidelines on management of hyperglycemia updated
Recommendations regarding management of hyperglycemia were changed in order to 
simplify and harmonize guidance between planned clinical studies. Modifications are based 
on review of the latest data on Phase I studies and Phase II study 16349. These modifications 
include changes in patient’s fasting requirements and subsequent modifications on glucose 
measurement time points on Cycle 1 Day 1 as these time points are tailored based on fasting.
It is considered as safe and beneficial to shorten the time-interval of both fasting requirements 
and blood glucose assessments. 
Language on monitoring blood glucose at home was modified. Guidance for glucose 
monitoring for non-diabetic patients on Cycle 1 Day 1 was changed: not all non-diabetic 
patients will be required to monitor their blood glucose at home, but only those who develop 
hyperglycemia > 250 mg/dL or require insulin administration. 
Modifications were made to specify management of short-term and long-term effects on 
glucose homeostasis.
In addition, language on home glucose monitoring supplies (diary etc.) was added.
Sections affected by this modification: 5.2.1.1 Withdrawal from study treatment, 6.4 Dosage 
and administration, 6.4.2.1 Management of hyperglycemia that can occur with study 
treatment, 7.1.1 Tabulated overview 7.1.2 Timing of assessments, 7.1.2.1 Screening period,
7.1.2.2.1 Treatment – Cycle 1 7.1.2.2.2 Treatment – Cycle 2 and higher.
13.1.1.14
Modification 14 – dose modification rules revised
Dose modification guidelines were modified in order to eliminate ambiguity.
A note was added to Table 6–4 (dose modification of study treatment for hematological 
toxicity) to clarify that this table should not be used to determine patient eligibility for 
infusion on days 1, 8 and 15. The modification was done to ensure that the patient has 
adequate bone marrow function prior to receiving study drug infusion, as the 
recommendations for infusion days are more conservative.


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Footnote indicating that the dose decrease by one dose level is not applicable to 45 mg dose 
level was removed from Table 6–5 and Table 6–6 (Dose modification of study treatment for 
non-hematological and dermatologic toxicity) as there is no safety concern in allowing dose 
of patients with these toxicities to be reduced to 30 mg dose level and determine if they can 
tolerate this dose before mandating that they will be taken off the trial.
Error in Table 6–5 was corrected: Grade 0 was replaced with Grade 1.
Sections affected by this modification: 6.4.1 Dose modification, 6.4.1.1 Hematological 
toxicity, 6.4.1.2 and Non-hematological toxicity.
13.1.1.15 Modification 15 – information on preservation of blinding removed
Detailed information about the measures to preserve the blinding was removed because it will 
be described in the Pharmacy Manual. Furthermore, as both copanlisib and placebo solutions 
are transparent, it was clarified that placebo is colorless. 
Section affected by this modification: 6.5 Blinding.
13.1.1.16 Modification 16 – prohibited concomitant modification modified
Modification was added to allow the use short term systemic corticosteroids for the 
management of acute conditions (e.g. allergic reaction to either study drug or something else 
or an asthma exacerbation), without need to permanently discontinue the study.
Sections affected by this modification: 6.9.1 Prohibited concomitant therapy.
13.1.1.17
Modification 17 – laboratory evaluations revised
High-density lipoprotein (HDL) measurement was removed from the complete chemistry 
panel. Only total cholesterol and LDL cholesterol will be checked following 
recommendations of Busaidy et al. (23).
Reference to turbidity was removed from urinalysis for easier site compliance. Clarification 
was also made that dipsticks should be available for urinalysis.
The unit for urine creatinine concentration was corrected to be mg/dl.
Sections affected by this modification: 7.1.1 Tabulated overview and 7.5.3.1 Laboratory.
13.1.1.18 Modification 18 – timing of MUGA/echocardiogram and ECG
measurements changed
The timing of MUGA scan/echocardiogram and 12-lead ECG measurement at Screening was 
changed from “less than 14 days before start of the study treatment” to “less than 28 days 
before start of the treatment”. This modification was done because there is no safety concern 
with checking cardiac function/ECG up to 4 weeks prior to first dose of study drug as this is 
unlikely to change within the new time frame.
ECG measurement on Day 15 of every 3rd cycle (associated with PK sampling) was removed 
(see also Section 13.1.1.22).


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Clarification was added that the time window for both pre-dose and end-of-infusion ECG 
measurements is 2 h.
Clarification was also added that MUGA scan/echocardiogram does not need to be performed 
at the EOT visit if already done within 4 weeks.
Sections affected by this modification: 7.1.1 Tabulated overview, 7.1.2.1 Screening period, 
7.1.2.2.1 Treatment – Cycle 1, 7.1.2.2 Treatment – Cycle 2 and higher and 7.1.2.4 End-of-
treatment visit.
13.1.1.19 Modification 19 – clarification of blood pressure and ECG 
measurements
The required position for the patient before blood pressure and ECG measurement was 
changed from “lying down” to “rest” as this is more common in clinical practice and as data 
on position will not be needed for data evaluation.
Time window of 5 min was also added to blood pressure measurements performed from 
Cycle 1 Day 8 onwards for consistency.
Sections affected by this modification: 7.1.1 Tabulated overview, 7.1.2.1 Screening period, 
7.1.2.2.1 Treatment – Cycle 1, 7.1.2.2.2 Treatment – Cycle 2 and higher, 7.5.3.3 Vital signs
and 7.5.3.4 12-lead ECG.
13.1.1.20 Modification 20 – survival sweep language added
Language was added to allow additional contact with the patient before their next scheduled 
telephone call or visit if the most recent data on survival is needed at specific time point 
during follow-up periods.
Sections affected by this modification: Synopsis, 4 Study design, 5.2.1.2 Withdrawal from 
follow-up period, 7.1.1 Tabulated overview, 7.1.2.5 Follow-up periods and 7.1.2.5.3 Survival 
follow-up.
13.1.1.21
Modification 21 – additional language on radiological tumor 
assessments introduced
Oral contrast agent for radiological tumor assessment was added to IV contrast to be 
consistent with the Imaging Manual.
Clarification was added that patient may stay on treatment at the investigator’s discretion until 
progression is confirmed on the subsequent tumor assessment.
Additional language regarding response assessment of WM patients was introduced for 
clarification.
Explanation was added that in certain countries MRI should be used based on local 
regulations.


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Guidance related to scans obtained for Screening, treatment period and Active follow-up was 
added to the protocol: the scans should be forwarded to the designated Imaging Core 
Laboratory for central review.
The word “screening” was added in front of CT/MRI throughout the protocol for consistency: 
corticosteroids must be stopped or reduced to the allowed dose at least 7 days before 
performing the screening CT/MRI.
Inconsistencies regarding the timing and time windows of tumor assessments were addressed.
Deviation of ± 2 days was allowed related to additional procedures that should be performed 
on the days of tumor assessments for flexibility (sites and imaging centers may be on different 
locations).
Sections affected by this modification: Synopsis, 4 Study design, 7.1.1 Tabulated overview, 
7.1.2.1 Screening period, 7.1.2.3 Tumor assessments, 7.1.2.4 End-of-treatment visit and 7.3.2
Radiological tumor assessments.
13.1.1.22 Modification 22 – collection of PK samples revised
PK sampling time points associated with 12-lead ECGs (Cycle 1 Day 1 and on Day 15 of 
every 3rd cycle) were removed to reduce the burden on the patients and the sites, and to reduce 
the overall number of samples to be shipped and processed.
Flexibility was added to the PK sampling time on Cycle 1 Day 8.
Sections affected by this modification: 7.1.1 Tabulated overview, 7.1.2.2.1 Treatment –
Cycle 1, 7.1.2.2.2 Treatment – Cycle 2 and higher and 7.4 Pharmacokinetics / 
pharmacodynamics.
13.1.1.23 Modification 23 – collection of tumor tissue/biomarker specimens 
revised 
Requirements about collection of tumor tissue were specified further to make sure the best 
material is received if available but at the same time not to restrict patients from participating 
in the study if sufficient sample is not available for both pathology and biomarkers. Timing of 
plasma collection for tumor genetics and non-genetic biomarker analysis was changed to be 
performed only at cycles 1, 2 (non-genetic sample only), and end-of-treatment visit, i.e. 
sampling at Day 1 of subsequent cycles was removed. This was done to reduce the burden on 
the patients and the sites, and to reduce the overall number of samples to be shipped and 
processed.
“Genetic biomarker analysis” was changed to “tumor genetics” throughout the protocol to 
clarify that separate consent for genetic research is not required to collect these samples.
The collection of material for tumor genetics and non-genetic biomarker analyses was 
changed from “blood” to “plasma” to clearly distinguish it from the whole blood sample for 
which genetic consent would be required.


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Sections affected by this modification: 4 Study design, 7.1.1 Tabulated overview, 
7.1.2.1 Screening period, 7.1.2.2.1 Treatment – Cycle 1, 7.1.2.2.2 Treatment – Cycle 2 and 
higher, 7.1.2.4 End-of-treatment visit and 7.6.1 Biomarker investigations.
13.1.1.24 Modification 24 – responsible person completing the PRO information 
sheet changed
Responsible person for completing the PRO information sheet (study nurse/investigator) was 
replaced with study personnel to allow flexibility. This information was also added to 
flowchart footnote and visit descriptions for clarity.
Language was slightly modified to clarify that patients will complete the QoL questionnaire.
Furthermore, it was clarified that QoL questionnaire does not need to be completed at the 
SFU evaluation if the post-treatment safety assessment is conducted via telephone. 
Sections affected by this modification: 7.1.1 Tabulated overview, 7.1.2.2.1 Treatment –
Cycle 1, 7.1.2.2.2 Treatment – Cycle 2 and higher, 7.1.2.4 End-of-treatment visit, 
7.1.2.5.1 Safety follow-up and 7.6.2 Quality of life questionnaire.
13.1.1.25
Modification 25 – sub-group analysis 
In accordance with the EMA draft guideline on the investigation of subgroups in confirmatory 
clinical trials, a section describing a pre-defined region definition, as well as briefly 
describing subgroup analyses for regions and other subgroups (e.g. based on stratification 
factors and other baseline characteristics), was added to the protocol.
Sections affected by this modification: 8.4.2.4 Subgroup analyses.
13.1.1.26 Modification 26 – link to GFR calculator added
Link to specific GFR calculator was provided. The calculator uses MDRD study equation 
which allows calculation of GFR using either one of two formulas, according to the two 
different methods of serum creatinine assessment (standardized or non-standardized) used at 
the site. The change was done because the MDRD formula provided in Appendix 14.5 is 
based on creatinine values determined by a non-standardized (old method) creatinine assay 
while currently many labs have changed to a standardized creatinine assay (called Isotope 
Dilution Mass Spectrometry –IDMS-traceable, which is a more accurate assessment).
Sections affected by this modification: 14.5 Glomerular filtration rate.
13.1.1.27
Modification 27 – other clarifications and corrections
In addition to the modifications specified above there have been minor corrections for better 
clarity and consistency.

Language on indolent NHL was modified: iNHL was changed to indolent B-cell NHL
in exclusion and withdrawal criteria.

The reference to ISO (International Organization for Standardization) code was 
removed.


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
Carbamazepine was removed from the list of permitted concomitant therapy (narrow 
therapeutic index medications) because this drug is already listed in the prohibited 
concomitant therapy.

IVRS/IWRS transaction was added to Table 7–1 to be performed at Screening as it 
was erroneously missing from the table.

Clarification was made that documentation of the first new anticancer treatment also 
includes documentation of response during survival follow-up.

In addition to date of response, also duration of response was added to be collected in 
disease history of the study indication.

Clarification was added that bone marrow biopsy will be performed as per local 
standard of care.

Editorial changes and minor clarifications/corrections were done.
CSP sections affected by this modification: Synopsis, 1.2 Rationale of the study, 4 Study 
design, 5.1.2 Exclusion criteria, 5.2.1.1 Withdrawal from study treatment, 5.3 Patient 
identification, 6.9.2 Permitted concomitant therapy, 7.1.1 Tabulated overview, 
7.1.2.1 Screening period, 7.1.2.5.3 Survival follow-up and 7.1.2.3 Tumor assessments.


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13.1.2
Changes to the protocol text
In this section, all affected protocol sections are detailed; the sequence of the sections follows 
the structure of the original protocol. In the display of modifications, the “old text” refers to 
the protocol version preceding this amendment. Deletions are crossed out in the “old text”. 
Additions are underlined in the “new text”. Corrections of typing errors or omissions are not 
highlighted in this amendment.
13.1.2.1
Title page
Old text:
A randomized, double-blind Phase III study of copanlisib versus placebo in patients 
with rituximab-refractory indolent non-Hodgkin’s lymphoma (iNHL)
New text:
A randomized, double-blind Phase III study of copanlisib versus placebo in patients 
with rituximab-refractory indolent non-Hodgkin’s lymphoma (iNHL) – CHRONOS-2
13.1.2.2
Signature of the sponsor’s medically responsible person
Old text:
Name:
 MD
Role:  
 (
)
New text:
Name:
 MD
Role:  
 (
)
PPD
PPD
PPD
PPD
PPD
PPD


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13.1.2.3
Synopsis
Old text:
Title
A randomized, double-blind Phase III study of copanlisib versus 
placebo in patients with rituximab-refractory indolent non-Hodgkin’s 
lymphoma (iNHL)
[...]
Study objectives
The primary objective of this study is:

To investigate whether copanlisib as monotherapy is superior to 
placebo in prolonging progression free survival (PFS) in patients 
with asymptomatic rituximab-refractory iNHL who have received 
one or more prior lines of treatment, have been exposed to 
rituximab and alkylating agents, and have progressed within six 
months of the end of the last previous rituximab-containing 
regimen.
The secondary objectives of this study are to evaluate:

Efficacy.

Time to deterioration in disease-related symptoms.

Safety.
The other objectives of this study are to evaluate:

Pharmacokinetics.
[...]
Duration of treatment
Treatment will be continued until disease progression (PD) (per central 
independent blinded radiology review) as defined in the Revised Response 
Criteria for Malignant Lymphoma, unacceptable toxicity, or until another 
criterion is met for withdrawal from the study treatment.
[...]
Indication
Asymptomatic rituximab-refractory iNHL.


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Diagnosis and main criteria 
for inclusion
[...]
Patients must have received one or more prior lines of treatment. A 
previous regimen is defined as one of the following: at least two months of 
single-agent therapy, at least two consecutive cycles of polychemotherapy, 
autologous transplant, radioimmunotherapy.
Prior therapy must include rituximab and alkylating agents.
Patients must be refractory to the last rituximab-based treatment (no 
response or response lasting < 6 months).
Patients must have at least one bi-dimensionally measurable lesion (which 
has not been previously irradiated) according to the recommendations of 
the Revised Response Criteria for Malignant Lymphoma.
In addition to the above measurable lesion criterion, patients affected by 
LPL/WM must have also measurable disease, defined as presence of 
immunoglobulin M (IgM) paraprotein with a minimum IgM level ≥ 2 x 
upper limit of normal (ULN) or over 10% of lymphoplasmacytic cells in 
the bone marrow. 
[...]
Main criteria for exclusion
[...]
Transformed disease (assessed by investigator):

histological confirmation of transformation, or

clinical and laboratory signs: rapid disease progression, high SUV
(> 12) by positron emission tomography (PET) at baseline if PET 
scans are performed (optional).
Presence of B-symptoms (fever above 38°C, night sweats, or weight loss 
of more than 10% in the previous 6 months).
Lymph nodes or tumor mass (except spleen) > 7 cm.
Nodes > 3 cm in 3 distinct areas.
Symptoms related to organ compression, pleural effusion, ascites, spleen 
enlargement, and renal, liver or bone involvement.
[...]
History or concurrent condition of interstitial lung disease and/or severely 
impaired lung function
[...]
Prior treatment with PI3K inhibitors.
Study design
A randomized, double-blind, two-arm Phase III study to evaluate the 
efficacy and safety of copanlisib as monotherapy in comparison to placebo 
in patients with asymptomatic rituximab-refractory iNHL.
Approximately 120 patients who meet the eligibility criteria will be 
randomly assigned in a 1:1 ratio to one of the double-blinded treatment 
arms: copanlisib monotherapy or placebo.
Patients will be stratified at randomization based on NHL histology 


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(FL histology vs. other histology) and the time between last course of 
systemic anticancer therapy and most recent progression (≤ 6 months vs. 
> 6 months).
[...]
Methodology
[...]
Secondary efficacy variables are objective tumor response rate (ORR), 
duration of response (DOR), complete response rate (CRR), time to 
progression (TTP), overall survival (OS) and the time to deterioration in 
disease-related symptoms - physical (DRS-P) of ≥3 points of lymphoma 
as measured by the FLymSI-18 questionnaire.
Other efficacy variables are FLymSI-18 subscale, total score analyses and 
time to onset of physical symptoms of lymphoma based on DRS-P, and 
ECOG performance status.
The study is composed of following periods: Screening, Treatment, 
Safety-follow-up, Active follow-up (if applicable) and Survival follow-up.
Patients randomized to the copanlisib treatment arm will receive 60 mg 
copanlisib IV infusion on Days 1, 8 and 15 of each 28-day treatment cycle.
Patients randomized to the placebo arm will receive placebo IV infusion 
on Days 1, 8 and 15 of each 28-day treatment cycle.
Treatment will be continued until PD (per central independent blinded 
radiology review) defined in the Revised Response Criteria for Malignant 
Lymphoma, unacceptable toxicity, or until another criterion is met for 
withdrawal from the study treatment. 
[...]
All patients will be followed off-study for overall survival at 3-month 
intervals during the Survival follow-up period (up to 3 years after the last 
patient started study treatment), except for patients who object to follow-
up data collection.
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, 
and at the SFU visit.
The first radiological tumor assessments with IV contrast enhanced 
computed tomography/magnetic resonance imaging (CT/MRI) scans of 
neck, chest, abdomen and pelvis will be performed at Screening. 
Corticosteroids must be stopped or reduced to the allowed dose (less than 
15 mg of prednisone or equivalent) at least 7 days before performing the 
CT/MRI (if a patient is on chronic corticosteroid therapy, corticosteroids 
should be de-escalated to the maximum allowed dose before the 
Screening). Tumor scans done up to 28 days prior to first dose can be used 
as baseline evaluation. The method chosen at the baseline must be the 
same throughout the study. During the treatment period as well as during 
the Active follow-up period tumor assessments with the same modality 
will be performed every 12 weeks (±7 days) during Year 1, every 
16 weeks (±7 days) during Year 2, and every 24 weeks (±7 days) during 
Year 3. CT/MRI scans are not required at the EOT visit if the patient 
discontinues due to PD which has been radiologically confirmed within 
the 4 weeks preceding EOT. As long as the patient has not experienced 


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PD, investigator’s assessment is sufficient for case management. In the 
event of progression, radiological real-time confirmation by central 
independent blinded evaluation is required before a final decision to stop 
the treatment is made. The final evaluation of treatment response (best 
response: ORR and CRR) will be done by central blinded review 
retrospectively.
[...]
Number of patients
Approximately 160 patients will be enrolled to this study. Approximately 
120 patients who meet the eligibility criteria will be randomized –
approximately 60 patients per treatment arm.
[...]
Plan for statistical analysis
Primary efficacy analysis:
The primary efficacy variable is PFS as assessed by central review. It will 
be evaluated whether PFS in copanlisib group is higher compared to PFS 
in the placebo group. All statistical tests will be one-sided, with a 
significance level of alpha = 0.01.
The following null hypothesis will be tested:
H0, PFS:  SCopanlisib(t) = SPlacebo(t) for all time points t ≥ 0
The alternative hypothesis will be:
H1,PFS:  SCopanlisib(t) > SPlacebo(t) for at least one time point t ≥ 0, and
            SCopanlisib(t) ≥ SPlacebo(t) for all time points t ≥ 0,
where SCopanlisib denotes the survival function of the copanlisib group and 
SPlacebo denotes the survival function of the placebo group.
The following decision rule to test the null hypothesis will be applied:
According to the size of this study it is justified to assume under H0, PFS 
sufficient close approximation of the one-sided log-rank test to the normal 
distribution. If the z-value from the one-sided log-rank test (for the 
difference SCopanlisib - SPlacebo, stratified by the same factors as used for 
randomization) is larger than the critical quantile from the normal 
distribution (z0.99 = 2.33), the null hypothesis will be rejected in favor of 
the alternative hypothesis.
Additional analyses of the primary efficacy variable:
Kaplan-Meier estimates of median times to PFS (including 98% 
confidence interval) and Kaplan-Meier curves will be presented for each 
treatment group.
The hazard ratio (including 98% confidence interval) will be derived from 
a Cox proportional hazards model and stratified by the same factors as 
used for randomization.
[...]


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New text:
Title
A randomized, double-blind Phase III study of copanlisib versus 
placebo in patients with rituximab-refractory indolent non-Hodgkin’s 
lymphoma (iNHL) – CHRONOS-2
[...]
Study objectives
The primary objective of this study is:

To investigate whether copanlisib as monotherapy is superior to 
placebo in prolonging progression-free survival (PFS) in patients 
with rituximab-refractory iNHL who have received two or more 
prior lines of treatment, have been exposed to rituximab and 
alkylating agent(s), and have progressed within six months of the 
end of the last previous rituximab-containing regimen.
The secondary objectives of this study are to evaluate:

Efficacy including tumor response, time to progression and overall 
survival.

The following characteristics of disease-related symptoms: time to 
deterioration and time to improvement. 

Safety.
The other objectives of this study are to evaluate:

PFS2 in placebo-treated patients who switched to open-label 
copanlisib treatment.

Pharmacokinetics.
[...]
Duration of treatment
Treatment will be continued until disease progression (PD) (per central 
independent blinded radiology review) as defined in the Recommendations 
for Initial Evaluation, Staging, and Response Assessment of Hodgkin and 
Non-Hodgkin Lymphoma: The Lugano Classification, unacceptable 
toxicity, or until another criterion is met for withdrawal from the study 
treatment. For patients with Waldenström macroglobulinemia (WM), 
response assessment will be done according to the Response Assessment 
in Waldenström macroglobulinemia: update from the VIth International 
Workshop.
[...]
Indication
Rituximab-refractory iNHL.


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Diagnosis and main criteria 
for inclusion
[...]
Patients must have received two or more prior lines of treatment. A 
previous regimen is defined as one of the following: at least two months of 
single-agent therapy, at least two consecutive cycles of polychemotherapy, 
autologous transplant, radioimmunotherapy.
Prior therapy must include rituximab and alkylating agent(s). Prior 
exposure to idelalisib or other PI3K inhibitors is acceptable provided that 
there is no resistance.
Patients must be refractory to the last rituximab-based treatment (no 
response or response lasting < 6 months).
Patients must have at least one bi-dimensionally measurable lesion (which 
has not been previously irradiated) according to the Recommendations for 
Initial Evaluation, Staging, and Response Assessment of Hodgkin and 
Non-Hodgkin Lymphoma: The Lugano Classification.
Patients affected by WM, who do not have at least one bi-dimensionally
measurable lesion in the baseline radiologic assessment, must have 
measurable disease, defined as presence of immunoglobulin M (IgM) 
paraprotein with a minimum IgM level ≥ 2 x upper limit of normal (ULN). 
[...]


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Main criteria for exclusion
[...]
Transformed disease (assessed by investigator):

histological confirmation of transformation, or

clinical and laboratory signs: rapid disease progression, high 
standardized uptake value (> 12) by positron emission 
tomography (PET) at baseline if PET scans are performed 
(optional).
Bulky disease:

Lymph nodes or tumor mass (except spleen) ≥7 cm LDi (longest 
diameter).
[...]
History or concurrent condition of interstitial lung disease of any severity
and/or severely impaired lung function
[...]
Documented evidence of resistance to a prior treatment with idelalisib or 
other PI3K inhibitors defined as:

No response (response defined as partial response [PR] or complete 
response [CR]) at any time during therapy, or

Progression (PD) after any response (PR/CR) or after stable disease 
(SD) within 6 months from the end of the therapy with a PI3K 
inhibitor.
Patients who discontinued treatment due to other reason than 
disease progression, and did not exhibit any signs of PD, will be 
allowed to enroll in this study after discussion with the sponsor.
Study design
A randomized, double-blind, two-arm Phase III study to evaluate the 
efficacy and safety of copanlisib as monotherapy in comparison to placebo 
in patients with rituximab-refractory iNHL.
Approximately 189 patients (144 FL and 45 other iNHL) who meet the 
eligibility criteria will be randomly assigned in a 2:1 ratio to one of the 
double-blinded treatment arms: copanlisib monotherapy or placebo, 
respectively.
Patients will be stratified at randomization based on NHL histology 
(FL histology vs. other iNHL histology), the time between last course of 
systemic anticancer therapy and most recent progression (≤ 6 months vs. 
> 6 months) and prior treatment with PI3K inhibitors (yes vs. no).
[...]
Methodology
[...]
Secondary efficacy variables are objective tumor response rate (ORR), 
duration of response (DOR), complete response rate (CRR), time to 
progression (TTP), overall survival (OS), time to deterioration and time to 
improvement in disease-related symptoms - physical (DRS-P) of at least
3 points of lymphoma as measured by the FLymSI-18 questionnaire.


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Other efficacy variables are PFS2, FLymSI-18 subscale, total score 
analyses and time to onset of physical symptoms of lymphoma based on 
DRS-P, and ECOG performance status.
The study is composed of the following periods: Screening, Treatment, 
Safety-follow-up, Active follow-up (if applicable) and Survival follow-up.
Patients randomized to the copanlisib treatment arm will receive 60 mg 
copanlisib IV infusion on Days 1, 8 and 15 of each 28-day treatment cycle.
Patients randomized to the placebo arm will receive placebo IV infusion 
on Days 1, 8 and 15 of each 28-day treatment cycle.
Treatment will be continued until PD (per central independent blinded 
radiology review), unacceptable toxicity, or until another criterion is met 
for withdrawal from the study treatment. 
[...]
All patients will be followed off-study for overall survival at least at 3-
month intervals during the Survival follow-up period (up to 3 years after 
the last patient started study treatment), except for patients who object to 
follow-up data collection.
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, 
and at the SFU visit.
The first radiological tumor assessments with IV (and oral, if indicated, 
per Imaging Manual) contrast enhanced computed tomography/magnetic 
resonance imaging (CT/MRI) scans of neck, chest, abdomen and pelvis 
will be performed at Screening (including WM patients). Corticosteroids 
must be stopped or reduced to the allowed dose (less than 15 mg of 
prednisone or equivalent) at least 7 days before performing the screening
CT/MRI (if a patient is on chronic corticosteroid therapy, corticosteroids 
should be de-escalated to the maximum allowed dose before the 
Screening). The method chosen at the baseline must be the same 
throughout the study. During the treatment period as well as during the 
Active follow-up period tumor assessments with the same modality will be 
performed every 12 weeks during Year 1, every 16 weeks during Year 2, 
and every 24 weeks during Year 3. CT/MRI scans are not required at the 
EOT visit if the patient discontinues due to PD which has been 
radiologically confirmed within the 4 weeks preceding EOT. As long as 
the patient has not experienced PD, investigator’s assessment is sufficient 
for case management. In the event of progression, radiological real-time 
confirmation by central independent blinded evaluation is required before 
a final decision to stop the treatment is made. The final evaluation of 
treatment response (best response: ORR and CRR) will be done by central 
blinded review retrospectively.
[...]


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Number of patients
Approximately 237 patients will be screened for enrollment to this study. 
Approximately 189 patients who meet the eligibility criteria will be 
randomized – the copanlisib monotherapy arm will consist of 
approximately 126 patients and placebo arm of approximately 63 patients.
[...]
Plan for statistical analysis
Primary efficacy analysis:
The primary efficacy variable is PFS as assessed by central review. It will 
be evaluated whether PFS in the copanlisib group is higher compared to 
PFS in the placebo group for the total study population and separately for 
the FL subgroup. All efficacy analyses will be performed when 
approximately 82 centrally evaluated PFS events are observed in the FL 
subgroup.
The study-wise alpha of 1% will initially be split, according to the test 
strategy for this study: with 80% * 1% = 0.8% assigned to the one-sided 
PFS test in the FL subgroup, and 20% * 1% = 0.2% to the one-sided PFS 
test in the total study population.
The following null hypothesis will be tested:
H0, PFS:  SCopanlisib(t) = SPlacebo(t) for all time points t ≥ 0
The alternative hypothesis will be:
H1,PFS:  SCopanlisib(t) > SPlacebo(t) for at least one time point t ≥ 0, and
            SCopanlisib(t) ≥ SPlacebo(t) for all time points t ≥ 0,
where SCopanlisib denotes the survival function of the copanlisib group and 
SPlacebo denotes the survival function of the placebo group in the total study 
population or the FL subgroup, respectively.
The following decision rule to test the null hypothesis will be applied:
According to the size of this study it is justified to assume that under H0, 
PFS the one-sided log-rank test is a sufficiently close approximation to the 
normal distribution. If the z-value from the one-sided log-rank test (for the 
difference SCopanlisib - SPlacebo, stratified by the same factors as used for 
randomization) is larger than the respective critical quantile from the 
normal distribution (for FL subgroup: z0.992 = 2.409, for the total study 
population: z0.998 = 2.878), the null hypothesis will be rejected in favor of 
the alternative hypothesis.
Additional analyses of the primary efficacy variable:
Kaplan-Meier estimates of median times to PFS (including 98% 
confidence interval) and Kaplan-Meier curves for the total study 
population and the FL subgroup will be presented for each treatment 
group.
The hazard ratio (including 98% confidence interval) will be derived for 
the total study population and separately for the FL subgroup from a Cox 
proportional hazards models that are stratified by the same factors as used 
for the primary efficacy analysis.
[...]


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13.1.2.4
Definitions of terms
Old text:
Throughout this document, the terms “complete response” and “partial response” are used 
when referring to disease evaluation. Originating from the Response Evaluation Criteria in 
Solid Tumors, these terms are used synonymously to “complete remission” and “partial 
remission” for consistency, even when referring to the Revised Response Criteria for 
Malignant Lymphoma (1) which use the term “remission”.
New text:
The tumor response assessment will be done according to the Recommendations for Initial 
Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: 
The Lugano Classification (21), henceforth referred to as the Lugano classification.
For patients with WM, response assessment will be done according to the Response 
Assessment in Waldenström macroglobulinemia: update from the VIth International 
Workshop (22), henceforth referred to as the Owen criteria.
13.1.2.5
Section 1.1 Background
Old text:
The use of these agents is further constrained by the complex procedures for their 
administration. For these reasons, 90Y-ibritumomab is used infrequently, and 131I-
tositumomab has been withdrawn from the market (15). 
Therefore, there is a continuing need for additional, active and safe drugs that can be used in 
the refractory setting. 
New text:
The use of these agents is further constrained by the complex procedures for their 
administration. For these reasons, 90Y-ibritumomab is used infrequently, and 131I-
tositumomab has been withdrawn from the market (14). Very recently, idelalisib (Zydelig) 
was approved for the treatment of patients with double-refractory FL after two prior lines of 
therapy (15).
There is a continuing need for additional, active and safe drugs that can be used in the 
refractory setting. 


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13.1.2.6
Section 1.1.2 Clinical experience
Old text:
Pharmacokinetic (PK) results indicate nearly dose proportional increase in maximum 
concentration (Cmax) and area under curve (AUC(0-25)) values in the 0.1 to 1.2 mg/kg dose 
range and lack of significant accumulation after once weekly dosing. At the MTD of 
0.8 mg/kg, the geometric mean half-life, (t1/2) was approximately 36-42 h (preliminary data), 
supporting a once weekly dosage regimen. To date, one metabolite, the morpholinone derivate 
M-1, showing approximately 4 to 16% of the AUC(0-25) of copanlisib has been identified and 
is currently being investigated in clinical studies. Preliminary results of a population PK 
analysis of copanlisib in studies 12871, 15205 (Phase I monotherapy study in Japanese 
subjects) and Phase II study 16349 (part A) showed no correlation between body weight and 
copanlisib clearance, indicating that body weight-based dosing does not reduce between-
subject variability in copanlisib PK. The use of a fixed dose regimen for all patients was 
therefore considered suitable. Using the available data on preliminary safety and efficacy of 
copanlisib monotherapy, a fixed dose of 60 mg copanlisib has been defined as the 
recommended dose for use in all patients in future clinical studies. 
In the ongoing study 16349 (part A), a total of 67 patients with various indolent and 
aggressive lymphomas were treated at a starting dose of 0.8 mg/kg. The objective of the study 
was to identify activity signals in various histologic NHL subtypes and to further explore the 
safety profile of copanlisib. In the group of patients with iNHL, the following histologies 
were represented: FL (16 patients), CLL/SLL (14 patients), and MZL (3 patients). Median age 
was 68 years and 63% of the patients had ≥4 previous lines of treatment. At the cut-off date 
of 11 NOV 2013 the median duration of treatment was 3 cycles. The response rate (RR) was 
40% in FL, 43% in CLL/SLL (100% in SLL), and 66% in MZL.
As of 04 SEP 2013, the most frequent TEAEs, regardless of relationship to study drug, 
occurring in > 20% of the whole study population were hyperglycemia (59.7%), hypertension 
(58.2%), fatigue (40.3%), diarrhea (35.8%), nausea, neutropenia (28.4% each), anemia 
(22.4%), and oral mucositis (20.9%). The two most common study drug-related TEAEs were 
hyperglycemia (58.2%) and hypertension (53.7%). A total of 43 patients (13 with indolent, 
and 30 with aggressive lymphomas) discontinued the study treatment. Altogether 22% of 
patients stopped treatment because of AEs. No conspicuous cluster of AEs causing treatment 
discontinuation emerged. Overall 13 out of 67 patients received treatment with short-acting 
insulin.
New text:
Pharmacokinetic (PK) results indicate nearly dose proportional increase in maximum 
concentration (Cmax) and area under curve (AUC(0-25)) values in the 0.1 to 1.2 mg/kg dose 
range and lack of significant accumulation after once weekly dosing. At the MTD of 
0.8 mg/kg, the geometric mean half-life, (t1/2) was approximately 36-42 h (preliminary data), 
supporting a once weekly dosage regimen. To date, one metabolite, the morpholinone derivate 
M-1, showing approximately 4 to 16% of the AUC(0-25) of copanlisib has been identified and 
is currently being investigated in clinical studies. Results of a preliminary population PK 
analysis of copanlisib in studies 12871, 15205 (Phase I monotherapy study in Japanese 


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subjects) and Phase II study 16349 (part A) showed no correlation between body weight and 
copanlisib clearance, indicating that body weight-based dosing does not reduce between-
subject variability in copanlisib PK. The use of a fixed dose regimen for all patients was 
therefore considered suitable. Using the available data on preliminary safety and efficacy of 
copanlisib monotherapy, a fixed dose of 60 mg copanlisib has been defined as the 
recommended dose for use in all patients in future clinical studies. 
In the ongoing study 16349 (part A), a total of 67 patients with various indolent and 
aggressive lymphomas were treated at a starting dose of 0.8 mg/kg. The objective of the study 
was to identify activity signals in various histologic NHL subtypes and to further explore the 
safety profile of copanlisib. In the group of patients with iNHL, the following histologies 
were represented: FL (16 patients), CLL/SLL (14 patients), and MZL (3 patients). Median age 
was 68 years and 61% of the patients had ≥4 previous lines of systemic treatment. At the cut-
off date of 04 NOV 2013 the median duration of treatment was 4 cycles in the indolent group. 
The objective response rate (ORR) was 47% in FL, 38% in CLL, 100% in SLL, and 67% in 
MZL.
As of 04 NOV 2013, the most frequent TEAEs, regardless of relationship to study drug, 
occurring in > 20% of the whole study population were hyperglycemia (62.7%), hypertension 
(61.2%), fatigue (44.8%), diarrhea (40.3%), nausea (34.3%), neutrophil count decreased 
(31.3%), anemia (26.9%), and oral mucositis (20.9%). The two most common study drug-
related TEAEs were hyperglycemia (61.2%) and hypertension (58.2%). A total of 50 patients 
(19 with indolent, and 31 with aggressive lymphomas) discontinued the study treatment. 
Altogether 25.4% of patients stopped treatment because of AEs. No conspicuous cluster of 
AEs causing treatment discontinuation emerged. Overall 13 out of 67 patients received 
treatment with short-acting insulin.
13.1.2.7
Section 1.2 Rationale of the study
Old text:
The natural history of patients with progressing iNHL refractory to rituximab and 
asymptomatic as per protocol is not known. Copanlisib is a targeted agent that works by 
controlling the signaling pathway relevant for the survival and proliferation of iNHL cells. In 
addition to objective responses, copanlisib appears to induce in a number of patients tumor 
regressions that are below response level, but can nevertheless have a positive effect on the 
course of the disease. The evaluation of copanlisib’s anticancer activity requires a clinical trial 
design that controls for the natural history of tumor growth and minimize investigator bias in 
assessing treatment outcomes.
Considering the pre-clinical profile of copanlisib and the clinical activity emerging from 
Phase I study 12871 and the ongoing Phase II study 16349, it is expected that copanlisib will 
improve progression free survival (PFS) in patients with asymptomatic rituximab-refractory 
iNHL who have received one or more prior lines of treatment.


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New text:
The natural history of patients with progressive iNHL refractory to rituximab as per protocol 
is not known. Copanlisib is a targeted agent that works by controlling the signaling pathway 
relevant for the survival and proliferation of iNHL cells. In addition to objective responses, 
copanlisib appears to induce, in a number of patients, tumor regressions that are below 
response level, but can nevertheless have a positive effect on the course of the disease. The 
evaluation of copanlisib’s anticancer activity via a clinical trial design that controls for the 
natural history of tumor growth minimizes investigator bias in assessing treatment outcomes.
In order to provide a scientifically rigorous answer about copanlisib single agent activity, the 
randomized study is the most appropriate approach. Because no standard of care is available 
for the selected patient population, placebo is an appropriate choice of control in this 
randomized study. To minimize risk, following parameters are included in this study design:

2:1 randomization.

Exclusion of patients with bulky disease.

Opportunity for patients in the control arm to switch to active treatment after 
progression will ensure that all patients with radiologically confirmed PD will be 
treated with copanlisib.
Considering the pre-clinical profile of copanlisib and the evidence of clinical activity 
emerging from Phase I study 12871 and the ongoing Phase II study 16349, it is expected that 
copanlisib will improve progression-free survival (PFS) in patients with rituximab-refractory 
iNHL who have received two or more prior lines of treatment.
13.1.2.8
Section 1.3 Benefit-risk assessment
Old text:
Copanlisib showed activity in patients with iNHL. In the Phase I study 12871 all 6 patients 
with FL responded (please see Section 1.1.2). In the Phase II study 16349 (part A), response 
rates in patients with iNHL of various histologies were: 40% in FL, 66% in MZL, and 100% 
in SLL. Responses included complete remissions. Patients with iNHL were heavily 
pretreated, with 88% having received ≥3, and 36% ≥5 lines of treatment prior to study start.
Hyperglycemia and hypertension, the most frequently observed and expected toxicities with 
copanlisib, have been manageable. No Common Terminology Criteria for Adverse Events 
(CTCAE) Grade 4 events were observed so far and toxicities will be carefully monitored 
during the course of the study with a detailed and tailored program of management. A Data 
Monitoring Committee (DMC) will be instituted to maximize the safety of the patients 
participating in the study.
New text:
Copanlisib has showed activity in patients with iNHL. In the Phase I study 12871 all 
6 patients with FL responded (please see Section 1.1.2). In the Phase II study 16349 (part A), 


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response rates in patients with iNHL of various histologies were: 47% in FL, 67% in MZL, 
and 100% in SLL. Responses included complete remissions. Patients with iNHL were heavily 
pretreated, with 82% having received ≥3, and 36% ≥5 lines of treatment prior to study start.
Hyperglycemia and hypertension, the most frequently observed and expected toxicities with 
copanlisib, have been manageable. Toxicities will be carefully monitored during the course of 
the study with a detailed and tailored program of management. A Data Monitoring Committee 
(DMC) will be instituted to maximize the safety of the patients participating in the study.
13.1.2.9
Section 2 Study objectives
Old text:
The primary objective of this study is:

To investigate whether copanlisib as monotherapy is superior to placebo in prolonging 
progression free survival (PFS) in patients with asymptomatic rituximab-refractory 
iNHL who have received one or more prior lines of treatment, have been exposed to 
rituximab and alkylating agents, and have progressed within six months of the end of 
the last previous rituximab-containing regimen.
The secondary objectives of this study are to evaluate:

Efficacy.

Time to deterioration in disease-related symptoms.

Safety.
The other objectives of this study are to evaluate:

Pharmacokinetics.

Biomarkers.

Quality of life.
New text:
The primary objective of this study is:

To investigate whether copanlisib as monotherapy is superior to placebo in prolonging 
progression-free survival (PFS) in patients with rituximab-refractory iNHL who have 
received two or more prior lines of treatment, have been exposed to rituximab and 
alkylating agent(s), and have progressed within six months of the end of the last 
previous rituximab-containing regimen.
The secondary objectives of this study are to evaluate:

Efficacy including tumor response, time to progression and overall survival.

The following characteristics of disease-related symptoms: time to deterioration and 
time to improvement.


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
Safety.
The other objectives of this study are to evaluate:

PFS2 in placebo-treated patients who switched to open-label copanlisib treatment.

Pharmacokinetics.

Biomarkers.

Quality of life.
13.1.2.10 Section 3 Investigator and other study personnel
Old text:
Coordinating Investigator:
The coordinating investigator will be selected among the participating investigators. The 
coordinating investigator is responsible for signing the clinical study report.
New text:
Coordinating Investigator
Name: Grzegorz S. Nowakowski, MD
Address: Division of Hematology
Mayo Clinic
200 First Street SW
Rochester, MN 55905, USA
13.1.2.11 Section 4 Study design
Old text:
Design overview
This is a randomized, double-blind, two-arm Phase III study to evaluate the efficacy and 
safety of copanlisib as monotherapy in comparison to placebo in patients with asymptomatic
rituximab-refractory iNHL.
The patients have failed at least one previous line of therapy. Previous treatments must have 
included rituximab and alkylating agents; and the patients must have progressed within six 
months of the end of the last previous rituximab-containing regimen.
[...]
The start of the study period is defined by signing of the informed consent form (ICF).
Approximately 160 patients will be enrolled to this study and approximately 120 patients who 


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meet the eligibility criteria (see Section 5.1) will be randomly assigned in a 1:1 ratio to one of
the double-blinded treatment arms: copanlisib monotherapy or placebo. Both arms will 
consist of approximately 60 patients who are fully evaluable for the primary endpoint. 
Patients will be stratified at randomization based on NHL histology (FL histology vs. other 
histology) and the time between last course of systemic anticancer therapy and most recent 
progression (≤ 6 months vs. > 6 months) (see Section 6.3).
[...]
Figure 4-2
Overall study design
NHL = Non-Hodgkin’s lymphoma.
The start of the treatment period is defined by first administration of study drug (copanlisib or 
placebo). Copanlisib will be administered IV over 1 h at starting dose of 60 mg on Days 1, 8 
and 15 of each 28-day treatment cycle. Patients in the placebo arm will receive a placebo IV 
infusion at the same schedule. Treatment will be continued until PD (per central independent 
blinded radiology review) as defined in the Revised Response Criteria for Malignant 
Lymphoma (1), unacceptable toxicity, or until another criterion is met for withdrawal from 
the study treatment (see Section 5.2). 
Patients who experience PD on placebo treatment (per central independent blinded radiology 
review) can be offered open-label copanlisib upon discretion of the investigator and patient’s 
consent. After individual patient unblinding, patients receiving placebo who switch to open-
label copanlisib will have all study assessments and timing reset to the initial schedule of 
study evaluations (i.e. as if the patient was restarting the study at Cycle 1 Day 1). These 
patients will be followed until further disease progression.
[...]
All patients will be followed off-study for overall survival at 3-month intervals during the 
Survival follow-up period (up to 3 years after the last patient started study treatment), except 
for patients who object to follow-up data collection. During this period, patients are not 
considered to be “on-study”.
Stratification
NHL histology 
Time between most recent 
progression and last course of 
systemic anticancer therapy
Randomization
1:1
(N=120)
Copanlisib 60 mg
Days 1,8 and 15      
of each 28-day Cycle
Placebo
Days 1,8 and 15      
of each 28-day Cycle
Change from placebo 
to copanlisib 
(discretion of the 
investigator/patient)
Follow-up until further 
disease progression
Unblinding
Disease 
progression
Blinded central 
radiology review
optional
O
F
F
T
R
E
A
T
M
E
N
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[...]
The first radiological tumor assessment with IV contrast enhanced computed 
tomography/magnetic resonance imaging (CT/MRI) scans of neck, chest, abdomen and pelvis 
will be performed at Screening (see Section 7.3.2). Corticosteroids must be stopped or 
reduced to the allowed dose (less than 15 mg of prednisone or equivalent) at least 7 days 
before performing the CT/MRI (if a patient is on chronic corticosteroid therapy, 
corticosteroids should be de-escalated to the maximum allowed dose before the Screening). 
Tumor scans done up to 28 days prior to first dose can be used as baseline evaluation. The 
method chosen at the baseline must be the same throughout the study. During the treatment 
period as well as during the Active follow-up period tumor assessments with the same 
modality will be performed every 12 weeks (±7 days) during Year 1, every 16 weeks 
(±7 days) during Year 2, and every 24 weeks (±7 days) during Year 3. CT/MRI scans are not 
required at the EOT visit if the patient discontinues due to PD which has been radiologically 
confirmed within the 4 weeks preceding EOT. The response assessment will be done 
according to the Revised Response Criteria for Malignant Lymphoma (1). For patients with 
WM, additional criteria apply. Detailed instructions on tumor assessment are provided in 
Appendix 14.1.
[...]
Tumor tissue collection will be mandatory at Screening for central pathology review and 
biomarker analysis. Fresh tumor tissue is preferred but archival tumor tissue will be requested 
if fresh tissue is not available (the latest biopsy available should be provided). Both may also 
be collected if available. Fresh tumor tissue will be collected between Day -28 and Day -8 
prior to start of study treatment. Fresh tissue is recommended in patients with clinical 
suspicion of transformed disease.
Sparse blood samples for PK analysis will be collected from all patients to characterize the 
PK of copanlisib (see Section 7.4).
Blood samples for biomarker analyses will be collected from all patients, according to the 
schedule specified in Section 7.6.1. Blood samples for exploratory genetic biomarker analysis 
will be collected at Screening from patients who provide “genetic research” consent 
(voluntary).
[...]
Primary variable
The primary efficacy variable of this study is progression free survival (PFS), defined as the 
time (in days) from randomization to PD as assessed by central review or death from any 
cause (if no progression is documented). Efficacy analyses will be performed when 
approximately 74 PFS events are observed in the study.
Justification of the design
The pre-clinical profile of copanlisib and preliminary efficacy data from Phase I study 12871 
and Phase II study 16349 suggest that copanlisib could improve PFS in patients with 


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rituximab-refractory iNHL who have received one or more prior lines of treatment, have been 
exposed to rituximab and alkylating agents, and who are asymptomatic as per 
inclusion/exclusion criteria.
The use of placebo as a comparator in this study is justified for the following reasons:

While causing tumor shrinkage in a proportion of patients with iNHL, the main benefit 
of copanlisib may reside in the prolonged control of tumor growth.

The natural course of disease in patients with rituximab-refractory iNHL and 
asymptomatic as per inclusion/exclusion criteria of this protocol is not known. 

Use of placebo can minimize investigator bias in assessing treatment effects beyond 
tumor shrinkage. This is particularly important when assessing duration endpoints.

Although treatment with copanlisib is associated with two specific AEs, 
hyperglycemia and hypertension, the risk of inadvertent unblinding is low. In the 
majority of the cases, the intensity of both symptoms is low; both symptoms are 
relatively frequently found in the age group to which the majority of iNHL patients 
belong; and most investigators will treat 1-2 patients only due to the expected rarity of 
patients with the requested profile.
Because of the slowly progressing nature of disease, the low symptom burden, and the 
opportunity to receive open-label copanlisib following PD on placebo, the patients assigned to 
the placebo arm will not be exposed to undue risk. The primary variable of the study, PFS, 
would not be influenced by this measure. The study design will be fully disclosed to patients.
New text:
Design overview
This is a randomized, double-blind, two-arm Phase III study to evaluate the efficacy and 
safety of copanlisib as monotherapy in comparison to placebo in patients with rituximab-
refractory iNHL.
The patients have failed at least two previous lines of therapy. Previous treatments must have 
included rituximab and alkylating agent(s); and the patients must have progressed within six 
months of the end of the last previous rituximab-containing regimen.
[...]
The start of the study period is defined by signing of the informed consent form (ICF). 
Assuming a 20% screen failure rate, approximately 237 patients will be screened for 
enrollment to this study. Approximately 189 patients who meet the eligibility criteria (see 
Section 5.1) will be randomly assigned in a 2:1 ratio to one of the double-blinded treatment 
arms: copanlisib monotherapy or placebo. The copanlisib monotherapy arm will consist of 
approximately 126 patients and placebo arm of approximately 63 patients. Patients will be 
stratified at randomization based on NHL histology (FL histology vs. other iNHL histology),
the time between last course of systemic anticancer therapy and most recent progression (≤ 6 
months vs. > 6 months) and prior treatment with PI3K inhibitors (yes vs. no) (see Section 6.3). 


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The study is planned to include approximately 144 patients with FL histology and 45 patients 
with other iNHL histologies.
[...]
Figure 4-2
Overall study design
NHL = Non-Hodgkin’s lymphoma, PI3K = Phosphatidylinositol 3-kinase.
The start of the treatment period is defined by first administration of study drug (copanlisib or 
placebo). Copanlisib will be administered IV over 1 h at starting dose of 60 mg on Days 1, 8 
and 15 of each 28-day treatment cycle. Patients in the placebo arm will receive a placebo IV 
infusion at the same schedule. Treatment will be continued until PD (per central independent 
blinded radiology review) as defined in the Lugano Classification (21), unacceptable toxicity, 
or until another criterion is met for withdrawal from the study treatment (see Section 5.2). For 
patients with WM, response assessment will be done according to the Owen criteria (22).
Patients who experience PD on placebo treatment (per central independent blinded radiology 
review) can be offered open-label copanlisib upon discretion of the investigator and patient’s 
consent. After individual patient unblinding, patients receiving placebo who switch to open-
label copanlisib will have all study assessments and timing reset to the initial schedule of 
study evaluations (i.e. as if the patient was restarting the study at Cycle 1 Day 1). These 
patients will be treated until further disease progression (per central review) unacceptable 
toxicity, or until another criterion is met for withdrawal from the study treatment (see 
Section 5.2).
[...]
All patients will be followed off-study for overall survival at least at 3-month intervals during 
the Survival follow-up period (up to 3 years after the last patient started study treatment), 
except for patients who object to follow-up data collection. During this period, patients are 
not considered to be “on-study”.
Stratification
NHL histology 
Time between most recent 
progression and last course of 
systemic anticancer therapy
Prior treatment with PI3K 
inhibitors
Randomization
2:1
(N=189)
Copanlisib 60 mg
Days 1,8 and 15      
of each 28-day Cycle
Placebo
Days 1,8 and 15      
of each 28-day Cycle
Change from placebo 
to copanlisib 
(discretion of the 
investigator/patient)
Follow-up until further 
disease progression
Unblinding
Disease 
progression
Blinded central 
radiology review
O
F
F
T
R
E
A
T
M
E
N
T


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[...]
The first radiological tumor assessment with IV (and oral, if indicated, per Imaging Manual)
contrast enhanced computed tomography/magnetic resonance imaging (CT/MRI) scans of 
neck, chest, abdomen and pelvis will be performed at Screening (including WM patients) (see 
Table 7-1 and Section 7.3.2). Corticosteroids must be stopped or reduced to the allowed dose 
(less than 15 mg of prednisone or equivalent) at least 7 days before performing the screening
CT/MRI (if a patient is on chronic corticosteroid therapy, corticosteroids should be de-
escalated to the maximum allowed dose before the Screening). The method chosen at the 
baseline must be the same throughout the study. During the treatment period as well as during 
the Active follow-up period tumor assessments with the same modality will be performed 
every 12 weeks during Year 1, every 16 weeks during Year 2, and every 24 weeks during 
Year 3. CT/MRI scans are not required at the EOT visit if the patient discontinues due to PD 
which has been radiologically confirmed within the 4 weeks preceding EOT. The response 
assessment will be done according to the Lugano Classification (21), and for patients with 
WM, according to the Owen criteria (22). Detailed instructions on tumor assessment are 
provided in Appendix 14.1.
[...]
Tumor tissue collection will be mandatory at Screening for central pathology review. In 
addition, additional pre-treatment tumor tissue samples will be collected when available to 
investigate or identify biomarkers that may be predictive of copanlisib effects/efficacy in 
NHL and to contribute to better understanding the disease (see Section 7.6.1).
Sparse blood samples for PK analysis will be collected from all patients to characterize the 
PK of copanlisib (see Section 7.4).
Plasma samples for biomarker analyses will be collected from all patients, according to the 
schedule specified in Section 7.6.1. Blood samples for exploratory genetic biomarker analysis 
will be collected on Cycle 1 Day 1 from patients who provide “genetic research” consent 
(voluntary).
[...]
Primary variable
The primary efficacy variable of this study is progression-free survival (PFS), defined as the 
time (in days) from randomization to PD as assessed by central review or death from any 
cause (if no progression is documented). All efficacy analyses will be performed when 
approximately 82 centrally evaluated PFS events are observed in the FL subgroup.
Justification of the design
The pre-clinical profile of copanlisib and preliminary efficacy data from Phase I study 12871 
and Phase II study 16349 suggest that copanlisib may improve PFS in patients with 
rituximab-refractory iNHL who have received two or more prior lines of treatment and have 
been exposed to rituximab and alkylating agent(s). The purpose of this study is to demonstrate 


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efficacy and safety of treatment with copanlisib in patients where treatment is indicated, with 
a controlled randomized study with PFS as the primary endpoint.
The use of placebo as a comparator in this study is justified for the following reasons:

No standard of care is available for the defined patient population.

Published data indicates multiple options of chemotherapy combinations or single 
agent therapy used in these patients based on data from, often small, single arm 
studies.

No randomized study has confirmed efficacy or safety of these therapeutic options, 
including for those agents where regulatory approval was granted (bendamustine, 
idelalisib). Potential control agents have limited data on PFS.

The natural course of disease in patients with rituximab-refractory iNHL is not known. 

Use of placebo can minimize investigator bias in assessing treatment effects beyond 
tumor shrinkage. This is particularly important when assessing duration endpoints.

This study is designed to show significant improvement in PFS for study drug vs. 
control (132% improvement in median PFS).

2:1 randomization will assure that the majority of patients will be treated with 
copanlisib from onset.

Exclusion of patients with bulky disease.

Available opportunity for patients in the control arm to switch to active treatment after 
progression will ensure that all patients with radiologically confirmed PD will be 
treated with copanlisib. Additional exploratory efficacy endpoint is PFS2, which will 
assess PFS for patients on placebo arm who switched to receive therapy with 
copanlisib.

Although treatment with copanlisib is associated with two specific AEs, 
hyperglycemia and hypertension, the risk of inadvertent unblinding is low. In the 
majority of the cases, the intensity of both symptoms is low; both symptoms are 
relatively frequently found in the age group to which the majority of iNHL patients 
belong; and most investigators will treat 1-2 patients only due to the expected rarity of 
patients eligible for enrollment.


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13.1.2.12 Section 5.1.1 Inclusion criteria
Old text:
1. Ability to understand and willingness to sign written informed consent. Signed 
informed consent must be obtained before any study specific procedure.
[...]
3. Patients must have received one or more prior lines of treatment. A previous regimen 
is defined as one of the following: at least two months of single-agent therapy, at least 
two consecutive cycles of polychemotherapy, autologous transplant, 
radioimmunotherapy. 
4. Prior therapy must include rituximab and alkylating agents.
[...]
6. Patients must have at least one bi-dimensionally measurable lesion (which has not 
been previously irradiated) according to the recommendations of the Revised 
Response Criteria for Malignant Lymphoma (1).
7. In addition to the above measurable lesion criterion, patients affected by LPL/WM 
must have also measurable disease, defined as presence of immunoglobulin M (IgM) 
paraprotein with a minimum IgM level ≥ 2 x upper limit of normal (ULN) or over 
10% of lymphoplasmacytic cells in the bone marrow. 
[...]
13. Adequate bone marrow, liver and renal function as assessed by the following 
laboratory requirements conducted within 7 days before start of study treatment:
[...]
o
Amylase and lipase ≤1.5 x the ULN.
o
Serum creatinine (SCR) ≤1.5 x the ULN. 
o
Glomerular filtration rate (GFR) ≥ 30 ml/min/1.73 m2 according to the 
Modification of Diet in Renal Disease (MDRD) abbreviated formula.
[...]
o
Absolute neutrophil count (ANC) ≥ 1500/mm3.
o
Serum lactate dehydrogenase (LDH) ≤ ULN.
o
Serum beta-2-microglobulin ≤ ULN.
New text:
1. Ability to understand and willingness to sign written informed consent. Signed 
informed consent must be obtained before any study specific procedure1.
1 Certain results from diagnostic testing performed as part of the standard of practice prior to the 
informed consent date and time may be used to fulfill screening criteria. This includes fresh tissue as 
noted in the protocol as well as results from CT/MRI scans, bone marrow sample, 


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MUGA/echocardiogram and hepatitis testing which may also be used provided that they fall into the 
protocol-specified time window. Archival tissue obtained from the patients at any time during the 
course of their iNHL may also be used prior to the informed consent date and time if performed as part 
of the standard of practice. CT/MRI must also meet the quality standards of the Imaging Manual.
[...]
3. Patients must have received two or more prior lines of treatment. A previous regimen 
is defined as one of the following: at least two months of single-agent therapy, at least 
two consecutive cycles of polychemotherapy, autologous transplant, 
radioimmunotherapy. 
4. Prior therapy must include rituximab and alkylating agent(s). Prior exposure to
idelalisib or other PI3K inhibitors is acceptable provided that there is no resistance.
[...]
6. Patients must have at least one bi-dimensionally measurable lesion (which has not 
been previously irradiated) according to the Recommendations for Initial Evaluation, 
Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The 
Lugano Classification (21).
7. Patients affected by WM, who do not have at least one bi-dimensionally measurable 
lesion in the baseline radiologic assessment, must have measurable disease, defined as 
presence of immunoglobulin M (IgM) paraprotein with a minimum IgM level ≥ 2 x 
upper limit of normal (ULN). 
[...]
13. Adequate bone marrow, liver and renal function as assessed by the following 
laboratory requirements conducted within 7 days before start of study treatment:
[...]
o
Amylase and lipase ≤1.5 x the ULN.
o
Glomerular filtration rate (GFR) ≥ 30 ml/min/1.73 m2 according to the 
Modification of Diet in Renal Disease (MDRD) abbreviated formula.
[...]
o
Absolute neutrophil count (ANC) ≥ 1500/mm3.
13.1.2.13 Section 5.1.2 Exclusion criteria
Old text:
6. Previous or concurrent cancer that is distinct in primary site or histology from iNHL 
within 5 years before start of study treatment 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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7. Presence of B-symptoms (fever above 38°C, night sweats, or weight loss of more than 
10% in the previous 6 months).
8. Lymph nodes or tumor mass (except spleen) > 7 cm.
9. Nodes > 3 cm in 3 distinct areas.
10. Symptoms related to organ compression, pleural effusion, ascites, spleen enlargement, 
and renal, liver or bone involvement.
11. Known lymphomatous involvement of the central nervous system.
[...]
25. History or concurrent condition of interstitial lung disease and/or severely impaired 
lung function (as judged by the investigator)
[...]
Excluded previous therapies and medications
32. Prior treatment with PI3K inhibitors.
33. Treatment with investigational drugs other than PI3K inhibitors within 28 days before 
start of study treatment.
[...]
44. Use of strong inducers of CYP3A4 is prohibited from Day -14 of Cycle 1 until the 
SFU visit.
For prohibited concomitant therapy please refer to Section 6.9.1.
New text:
6. Previous or concurrent cancer that is distinct in primary site or histology from indolent 
B-cell NHL within 5 years before start of study treatment 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)].
7.
8. Bulky disease:
o
Lymph nodes or tumor mass (except spleen) ≥7 cm LDi (longest diameter).
9.
10.
11. Known lymphomatous involvement of the central nervous system.
[...]
25. History or concurrent condition of interstitial lung disease of any severity and/or 
severely impaired lung function (as judged by the investigator)
[...]


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Excluded previous therapies and medications
32.
33. Treatment with investigational drugs within 28 days before start of study treatment.
[...]
44. Use of strong inducers of CYP3A4 is prohibited from Day -14 of Cycle 1 until the 
SFU visit.
45. Documented evidence of resistance to a prior treatment with idelalisib or other PI3K 
inhibitors defined as:
o
No response (response defined as PR or CR) at any time during therapy, or
o
Progression (PD) after any response (PR/CR) or after stable disease (SD)
within 6 months from the end of the therapy with a PI3K inhibitor.
Patients who discontinued treatment due to other reason than disease 
progression, and did not exhibit any signs of PD, will be allowed to enroll in 
this study after discussion with the sponsor.
For prohibited concomitant therapy please refer to Section 6.9.1.
13.1.2.14 Section 5.2.1 Withdrawal
Old text:
Re-screening of patients who have failed screening may only be allowed once after discussion 
with the sponsor’s designated medical representative and after approval by the sponsor. 
Sponsor approval of re-screening for the patient who has failed screening must be 
documented. No re-consent will be required for re-screened patients.
If one or more screening laboratory tests do not support eligibility, laboratory re-test is 
permitted only once. Only the laboratory tests which resulted out of range need to be repeated. 
Re-testing must be performed within 14 days of the initial test and with approval from the 
sponsor and screening procedures already performed and resulted within required ranges for 
eligibility will not need to be repeated again. All screening laboratory tests will need to be 
taken within 7 days prior to start of study treatment.
In patients with newly diagnosed diabetes mellitus, if plasma glucose and/or HbA1c do not 
support eligibility, re-testing can be performed within 28 days of the initial test and all other 
screening procedures will be repeated again, if necessary, to meet the required time frame 
prior to start of study treatment.
If re-test laboratory results are still out of eligibility range, this will be considered a full 
screening failure, and only one re-screening will be allowed following the rules as outlined 
above.


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New text:
Re-screening of patients who have failed screening may only be allowed once after discussion 
with the sponsor’s designated medical representative and after approval by the sponsor. 
Sponsor approval of re-screening for the patient who has failed screening must be 
documented. The screening failure will be registered in IVRS/IWRS 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.
All initial screening laboratory tests will need to be taken within 7 days prior to planned 
Cycle 1 Day 1. 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 need to be repeated. Re-testing must be performed within 14 days of the 
initial test and with approval from the sponsor. However if this re-testing cannot be completed 
within 7 days of the Cycle 1 Day 1, all blood and urinary tests that are required to be within 
7 days of Cycle 1 Day 1 will need to be repeated. Patients may not begin study drug treatment 
until the results of re-testing are available and documented to be within protocol-required 
range. Diagnostic testing performed as part of the original screening or standard of practice 
(e.g. including fresh tumor tissue, CT/MRI scans, bone marrow sample, 
MUGA/echocardiogram and hepatitis testing) will not need to be repeated during the 14 day 
re-testing period.
If re-test laboratory results are still out of eligibility range, this will be considered a full 
screening failure, and only one re-screening will be allowed following the rules as outlined 
above.
For patients with newly diagnosed diabetes mellitus that cannot meet protocol requirements, a 
single re-screening (which includes all screening procedures) should be performed when the 
patient’s diabetes is controlled and can meet protocol requirements for glucose and HbA1c.
13.1.2.15 Section 5.2.1.1 Withdrawal from study treatment
Old text:

Disease progression (PD) as defined in the Revised Response Criteria for Malignant 
Lymphoma (1). For patients with WM, additional criteria apply. Detailed instructions 
on tumor assessment are provided in Appendix 14.1. Radiological PD must be 
assessed by central independent blinded review before unblinding of study treatment 
(copanlisib or placebo). The result of PD per central review instead of investigational 
site image assessment will be used to unblind the patient. Patients who have received 
placebo can be offered open-label copanlisib upon discretion of the investigator and 
patient’s consent.

AEs due to disease-related complications.

Occurrence of unacceptable toxicity.

CTCAE Grade 4 arterial hypertension.

CTCAE Grade 4 symptomatic hyperglycemia.


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[...]

Development of a malignancy other than iNHL. New malignancy will be reported as a 
SAE.
[...]

Delay in study drug administration due to toxicities for > 21 days (a delay of study 
drug dosing due to reasons other than toxicity is not included in this definition).
New text:

Disease progression (PD) as defined in the Lugano Classification (21), and for patients 
with WM, according to the Owen criteria (22). Detailed instructions on tumor 
assessment are provided in Appendix 14.1. Radiological PD must be assessed by 
central independent blinded review before unblinding of study treatment (copanlisib or 
placebo). The result of PD per central review instead of investigational site image 
assessment will be used to unblind the patient. Patients who have received placebo can 
be offered open-label copanlisib upon discretion of the investigator and patient’s 
consent.

Occurrence of unacceptable toxicity.

CTCAE Grade 4 arterial hypertension.

CTCAE Grade 4 symptomatic hyperglycemia or glucose intolerance.
[...]

Development of a malignancy other than indolent B-cell NHL. New malignancy will 
be reported as a SAE.
[...]

Delay in study drug administration due to toxicities for > 21 days (this does not 
include the required 1 week break), a delay of study drug dosing due to reasons other 
than toxicity is not included in this definition.


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13.1.2.16 Section 5.2.1.2 Withdrawal from follow-up period 
Old text:
All patients will be contacted every 3 months to determine survival status during the Survival 
follow-up period (up to 3 years after the last patient started study treatment).
New text:
All patients will be contacted at least every 3 months to determine survival status during the 
Survival follow-up period (up to 3 years after the last patient started study treatment).
13.1.2.17 Section 5.3 Patient identification
Old text:
a.
Digits 1 to 2: Unique country code (International Organization for 
Standardization [ISO] code).
New text:
a.
Digits 1 to 2: Unique country code.
13.1.2.18 Section 6.1 Treatments to be administered
Old text:
should the administered dose exceed the starting dose of 60 mg. Patients who do not tolerate 
the dose of at least 30 mg must discontinue study treatment permanently (see Section 5.2).
New text:
should the administered dose exceed the starting dose of 60 mg. Patients who do not tolerate 
the dose of at least 30 mg must discontinue study treatment permanently (see Section 5.2).
See Pharmacy Manual for additional details.
13.1.2.19 Section 6.2 Identity of study treatment
Old text:
of the lyophilisate with normal saline solution. Reconstitution and dilution should be 
performed according to separate handling instructions.
[...]
Copanlisib is a cytotoxic drug without mutagenic properties. Refer to IB for copanlisib for 
more details regarding drug properties and formulation.


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New text:
of the lyophilisate with normal saline solution. Reconstitution and dilution should be 
performed according to separate handling instructions specified in the Pharmacy Manual.
[...]
Refer to IB for copanlisib for more details regarding drug properties and formulation.
13.1.2.20 Section 6.3 Treatment assignment
Old text:
At the end of the Screening period, eligible patients will be randomly assigned in a 1:1 ratio to 
one of the double-blinded treatment arms: copanlisib monotherapy or placebo. The 
randomization must be performed within 48 h before the first dose of study drug.
Treatment will be assigned based on information obtained from IVRS/IWRS. 
IVRS/IWRS will stratify patients according to two factors based on baseline characteristics:

NHL histology, with categories: 
o
FL histology 
o
Other NHL histology, and

time between last course of systemic anticancer therapy and most recent progression, 
with categories:
o
≤ 6 months
o
> 6 months
Resulting from the combination of these two stratification factors, patients will be randomized 
into 4 different strata.
New text:
At the end of the Screening period, eligible patients will be randomly assigned in a 2:1 ratio to 
one of the double-blinded treatment arms: copanlisib monotherapy or placebo, respectively. 
The randomization must be performed within 48 h before the first dose of study drug.
Treatment will be assigned based on information obtained from IVRS/IWRS. 
IVRS/IWRS will stratify patients according to three factors based on baseline characteristics:

NHL histology, with categories: 
o
FL histology 
o
Other NHL histology, and

Time between last course of systemic anticancer therapy and most recent progression, 
with categories:
o
≤ 6 months


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o
> 6 months, and

Prior treatment with PI3K inhibitors:
o
Yes
o
No
Resulting from the combination of these three stratification factors, patients will be 
randomized into 8 different strata.
13.1.2.21 Section 6.4 Dosage and administration
Old text:
Study drug (copanlisib or placebo) is administered in a normal saline solution, 100 mL,
intravenously, over 1 h. No intravenous glucose preparations should be administered on the 
days of infusion.
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).
On Cycle 1 Day 1, patients should be fasting for at least 8 h prior to the dose and until 2 h 
after completion of the infusion. During the fasting period, water and beverages with artificial 
sweeteners may be consumed. Patient’s fasting pre-dose glucose level should be ≤125 mg/dL 
(non-diabetic patients) or < 160 mg/dL (diabetic patients) before the first infusion. 
Approximately 3 h after the start of the infusion, patients should have a low carbohydrate 
meal (eggs, cheese and/or plain yoghurt, vegetables, meat). If no hyperglycemia CTCAE 
Grade 2 (fasting glucose increase > 160 mg/dL) occurs after the first infusion on Cycle 1 
Day 1, investigators may allow patients to have a low carbohydrate breakfast before the 
subsequent infusions (e.g. eggs, cheese, plain yoghurt, vegetables, meat). Pre-dose glucose 
levels for subsequent infusions should be < 160 mg/dL (fasting) or < 200 mg/dL (non-
fasting).
[...]
Patients will continue study treatment until PD (per central independent blinded radiology 
review) or they meet the criteria described in Section 5.2. Patients who experience PD on 
placebo treatment can be offered open-label copanlisib upon discretion of the investigator and 
patient’s consent. After individual patient unblinding, patients receiving placebo who switch 
to open-label copanlisib will have all study assessments and timing reset to the initial 
schedule of study evaluations (i.e. as if the patient was restarting the study at Cycle 1 Day 1). 
These patients will be followed until further disease progression.
[...]


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Table 6-1
Laboratory test criteria for Day 1 dose of subsequent cycles
Laboratory Test
Criteria for Day 1 dose (Cycle 2 and higher)
Glucose 
< 160 mg/dL (fasting) or < 200 mg/dL (non-fasting)
Hemoglobin 
≥ 8 g/dLa
ANC
≥ 1,000/mm3
Platelets
≥ 50,000/mm3
ALT
≤ 5 x ULN 
AST
≤ 5 x ULN
Total bilirubin
≤ 3 x ULN
Creatinine
≤ 1.5 x ULN 
ANC = Absolute neutrophil count; ALT = Alanine aminotransferase; AST = Aspartate 
aminotransferase; ULN = Upper limit of normal.
a: If the hemoglobin is < 9 g/dL on the day of planned study drug administration, and the patient is 
hemodynamically stable, it is permissible to give the study drug dose on schedule and 
transfuse within 48 h after the dose.
New text:
Study drug (copanlisib or placebo) is administered in a normal saline solution, intravenously, 
over 1 h. No intravenous glucose preparations should be administered on the days of infusion. 
See Pharmacy Manual for additional details.
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).
The requirements for fasting and pre-dose glucose levels are presented in Table 6-1.
Table 6-1
Fasting requirements and pre-dose glucose levels
Period
Fasting ≥ 8 h required 
before first glucose 
measurement
Pre-dose glucose levels
Fasting required before 
study drug infusion
Day 1 of
cycle 1
Yes
≤125 mg/dL (non-diabetic patients)
<160 mg/dL (diabetic patients)
No a
Day 1 of 
subsequent 
cycles
Yes
<160 mg/dL (fasting)
< 200 mg/dL (non-fasting) c
No b
Days 8 and 15 
of each cycle
No
<160 mg/dL (fasting)
<200 mg/dL (non-fasting)
No b
a: Within 1 h before the start of study drug infusion patients may have a low carbohydrate 
breakfast (e.g. eggs, cheese, plain yoghurt, vegetables, meat).
b: Patients may have a low carbohydrate breakfast (e.g. eggs, cheese, plain yoghurt, vegetables, 
meat) at any time after pre-dose glucose measurement.
c: In case of non-compliance with the fasting requirement.
The investigator will accurately document fasting/non-fasting for each glucose measurement 
done at the site. Fasting for this purpose refers to a ≥ 8 h fast. 
[...]


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Patients will continue study treatment until PD (per central independent blinded radiology 
review) or they meet the criteria described in Section 5.2. Patients who experience PD on 
placebo treatment can be offered open-label copanlisib upon discretion of the investigator and 
patient’s consent. After individual patient unblinding, patients receiving placebo who switch 
to open-label copanlisib will have all study assessments and timing reset to the initial 
schedule of study evaluations (i.e. as if the patient was restarting the study at Cycle 1 Day 1). 
If not previously done within 7 days, patients switching to open-label copanlisib must 
complete the following within 7 days prior to the first dose of open-label copanlisib: UPCR 
measurement, GFR measurement, urinalysis, HbA1c, CBC, chemistry and coagulation panels 
Dosing criteria outlined in Table 6–2 apply also for patients who switch to open-label 
treatment. These patients will be treated until further disease progression (per central review) 
unacceptable toxicity, or until another criterion is met for withdrawal from the study treatment 
(see Section 5.2).
[...]
Table 6–2
Laboratory test criteria for Day 1 dose of subsequent cycles
Laboratory Test
Criteria for Day 1 dose (Cycle 2 and higher)
Glucose 
< 160 mg/dL (fasting) or < 200 mg/dL (non-fasting)
Hemoglobin 
≥ 8 g/dLa
ANC
≥ 1,000/mm3
Platelets
≥ 50,000/mm3
ALT
≤ 5 x ULN 
AST
≤ 5 x ULN
Total bilirubin
≤ 3 x ULN
GFR (MDRD)
≥ 30 mL/min/1.73 m2
ANC = Absolute neutrophil count; ALT = Alanine aminotransferase; AST = Aspartate 
aminotransferase; GFR = Glomerular filtration rate; MDRD = Modification of Diet in Renal 
Disease; ULN = Upper limit of normal.
a: If hemoglobin is < 8 g/dL but ≥ 6 g/dL on the day of planned study drug administration it is 
permissible to give the study drug dose on schedule and transfuse within 48 h after the dose, if 
the patient is hemodynamically stable and in opinion of investigator benefits outweigh risks. 
Rationale and treatment should be recorded in the source documentation and in the eCRF.
13.1.2.22 Section 6.4.1 Dose modification
Old text:
It is recognized that attribution of causality of any AE to the test drug specifically may be 
difficult. However, certain toxicities were seen only in relation to copanlisib in Phase I trials: 
e.g., hyperglycemia and arterial hypertension. Based on this knowledge the investigator may 
decide on the necessary dose modifications. 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.
New text:
It is recognized that attribution of causality of any AE to the test drug specifically may be 
difficult. However, certain toxicities were seen only in relation to copanlisib in Phase I trials: 


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e.g., hyperglycemia and arterial hypertension. Based on this knowledge the investigator may 
decide on the necessary dose modifications. 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. 
Dose modifications must be done according to the guidelines given in Section 6.4.1.1 and 
Section 6.4.1.2. The investigator may judge a more conservative dose modification 
appropriate. If therefore these guidelines are not followed, the rationale for other measures is 
to be documented in detail in patient’s medical record. Deviations from the guidelines must be 
discussed with the sponsor.
13.1.2.23 Section 6.4.1.1 Hematological toxicity
Old text:
Neutropenia and febrile neutropenia are listed in the current version of IB as expected adverse 
events. The clinician should proceed as dictated by the clinical situation, medical practice, and 
their experience as an investigator. The guidelines in Table 6-3 can be used as support for the 
clinical decision. If these guidelines are not followed, the rationale for other measures is to be 
documented in detail in the patient’s medical record.
Table 6-3
Dose modification of study treatment for hematological toxicity
Hematological toxicity of CTCAE Grade
(any of the following)
Study drug action (for all toxicities)
New text:
Neutropenia and febrile neutropenia are listed in the current version of IB as expected adverse 
events. The guidelines for dose modifications in case of hematological toxicity are given in 
Table 6-4.
Table 6-4
Dose modification of study treatment for hematological toxicity
Note: This table should not be used to determine patient eligibility for infusion on days 1, 8 and 15. 
Please follow specific guidance given for laboratory test criteria on days 1, 8 and 15
Hematological toxicity of CTCAE Grade
(any of the following)
Study drug action (for all toxicities)
13.1.2.24 Section 6.4.1.2 Non-hematological toxicity
Old text:
Dose modifications for non-hematologic toxicities except hyperglycemia, dermatologic 
toxicity, NIP and arterial hypertension are outlined in Table 6-4.


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Table 6–4
Dose modification of study treatment for non-hematological toxicity
(except hyperglycemia, 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 0-2
Any appearance
No change
No change
Grade 3a
1st appearance
Interruption until Grade 2
No change
2nd appearance
Interruption until Grade 2
Decrease by one dose levelb
3rd appearance
Interruption until Grade 2
Decrease by one dose levelc
4th appearance
Permanent discontinuation
–
Grade 4
Any appearance
Permanent discontinuation
–
Toxicity requiring delay for > 21 days
Permanent discontinuation
–
CTCAE = Common Terminology Criteria of Adverse Events.
a: Despite maximum supportive therapy.
b: Not applicable for 30 mg dose level.
c: Not applicable for 30 mg and 45 mg dose levels.
A delay > 21 days in study drug administration due to toxicities will cause permanent discontinuation 
of study treatment.
Study treatment must be discontinued if the lowest dose level of 30 mg is not tolerated.
After having fully recovered from toxicity and in the absence of any criteria for further dose reduction 
or study drug discontinuation, re-escalation to dose level -1 or 1 will be allowed at the 
investigator’s discretion.
Dermatologic toxicity
According to the grade and incidence of dermatologic reaction for a given patient, the 
clinician should proceed as dictated by the clinical situation, medical practice, and their 
experience as an investigator. The guidelines in Table 6-5 can be used as support for the 
clinical decision. If these guidelines are not followed, the rationale for other measures is to be 
documented in detail in the patient’s medical record.
Table 6–5
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
No change
No change
Grade 2a
1st appearance
Interruption until Grade ≤1
No change
2nd appearance
Interruption until Grade ≤1
Decrease by one dose levelb
3rd appearance
Interruption until Grade ≤1
Decrease by one dose levelc
4th appearance
Permanent discontinuation 
–
Grade 3a
1st appearance
Interruption until Grade ≤1
Decrease by one dose levelb
2nd appearance
Interruption until Grade ≤1
Decrease by one dose levelc
3rd 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.


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b: Not applicable for 30 mg dose level.
c: Not applicable for 30 mg and 45 mg dose levels.
The lowest dose level is 30 mg; if a patient is already on the 30 mg dose level and meets criteria for 
further dose decrease, study treatment will be discontinued permanently.
[…]
Hyperglycemia and arterial hypertension
a)
Hyperglycemia
Patients who develop transient post-infusion hyperglycemia of CTCAE Grade 3 (glucose 
level > 250 mg/dL) after study drug administration may continue treatment. However, the 
next infusion must be delayed until the patient’s pre-infusion glucose levels return to 
< 160 mg/dL (fasting) or < 200 mg/dL (non-fasting). Guidelines for the treatment of 
hyperglycemia are given in Section 6.4.2.1.
A dose reduction of study drug by one dose level is mandatory in the event of CTCAE 
Grade 4 asymptomatic hyperglycemia. No further dose reductions will be allowed in the event 
of re-occurrence of CTCAE Grade 4 asymptomatic hyperglycemia and the patient will be 
permanently discontinued.
If symptomatic CTCAE Grade 4 hyperglycemia occurs, permanent discontinuation of the 
study drug is mandatory.
New text:
Dose modifications for non-hematologic toxicities except hyperglycemia, dermatologic 
toxicity, NIP and arterial hypertension are outlined in Table 6-5.
Table 6–5
Dose modification of study treatment for non-hematological toxicity
(except hyperglycemia, 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 3a
1st appearance
Interruption until Grade 2
No change
2nd appearance
Interruption until Grade 2
Decrease by one dose levelb
3rd appearance
Interruption until Grade 2
Decrease by one dose levelb
4th appearance
Permanent discontinuation
–
Grade 4
Any appearance
Permanent discontinuation
–
Toxicity requiring delay for > 21 days
Permanent discontinuation
–
CTCAE = Common Terminology Criteria of Adverse Events.
a: Despite maximum supportive therapy.
b: Not applicable for 30 mg dose level.
A delay > 21 days in study drug administration due to toxicities will cause permanent discontinuation 
of study treatment.
Study treatment must be discontinued if the lowest dose level of 30 mg is not tolerated.
After having fully recovered from toxicity and in the absence of any criteria for further dose reduction 
or study drug discontinuation, re-escalation to dose level -1 or 1 will be allowed at the 


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investigator’s discretion.
Dermatologic toxicity
The guidelines for dose modifications in case of dermatologic toxicity are given in Table 6-6.
Table 6–6
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 2a
1st appearance
Interruption until Grade ≤1
No change
2nd appearance
Interruption until Grade ≤1
Decrease by one dose levelb
3rd appearance
Interruption until Grade ≤1
Decrease by one dose levelb
4th appearance
Permanent discontinuation 
–
Grade 3a
1st appearance
Interruption until Grade ≤1
Decrease by one dose levelb
2nd appearance
Interruption until Grade ≤1
Decrease by one dose levelb
3rd 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 30 mg dose level.
The lowest dose level is 30 mg; if a patient is already on the 30 mg dose level and meets criteria for 
further dose decrease, study treatment will be discontinued permanently.
[…]
Hyperglycemia and arterial hypertension
Hyperglycemia
Patients who develop transient post-infusion hyperglycemia (glucose intolerance) of
> 250 mg/dL after study drug administration may continue treatment. However, the next 
infusion must be delayed until the patient’s pre-infusion glucose levels return to < 160 mg/dL 
(fasting) or < 200 mg/dL (non-fasting). Guidelines for the treatment of hyperglycemia are 
given in Section 6.4.2.1.
A dose reduction of study drug by one dose level is mandatory in the event of asymptomatic 
hyperglycemia > 500 mg/dL. No further dose reductions will be allowed in the event of re-
occurrence of asymptomatic hyperglycemia > 500 mg/dL and the treatment will be 
permanently discontinued.
If CTCAE Grade 4 glucose intolerance occurs, permanent discontinuation of the study drug is 
mandatory.


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13.1.2.25 Section 6.4.2.1 Management of hyperglycemia that can occur with 
study treatment
Old text:
a)
Management of transient post-infusion hyperglycemia
Only the use of rapid or short acting (regular) insulin is allowed for the treatment of transient 
hyperglycemia. The prophylactic administration of rapid or short acting (regular) insulin prior 
to study drug infusion is not permitted.
In the event of CTCAE Grade 3 hyperglycemia (post-dose glucose > 250 mg/dL) on the day 
of infusion, the administration of rapid or short acting (regular) insulin is recommended 
according the institution’s insulin sliding scale regimen.
All patients (diabetic and non-diabetic) should be kept under close observation if the glucose 
level is > 250 mg/dL (CTCAE Grade 3 hyperglycemia) until the glucose level decreases to 
< 160 mg/dL at any cycle. In the event of rapid or short acting (regular) insulin administration 
at any cycle, a 3 h close observation time is required post-administration. Meals should be 
provided for patients who are kept for continued observation. A low dose carbohydrate diet is 
recommended for the first 48 h after study drug infusion. However, carbohydrate restriction is 
not meant as caloric restriction in the population under study.
Patients will be trained to measure their capillary blood glucose levels at home starting at 
Screening and will be provided with glucose meter and strips, if applicable. The appropriate 
calibration of glucose meters will be documented.
[…]
Monitoring of non-diabetic patients
On Cycle 1 Day 1 all non-diabetic patients (regardless of their post-infusion glucose value)
will be instructed to check blood glucose at home at least 3 times per full day for at least 72 h 
after the start of infusion. This includes fasting glucose (morning before breakfast) and 
2 further random non-fasting measurements approximately 2 h after intake of food. This 
monitoring will continue until blood glucose values are at goal (fasting glucose ≤125 mg/dL 
or random non-fasting glucose ≤ 160 mg/dL).
From Cycle 1 Day 8, the need to keep home monitoring will be re-assessed after each 
infusion. Non-diabetic patients will be instructed to check blood glucose at home only if they 
experience CTCAE Grade 3 hyperglycemia or require insulin administration. The 
measurements will be taken at least 3 times per full day for at least 72 h after the start of 
infusion. This includes fasting glucose (morning before breakfast) and 2 further random non-
fasting measurements approximately 2 h after intake of food. This monitoring will continue 
until blood glucose values are at goal (fasting glucose ≤125 mg/dL or random non-fasting 
glucose ≤160 mg/dL).


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Monitoring of diabetic patients
All diabetic patients will be instructed to check blood glucose at home at least 3 times per full 
day for at least 72 h after start of each infusion. This includes fasting glucose (morning before 
breakfast) and 2 further random non-fasting measurements approximately 2 h after intake of 
food. This monitoring will continue until blood glucose values are at goal (fasting glucose 
< 160 mg/dL or random non fasting glucose < 200 mg/dL).
If the patient already monitors his/her blood glucose as part of routine antidiabetic care, the 
routine measurements should not be replaced by the study specific measurements. In this 
situation, patients should add the study specific measurements to their routine, if applicable. 
When blood glucose values are at goal (fasting glucose < 160 mg/dL or random non-fasting 
glucose < 200 mg/dL) after each infusion, patients can then stop only the study specific 
measurements until the next day of infusion, but should keep their routine measurements 
unchanged and ongoing as usual.
Sites recruiting patients with diabetes should have the option to extend glucose monitoring 
overnight.
b)
Management of diabetic patients (non-transient hyperglycemia) for the duration of 
the study
[...]
To monitor non-transient hyperglycemia fasting glucose is recommended. Glucose 
measurement prior to the infusion on Day 1 of each cycle is recommended for the 
management of non-transient hyperglycemia. The following guideline applies:
New text:
a)
Management of transient post-infusion hyperglycemia
Only the use of rapid or short acting (regular) insulin is allowed for the treatment of transient 
hyperglycemia (glucose intolerance). The prophylactic administration of rapid or short acting 
(regular) insulin prior to study drug infusion is not permitted.
In the event of post-dose glucose > 250 mg/dL on the day of infusion, the administration of 
rapid or short acting (regular) insulin is recommended according the institution’s insulin 
sliding scale regimen.
All patients (diabetic and non-diabetic) should be kept under close observation if the glucose 
level is > 250 mg/dL until the glucose level decreases to < 160 mg/dL at any cycle. In the 
event of rapid or short acting (regular) insulin administration at any cycle, a 3 h close 
observation time is required post-administration. Meals should be provided for patients who 
are kept for continued observation. A low dose carbohydrate diet is recommended for the first 
48 h after study drug infusion. However, carbohydrate restriction is not meant as caloric 
restriction in the population under study.
Patients will be trained to measure their capillary blood glucose levels at home starting at 
Screening and will be provided with glucose meter and supplies (lancets, test strips and diary) 


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to register measured values and record insulin administration, if applicable. The appropriate 
calibration of glucose meters will be documented.
[…]
Monitoring of non-diabetic patients
All non-diabetic patients who experience hyperglycemia > 250 mg/dL or require insulin
administration will be instructed to check blood glucose at home at least 3 times per full day 
for at least 72 h after the start of infusion. This includes fasting glucose (morning before 
breakfast) and 2 further random non-fasting measurements approximately 2 h after intake of 
food. If after the required 72 h the glucose values are not at goal (fasting glucose ≤125 mg/dL 
or random non-fasting glucose ≤160 mg/dL), this monitoring will continue until blood 
glucose values are at goal.
Monitoring of diabetic patients
All diabetic patients will be instructed to check blood glucose at home at least 3 times per full 
day for at least 72 h after start of each infusion. This includes fasting glucose (morning before 
breakfast) and 2 further random non-fasting measurements approximately 2 h after intake of 
food. If after the required 72 h the glucose values are not at goal (fasting glucose < 160 mg/dL 
or random non fasting glucose < 200 mg/dL), this monitoring will continue until blood 
glucose values are at goal, and the patient should be immediately referred to the local diabetes 
center/endocrinologist to adjust treatment.
If the patient already monitors his/her blood glucose as part of routine antidiabetic care, the 
routine measurements should not be replaced by the study specific measurements. In this 
situation, patients should add the study specific measurements to their routine, if applicable. 
After the required 72 h, if blood glucose values are at goal (fasting glucose < 160 mg/dL or 
random non-fasting glucose < 200 mg/dL) after each infusion, patients can then stop only the 
study specific measurements until the next day of infusion, but should keep their routine 
measurements unchanged and ongoing as usual.
Sites recruiting patients with diabetes should have the option to extend glucose monitoring 
overnight.
b)
Management of diabetic patients (non-transient hyperglycemia) for the duration of 
the study
[...]
To monitor non-transient hyperglycemia fasting glucose is recommended. Glucose 
measurement prior to the infusion on Day 1 of each cycle is needed for the management of 
non-transient hyperglycemia. The following guideline applies:


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13.1.2.26 Section 6.5 Blinding
Old text:
Because copanlisib solution may have a yellowish color while the placebo solution is 
transparent, the following measures will be taken to preserve the blind:

Yellow syringes must be used.

All tissues used for removing any spillage must be colored.
An unblinded, study-independent pharmacist (or qualified person) will handle the preparation 
of the study drug.
New text:
Because copanlisib solution may have a yellowish color while the placebo solution is 
colorless, measures will be taken to preserve the blind. This includes an unblinded, study-
independent pharmacist (or qualified person) who will handle the preparation of the study 
drug, and unblinded monitors, separate from the blinded monitoring team, to conduct the 
monitoring of the pharmacy and drug supplies. Additional details will be described in the 
Pharmacy Manual.
13.1.2.27 Section 6.9.1 Prohibited concomitant therapy
Old text:

Systemic corticosteroid therapy at a daily dose higher than 15 mg prednisone or 
equivalent. Previous corticosteroid therapy must be stopped or reduced to the allowed 
dose 7 days prior to the screening CT/MRI and again prior to the first administration 
of study drug. If a patient is on chronic corticosteroid therapy, corticosteroids should 
be de-escalated to the maximum allowed dose before the Screening. Patients may use 
topical or inhaled corticosteroids. Systemic corticosteroids will be allowed for the 
treatment of NIP. The use of corticosteroids as antiemetics prior to study drug 
administration will not be allowed.
New text:

Systemic corticosteroid therapy at a daily dose higher than 15 mg prednisone or 
equivalent. Previous corticosteroid therapy must be stopped or reduced to the allowed 
dose 7 days prior to the screening CT/MRI and again prior to the first administration 
of study drug. If a patient is on chronic corticosteroid therapy, corticosteroids should 
be de-escalated to the maximum allowed dose before the Screening. Patients may use 
topical or inhaled corticosteroids. Short term systemic corticosteroids above 15 mg 
prednisolone or equivalent will be allowed for the management of acute conditions 
(e.g. treatment of NIP). The use of corticosteroids as antiemetics prior to study drug 
administration will not be allowed.


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13.1.2.28 Section 6.9.2 Permitted concomitant therapy
Old text:

Patients taking narrow therapeutic index medications should be monitored proactively, 
if these medications cannot be avoided. These medications may include quinidine, 
carbamazepine, cyclosporine and digoxin.
New text:

Patients taking narrow therapeutic index medications should be monitored proactively, 
if these medications cannot be avoided. These medications may include quinidine, 
cyclosporine and digoxin.


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13.1.2.29 Section 7.1.1 Tabulated overview
Old text:
Table 7–1
Study flow chart 
Screening 
maximum days 
before C1D1
Treatment *
EOT
SFU
Active 
follow-
up aa
Survival
follow-
up bb
Cycle 1
Cycle 2 and higher
Within (days) after
Days
-28 -14
-7
D1
D4
D8
D15
D22
D1
D8
D15
D22 y
7
30-35 z
every 3 
months
Acceptable deviation (in days)
-1 to +2 days
-1 to +2 days
Decision 
to stop
Last 
dose
14 days
Screening and enrollment
Patient informed consent (including genetic)
Written informed consent must be obtained prior to any study-specific procedures
Check in- and exclusion criteria
X
X
X
Medical history a
X
IVRS/IWRS transaction b
X
Xb
X
X
HBsAg, HBcAb, HCV IgG
X
Serum beta-2-microglobulin
X
Serum pregnancy test (if applicable) c
X
Xc
UPCR
X
GFR
X
Safety
Toxicity / AE assessment d
X
X
X
X
X
X
X
X
X
X
(X)d
Concomitant medication d
X
X
X
X
X
X
X
X
X
X
Complete physical examination e
X
X
X
X
Brief physical examination f
X
X
X
X
X
(X)
(X)
12-lead ECG g
X
Xg
Xg
Xg
Xg
MUGA scan or echocardiogram h
Xh
Xh
Xh
Hemoglobin A1c (HbA1c) i
X
Xi
X
Complete blood count j
X
Xx
Xx
X
Xx
C2 onlyx C2 onlyx
X
(X)
Hemoglobin, ANC and platelet counts (C3->)
Xx
Xx
Chemistry panel k
Xk
Xx
Xx
X
Xk,x
C2 onlyx C2 onlyx
Xk
(X)
Coagulation panel: PT, INR and PTT
X
Xx
Xx
X
(X)
Urinalysis (dipstick)
X
X
X


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Table 7–1
Study flow chart 
Screening 
maximum days 
before C1D1
Treatment *
EOT
SFU
Active 
follow-
up aa
Survival
follow-
up bb
Cycle 1
Cycle 2 and higher
Within (days) after
Days
-28 -14
-7
D1
D4
D8
D15
D22
D1
D8
D15
D22 y
7
30-35 z
every 3 
months
Acceptable deviation (in days)
-1 to +2 days
-1 to +2 days
Decision 
to stop
Last 
dose
14 days
Glucose l
X
X
X
X
X
X
Home glucose test (training, strips, review) m
X
X
X
X
X
X
X
X
X
X
Blood pressure n
X
X
X
X
X
X
Efficacy
Bone marrow biopsy o
X
Xo
CT/MRI and tumor evaluations p
X
Xp
Xp
Xp
Quality of life questionnaire (FLymSI-18) q 
X
X
X
X
Pharmacokinetic sampling r
Xg
X
Xg
Biomarkers
Tumor tissue s
X
Plasma for genetic biomarker analysis t
X
Xt
X
Plasma for non-genetic biomarker analysis u
X
X
X
X
C2 only
C2 only
X
Whole blood for biomarkers v
X
[…]
X
For LPL/WM patients only
Serum protein electrophoresis w
Xw
Xw
(X)w
Immunofixation w
Xw
Xw
(X)w
Serum quantitative IgM test w
Xw
Xw
(X)w
Serum or plasma viscosity w
Xw
(X)w
(X)w
[...]


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*
NOTE: Patients who experience PD on placebo treatment (per central independent blinded radiology review) can be offered open-label 
copanlisib upon discretion of the investigator and patient’s consent. After individual patient unblinding, patients receiving placebo who switch 
to open-label copanlisib will have all study assessments and timing reset to the initial schedule of study evaluations (i.e. as if the patient was 
restarting the study at Cycle 1 Day 1).
a
Demographics, relevant medical history findings, concomitant illnesses, allergy history, prior surgeries, most recent histology of tumor, most 
recent staging and grading of tumor, FLIPI score (for patients with FL), history of anticancer treatments (including type of treatment, type of 
response, date of response and date of subsequent relapse), assessment of baseline toxicity and smoking history.
b
IVRS/IWRS randomization transaction will take place within 48 h before the first dose of study drug. IVRS/IWRS transactions for medication 
dispensing will be on Day 1 of each cycle. IVRS/IWRS transaction to register end of treatment will be at the EOT visit.
c
After Cycle 1 serum pregnancy test is mandatory at every cycle for France, Belgium, Canada and other countries where it is required by local 
regulations.
d
After Screening: AE assessment and concomitant medication review must be updated before each dose and 30-35 days after last dose. After 
the patient signs the informed consent, any new finding discovered not present in the patient’s medical history or a worsening of a prior 
medical history finding must be recorded as an AE. Contrast media does not need to be recorded as concomitant medication unless there is 
an AE related to its administration (e.g. allergic reaction). During the Active follow-up period, AEs and SAEs assessed as related to study 
procedures by the investigator will be reported in the usual manner.
e
Complete physical examination to include: ECOG performance status, NYHA classification, height (only at Screening), weight, vital signs 
(temperature, pulse and blood pressure), and a complete review of body systems (including physical examination for lymphadenopathy, 
abdominal masses, or organomegaly).
f
Brief physical examination to include: ECOG performance status, vital signs (temperature, pulse and blood pressure), examination of 
pertinent organ systems, and brief interim history (change of symptoms).
g
12-lead ECG (including QTcB and QTcF evaluation) will be performed at Screening (within 14 days before Cycle 1 Day 1) and within 7 days 
prior to dosing on Day 1 of every 3rd cycle (3, 6, 9, etc.). At the EOT visit, a 12-lead ECG is necessary only if not recorded within the previous 
4 weeks. At centers with adequate facilities and equipment: additional 12-lead ECGs will be recorded on Cycle 1 Day 1 and on Day 15 of 
every 3rd cycle (3, 6, 9 etc.) pre-infusion and at the end of infusion (Cmax). At these centers, a PK sample is to be drawn after each 12-lead 
ECG recording on Cycle 1 Day 1, and on Day 15 of every 3rd cycle (3, 6, 9 etc.).
h
MUGA scan or echocardiogram to measure LVEF at Screening (within 14 days before Cycle 1 Day 1), within 7 days prior to dosing on Day 1 
of every 3rd cycle (3, 6, 9, etc.), and at the EOT visit. The method chosen at Screening must be the same throughout the whole study.
i
Hemoglobin A1c (HbA1c) at Screening, on Day 1 of every odd cycle (3, 5, 7, etc.) starting from Cycle 3 and at the EOT visit.
j
Complete blood count (CBC): Hemoglobin, hematocrit, RBC, WBC (with differential to include absolute neutrophil, lymphocyte, monocyte, 
basophil and eosinophil counts and platelet count). From Cycle 3 onwards, only hemoglobin, platelet and ANC counts will be performed on 
Day 8 and Day 15 prior to each infusion.


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k
Chemistry panel: calcium, sodium, potassium, chloride, phosphorous, magnesium, bicarbonate (or carbon dioxide, if bicarbonate is not 
routinely measured at the site), total protein, albumin, glucose, BUN (or urea if BUN is not routinely measured at the site), SCR, uric acid, 
total bilirubin, creatine phosphokinase, ALT, AST, LDH, ALP, lipase, amylase (or pancreatic amylase, if total amylase is not routinely 
measured at the site), cholesterol (total, LDL, HDL) and triglycerides. 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 for 11 h prior to sampling. If a 
patient can’t adhere to fasting requirements, the evaluation of lipid-panels including triglycerides is considered not feasible.
l
On Cycle 1 Day 1, glucose will be measured at pre-dose, and 3 h, 5 h, 6 h and 8 h after the start of the infusion. Additional measurements to 
be performed as clinically indicated. The first pre-dose glucose sample on Cycle 1 Day 1 should be after an 8 h fasting. Patient’s fasting pre-
dose glucose level should be ≤125 mg/dL (non-diabetic patients) or < 160 mg/dL (diabetic patients) before the first infusion. On subsequent 
infusions, glucose will be measured prior to and after infusion. Pre-dose glucose levels for subsequent infusions should be < 160 mg/dL 
(fasting) or < 200 mg/dL (non-fasting). For details, see Section 6.4.
m
Home glucose measurement is required for all diabetic patients after each infusion. For non-diabetic patients home glucose measurement is 
required on Cycle 1 Day 1 (regardless of their post infusion glucose value), and from Cycle 1 Day 8 onwards only if they develop CTCAE 
Grade 3 hyperglycemia or require insulin administration after any infusion. Measurements should be taken at least 3 times per full day for at 
least 72 h after the start of infusion. This includes fasting glucose (morning before breakfast) and 2 further random non-fasting measurements 
approximately 2 h after intake of food. This monitoring will continue until blood glucose values are at goal (fasting glucose ≤125 mg/dL/< 160 
mg/dL or random non-fasting glucose ≤160 mg/dL/< 200 mg/dL for non-diabetic/diabetic patients, respectively). For details see Section 
6.4.2.1.
n
Blood pressure will be measured every 5-10 min prior to infusion of study drug (no more than 4 measurements) until there are 2 consecutive 
results < 150/90 mmHg. If blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention or delaying the infusion of 
study drug. At Cycle 1 Day 1 blood pressure will be measured at 0 h (pre-dose), 30 min (mid-infusion), 60 min (end of infusion), 90 min, 2 h, 3 
h, 4 h and 6 h after the start of infusion (deviation 5 min). From Cycle 1 Day 8 onwards a single blood pressure measurement is to be 
performed prior to each infusion, 30 min after the start of infusion and at the end of each infusion.
o
Bone marrow biopsy is mandatory at Screening (biopsy done up to 28 days prior to first dose can be used as baseline evaluation) and to 
confirm the first complete response, if positive at baseline.
p
The first IV contrast enhanced CT/MRI scans of neck, chest, abdomen and pelvis must be performed at Screening. Corticosteroids must be 
stopped or reduced to the allowed dose (less than 15 mg of prednisone or equivalent) at least 7 days before performing the CT/MRI (if a 
patient is on chronic corticosteroid therapy, corticosteroids should be de-escalated to the maximum allowed dose before the Screening). 
Scans done up to 28 days prior to first dose can be used as baseline evaluation. The method chosen at the baseline must be the same 
throughout the study. During treatment, tumor scans will be done with the same modality every 12 weeks (±7 days) during Year 1, every 16 
weeks (±7 days) during Year 2, and every 24 weeks (±7 days) during Year 3. CT/MRI scans are not required at the EOT visit if the patient 
discontinued due to PD which has been radiologically evaluated within the 4 weeks preceding EOT. During Active follow-up period patients 
will have radiological assessments as outlined in this protocol until PD is documented or new anti-tumor treatment is administered, whichever 
occurs first.


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q
FLymSI-18 questionnaire is to be completed on Cycle 1 Day 1 and every cycle thereafter (i.e. on Day 1 of Cycles 2, 3, 4 etc.), at the EOT visit 
and at the SFU visit in both treatment arms. Questionnaire should be self-administered by the patient via an ePRO at the start of the visit 
before contact with the investigator or other investigative site personnel.
r
PK sampling will be performed for copanlisib, its metabolite M-1 and other metabolites, if needed, in all patients on On Cycle 1 Day 8: pre-
infusion, 5 to 15 min, 55 min (within 5 min prior to end of infusion) and 1.5 to 5 h after start of 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. At centers with adequate facilities and equipment: 
additional PK sampling will be performed after each 12-lead ECG recording pre- infusion and end of infusion (within 5 min prior to the end of 
infusion) on Cycle 1 Day 1, and on Day 15 of every 3rd cycle (3, 6, 9 etc.).
s
Tumor tissue for central pathology review and biomarker analysis (mandatory). Fresh tumor tissue (preferred) will be collected between Day -
28 and Day -8 prior to the start of study treatment. Detailed guidance on fresh biopsy sample preparation and storage will be provided to the
sites. Archival tumor tissue will be requested if fresh tissue is not available (the latest biopsy available should be provided). Both may also be 
collected if available. Archival tissue may be supplied as a block (preferred) or as precut slides. Details on the preparation of slides and 
number of slides to be prepared will be described in separate documents (e.g. Sample Handling Sheets or laboratory manual). 
t
Plasma for genetic biomarker analysis: blood samples will be collected at Cycle 1 Day 1, on Day 1 of every odd cycle (3, 5, 7 etc.), and at the 
EOT visit. On treatment days, blood for plasma preparation should be drawn prior to drug administration.
u
Plasma for non-genetic biomarker analysis will be prepared from whole blood samples. On treatment days, blood for plasma preparation 
should be drawn prior to drug administration. Samples are to be collected on Cycle 1 (Days 1, 8 and 15), Cycle 2 (Days 1, 8 and 15), on Day 
1 of all subsequent cycles and at the EOT visit.
v
Whole blood for biomarkers will be collected on Cycle 1 Day 1 (only from patients who provide a separate consent for genetic research).
w
Only for patients affected by LPL/WM: Serum protein electrophoresis, immunofixation and serum quantitative IgM test will be performed at 
Screening. Serum or plasma viscosity will be tested at Screening only if hyperviscosity syndrome is suspected. Only for patients affected by 
WM: Serum protein electrophoresis, immunofixation and serum quantitative IgM test will be performed on the days of tumor evaluation and at 
the EOT visit only if the last assessment is older than 4 weeks. If serum or plasma viscosity is abnormal at baseline, the measurement will be 
repeated every 3rd cycle starting from Day 1 of Cycle 3, and at the EOT visit.
x
Laboratory tests prior to each infusion may be performed either the day before or on the planned date of infusion, with the exception of blood 
glucose, which must be performed on the day of infusion. For dosing criteria, see Section 6.4.
y
After Cycle 1, there are no mandatory procedures on Day 22 of subsequent cycles. Day 22 from Cycle 2 onwards is the earliest time for 
procedures due at latest on Day 1 of the next cycle.
z
The post-treatment follow-up within 30-35 days after the last administration of study drug can be conducted via telephone if the patient is no 
longer being actively seen at the clinic or has started another therapy. Procedures marked with “(X)” are only to be performed, if clinically 
indicated.
aa Patients who discontinue study treatment for reasons other than PD will enter the Active follow-up period (which also serves as a Safety 
follow-up), except for patients who object to follow-up data collection. The patients in the Active follow-up will have radiological assessments 


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as outlined in this protocol from the day of randomization until PD is documented or new anti-tumor treatment is administered, whichever 
occurs first.
bb Patients or their health care providers will be contacted either in person or by telephone (except for patients who object to FU data collection). 
The contacts will be made every 3 months (± 14 days), until death or until the end of the trial (up to 3 years after the last patient started study 
treatment), whichever comes first. Information to be recorded: date of contact, survival status, the first new anticancer regiment (if applicable), 
and date and cause of death (if applicable).


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New text:
Table 7–1
Study flow chart
Screening 
maximum days 
before C1D1
Treatment *
EOT
SFU
Active 
follow-
up aa
Survival
follow-
up bb
Cycle 1
Cycle 2 and higher
Within (days) after
Days
-28 -14
-7
D1
D4
D8
D15
D22
D1
D8
D15
D22 y
7
30-35 z
every 3 
months
Acceptable deviation (in days)
-1 to +2 days
-1 to +2 days
Decision 
to stop
Last 
dose
14 days
Screening and enrollment
Patient informed consent (including genetic)
Xcc,dd
Check in- and exclusion criteria
X
X
X
Medical history a
X
IVRS/IWRS transaction b, dd
X
Xb
X
X
HBsAg, HBcAb, HCV IgG
X
Serum pregnancy test (if applicable) c
X
Xc
UPCR
X
GFR dd
X
X
Safety
Toxicity / AE assessment d
X
X
X
X
X
X
X
X
X
X
(X)d
Concomitant medication d
X
X
X
X
X
X
X
X
X
X
Complete physical examination e
X
X
X
X
Brief physical examination f, dd
X
X
X
X
X
(X)
12-lead ECG g, dd
X
X
Xg
Xg
MUGA scan or echocardiogram h, dd
Xh
Xh
Xh
HbA1c i
X
Xi
X
Complete blood count j
X
Xx
Xx
X
Xx
C2 
onlyx
C2 
onlyx
X
(X)
Hemoglobin, ANC and platelet counts (C3->)
Xx
Xx
Chemistry panel k
Xk
Xx
Xx
X
Xk,x
C2 
onlyx
C2 
onlyx
Xk
(X)
Coagulation panel: PT, INR and PTT
X
Xx
Xx
X
(X)
Urinalysis (dipstick)
X
X
X
Glucose l
X
X
X
X
X
X


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Table 7–1
Study flow chart
Screening 
maximum days 
before C1D1
Treatment *
EOT
SFU
Active 
follow-
up aa
Survival
follow-
up bb
Cycle 1
Cycle 2 and higher
Within (days) after
Days
-28 -14
-7
D1
D4
D8
D15
D22
D1
D8
D15
D22 y
7
30-35 z
every 3 
months
Acceptable deviation (in days)
-1 to +2 days
-1 to +2 days
Decision 
to stop
Last 
dose
14 days
Home glucose monitoring m, dd
X
X
X
X
X
X
X
X
X
X
Blood pressure n
X
X
X
X
X
X
Efficacy
Bone marrow biopsy o
X
Xo
CT/MRI and tumor evaluations p
Xp
Xp
Xp
Xp
Quality of life questionnaire (FLymSI-18) q 
X
X
X
X
Pharmacokinetic sampling r, dd
X
Biomarkers
Tumor tissue for central pathology and 
biomarkers s, dd
X
(X)
Plasma for tumor genetics t, dd
X
X
Plasma for non-genetic biomarker 
analysis u dd
X
X
X
C2
only
C2 
only
C2
only
X
Whole blood for biomarkers v
X
[…]
X
For LPL/WM patients only
Serum protein electrophoresis w
Xw
Xw
(X)w
Immunofixation w
Xw
Xw
(X)w
Serum quantitative IgM test w
Xw
Xw
(X)w
Serum beta-2-microglobulin dd
Xw
Serum or plasma viscosity w
Xw
(X)w
(X)w
[...]


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*
NOTE: Patients who experience PD on placebo treatment (per central independent blinded radiology review) can be offered open-label 
copanlisib upon discretion of the investigator and patient’s consent. After individual patient unblinding, patients receiving placebo who switch 
to open-label copanlisib will have all study assessments and timing reset to the initial schedule of study evaluations (i.e. as if the patient was 
restarting the study at Cycle 1 Day 1). If not previously done within 7 days, patients switching to open-label copanlisib must complete the 
following within 7 days prior to the first dose of open-label copanlisib: UPCR measurement, GFR measurement, urinalysis, HbA1c, CBC, 
chemistry and coagulation panels (see dosing criteria in Table 6–2).
a
Demographics, relevant medical history findings, concomitant illnesses, allergy history, prior surgeries, most recent histology of tumor, most 
recent staging and grading of tumor, FLIPI score (for patients with FL), 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 and smoking history.
b
IVRS/IWRS transaction to register the patient in the system will be at Screening. IVRS/IWRS randomization transaction will take place within 
48 h before the first dose of study drug. IVRS/IWRS transactions for medication dispensing will be on Day 1 of each cycle. IVRS/IWRS 
transaction to register end of treatment will be at the EOT visit.
c
After Cycle 1 serum pregnancy test is mandatory at every cycle for France, Belgium, Canada and other countries where it is required by local 
regulations.
d
After Screening: AE assessment and concomitant medication review must be updated before each dose and 30-35 days after last dose. After 
the patient signs the informed consent, any new finding discovered not present in the patient’s medical history or a worsening of a prior 
medical history finding must be recorded as an AE. Contrast media does not need to be recorded as concomitant medication unless there is 
an AE related to its administration (e.g. allergic reaction). During the Active follow-up period, AEs and SAEs assessed as related to study 
procedures by the investigator will be reported in the usual manner.
e
Complete physical examination to include: ECOG performance status, NYHA classification, height (only at Screening), weight, vital signs 
(temperature, pulse and blood pressure), and a complete review of body systems.
f
Brief physical examination to include: ECOG performance status, vital signs (temperature, pulse and blood pressure), examination of 
pertinent organ systems, and brief interim history (change of symptoms).
g
12-lead ECG (including QTcB and QTcF evaluation) will be performed at Screening (within 28 days before Cycle 1 Day 1), on Cycle 1 Day 1, 
and on Day 1 of every 3rd cycle starting from Cycle 3 (3, 6, 9, etc.) prior to infusion and at the end of infusion (window of up to 2 h prior to and 
post-infusion is allowed). At the EOT visit, a 12-lead ECG is necessary only if not recorded within the previous 4 weeks.
h
MUGA scan or echocardiogram to measure LVEF at Screening (within 28 days before Cycle 1 Day 1), within 7 days prior to dosing on Day 1 
of every 3rd cycle (3, 6, 9, etc.), and at the EOT visit (if not previously done within 4 weeks). The method chosen at Screening must be the 
same throughout the whole study.
i
HbA1c at Screening, on Day 1 of every odd cycle (3, 5, 7, etc.) starting from Cycle 3 and at the EOT visit.
j
CBC: Hemoglobin, hematocrit, RBC, WBC (with differential to include absolute neutrophil, lymphocyte, monocyte, basophil and eosinophil 
counts and platelet count). From Cycle 3 onwards, only hemoglobin, platelet and ANC counts will be performed on Day 8 and Day 15 prior to 
each infusion.


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k
Chemistry panel: calcium, sodium, potassium, chloride, phosphorous, magnesium, bicarbonate (or carbon dioxide, if bicarbonate is not 
routinely measured at the site), total protein, albumin, glucose, BUN (or urea if BUN is not routinely measured at the site), SCR, uric acid, 
total bilirubin, creatine phosphokinase, ALT, AST, LDH, ALP, lipase, amylase (or pancreatic amylase, if total amylase is not routinely 
measured at the site), cholesterol (total and LDL) and triglycerides. 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 for 11 h prior to sampling. If a 
patient can’t adhere to fasting requirements, the evaluation of lipid-panels including triglycerides is considered not feasible.
l
On Cycle 1 Day 1, glucose will be measured at pre-dose and after the start of study drug infusion (post-infusion). For patients who had a low 
carbohydrate breakfast prior to the start of infusion, glucose monitoring will be up to 3 h post-infusion (1 h, 2 h and 3 h). For patients who did 
not have a low carbohydrate breakfast prior to infusion, monitoring will continue for up to 5 h post-infusion (1 h, 2 h and 5 h). Additional 
measurements to be performed at the clinic as clinically indicated. On subsequent infusions, glucose will be measured prior to and after 
infusion. The pre-dose glucose sample on Day 1 of each cycle should be after an 8 h fasting. On Cycle 1 Day 1, patient’s fasting pre-dose 
glucose level should be ≤125 mg/dL (non-diabetic patients) or < 160 mg/dL (diabetic patients) before the infusion. Pre-dose glucose levels 
for subsequent infusions should be < 160 mg/dL (fasting) or < 200 mg/dL (non-fasting). For fasting requirements, see Section 6.4.
m
Home glucose monitoring is required for all diabetic patients after each infusion. For non-diabetic patients home glucose measurement is 
required if patients develop hyperglycemia > 250 mg/dL or require insulin administration after any infusion. Measurements should be taken at 
least 3 times per full day for at least 72 h after the start of infusion. This includes fasting glucose (morning before breakfast) and 2 further 
random non-fasting measurements approximately 2 h after intake of food. If after the required 72 h the glucose values are not at goal (fasting 
glucose ≤125 mg/dL/< 160 mg/dL or random non-fasting glucose ≤160 mg/dL/< 200 mg/dL for non-diabetic/diabetic patients, respectively), 
this monitoring will continue until blood glucose values are at goal. Patients will be trained to measure their capillary blood glucose levels at 
home starting at Screening. On Cycle 1 Day 1, patients will be provided with glucose meter and supplies, (lancets, test strips and diary) to 
record glucose values and insulin doses, if applicable. For details see Section 6.4.2.1.
n
Blood pressure will be measured every 5-10 min prior to infusion of study drug (no more than 4 measurements) until there are 2 consecutive 
results < 150/90 mmHg. If blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention or delaying the infusion of 
study drug. At Cycle 1 Day 1 blood pressure will be measured at 0 h (pre-dose), 30 min (mid-infusion), 60 min (end of infusion), 90 min, 2 h, 3 
h, 4 h and 6 h after the start of infusion (deviation 5 min). From Cycle 1 Day 8 onwards a single blood pressure measurement is to be 
performed prior to each infusion, 30 min after the start of infusion and at the end of each infusion (deviation of 5 min is allowed). The patient 
should rest for 5-10 min before blood pressure is recorded.
o
Bone marrow biopsy is mandatory at Screening (biopsy done up to 28 days prior to first dose can be used as baseline evaluation) and to 
confirm the first complete response, if positive at baseline. Biopsy will be performed as per local standard of care.


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p
The first IV (and oral, if indicated, per Imaging Manual) contrast enhanced CT/MRI scans of neck, chest, abdomen and pelvis must be 
performed at Screening (including WM patients). Corticosteroids must be stopped or reduced to the allowed dose (less than 15 mg of 
prednisone or equivalent) at least 7 days before performing the screening CT/MRI (if a patient is on chronic corticosteroid therapy, 
corticosteroids should be de-escalated to the maximum allowed dose before the Screening). The method chosen at the baseline must be the 
same throughout the study. During treatment, tumor scans will be done with the same modality every 12 weeks during Year 1, every 16 
weeks during Year 2, and every 24 weeks during Year 3. Time points for assessments are calculated from Cycle 1 Day 1. Tumor 
assessments must be performed within 14 days after the last dose (Day 15) and before the next dose (Day 1 of the subsequent cycle) 
starting from Cycle 3. CT/MRI scans are not required at the EOT visit if the patient discontinued due to PD which has been radiologically 
evaluated within the 4 weeks preceding EOT. During Active follow-up period patients will have radiological assessments at same intervals as 
during treatment (time window of ±14 days is allowed) until PD is documented or new anti-tumor treatment is administered (see Section 
7.1.2.3 and 7.3.2).
q
FLymSI-18 questionnaire is to be completed on Cycle 1 Day 1 and every cycle thereafter (i.e. on Day 1 of Cycles 2, 3, 4 etc.), at the EOT visit 
and at the SFU visit in both treatment arms. Questionnaire should be self-administered by the patient via an ePRO at the start of the visit 
before the patient sees the physician. A PRO information sheet will be provided and completed by the study personnel at each visit at which 
the FLymSI-18 questionnaire is to be administered, regardless of whether or not the FLymSI-18 questionnaire is completed by the patient.
r
PK sampling will be performed for copanlisib, its metabolite M-1 and other metabolites, if needed, in all patients on Cycle 1 Day 8: pre-
infusion, 5 to 15 min, 55 min (or within 5 min prior to end of infusion) and 1.5 to 5 h after start of 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.
s
Tumor tissue collection will be mandatory at Screening for central pathology review. In addition, additional pre-treatment tumor tissue
samples will be collected when available to investigate or identify biomarkers that may be predictive of copanlisib effects/efficacy in NHL and 
to contribute to better understanding the disease. A tumor biopsy is also encouraged at the time of progression (optional) to allow 
investigation of copanlisib resistance. In addition, if a tumor biopsy/excision occurs during the course of the study based on medical need, a 
sample should be submitted (though no biopsy is required during treatment) (see Section 7.6.1).
t
Plasma for tumor genetics: blood samples will be collected on Cycle 1 Day 1 and at the EOT visit. On Cycle 1 Day 1, blood for plasma 
preparation should be drawn prior to drug administration.
u
Plasma for non-genetic biomarker analysis will be prepared from whole blood samples. On treatment days, blood for plasma preparation 
should be drawn prior to drug administration. Samples are to be collected on Cycle 1 (Days 1, 8 and 15), Cycle 2 (Days 1, 8 and 15), and at 
the EOT visit.
v
Whole blood for biomarkers will be collected on Cycle 1 Day 1 prior to drug administration (only from patients who provide a separate consent 
for genetic research).


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w
Only for patients affected by LPL/WM: Serum protein electrophoresis, immunofixation, serum quantitative IgM test and serum beta-2-
microglobulin measurement will be performed at Screening. Serum or plasma viscosity will be tested at Screening only if hyperviscosity 
syndrome is suspected. Only for patients affected by WM: Serum protein electrophoresis, immunofixation and serum quantitative IgM test will 
be performed on the days of tumor evaluation and at the EOT visit only if the last assessment is older than 4 weeks. If serum or plasma 
viscosity is abnormal at baseline, the measurement will be repeated every 3rd cycle starting from Day 1 of Cycle 3, and at the EOT visit.
x
Laboratory tests prior to each infusion may be performed either the day before or on the planned date of infusion, with the exception of blood 
glucose (or capillary glucose sampling via glucose meter), which must be performed on the day of infusion. For dosing criteria, see Section 
6.4.
y
After Cycle 1, there are no mandatory procedures on Day 22 of subsequent cycles. Tumor assessments and related procedures marked for 
Day 22 will be done according to schedule specified in Section 7.1.2.3.
z
The post-treatment follow-up 30-35 days after the last administration of study drug can be conducted via telephone if the patient is no longer 
being actively seen at the clinic or has started another therapy. In this case, FLymSI-18 questionnaire does not need to be completed at the 
SFU evaluation. Procedures marked with “(X)” are only to be performed, if clinically indicated.
aa Patients who discontinue study treatment for reasons other than PD will enter the Active follow-up period (which also serves as a Safety 
follow-up), except for patients who object to follow-up data collection. The patients in the Active follow-up will have radiological assessments 
as outlined in this protocol from the day of randomization until PD is documented or new anti-tumor treatment is administered, whichever 
occurs first.
bb Patients or their health care providers will be contacted either in person or by telephone (except for patients who object to FU data collection). 
The contacts will be made at least every 3 months (± 14 days), until death or until the end of the trial (up to 3 years after the last patient 
started study treatment), whichever comes first. Information to be recorded: date of contact, survival status, the first new anticancer regimen
including response (if applicable), and date and cause of death (if applicable).
cc
Written informed consent must be obtained prior to any study-specific procedures.Certain results from diagnostic testing performed as part of 
the standard of practice prior to the informed consent date and time may be used to fulfill screening criteria. This includes fresh tissue as 
noted in the protocol as well as results from CT/MRI scans, bone marrow sample, MUGA/echocardiogram and hepatitis testing which may 
also be used provided that they fall into the protocol-specified time window. Archival tissue obtained from the patients at any time during the 
course of their iNHL may also be used prior to the informed consent date and time if performed as part of the standard of practice. CT/MRI 
must also meet the quality standards of the Imaging Manual. The maximum interval allowed between signature of informed consent and start 
of treatment is 28 days unless written sponsor authorization has been obtained for laboratory re-testing (up to additional 14 days permitted).
dd Modified by amendment 1.


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13.1.2.30 Section 7.1.2 Timing of assessments
Old text:
All procedures during the treatment period should be done according to the relative days 
mentioned in this CSP. Deviations of -1 day and +2 days are acceptable with the exception of 
blood glucose and blood pressure measurement before study drug infusion.
New text:
All procedures during the treatment period should be done according to the relative days 
mentioned in this CSP. Deviations of -1 day and +2 days are acceptable with the exception of 
blood glucose (or capillary glucose sampling via glucose meter) and blood pressure 
measurement before study drug infusion.
13.1.2.31 Section 7.1.2.1 Screening period
Old text:
Screening examinations will only be performed after the patient has given written informed 
consent. The maximum interval allowed between signature of informed consent and start of 
treatment is 28 days.
Less than 28 days before the first administration of study drug:

IVRS/IWRS transaction to register the patient in the system.

Blood test for HBV and HCV: HBsAg, HBcAb and HCV IgG. 
(If HBsAg or HBcAb positive also HBV DNA; if HCV IgG positive also HCV RNA).

Bone marrow biopsy: mandatory at Screening (biopsy done up to 28 days prior to first 
dose can be used as baseline evaluation) and to confirm the first complete response, if 
positive at baseline.

IV contrast-enhanced CT/MRI of neck, chest, abdomen and pelvis. Corticosteroids 
must be stopped or reduced to the allowed dose (less than 15 mg of prednisone or 
equivalent) at least 7 days before performing the CT/MRI (if a patient is on chronic 
corticosteroid therapy, corticosteroids should be de-escalated to the maximum allowed 
dose before the Screening). Scans done up to 28 days prior to first dose can be used as 
baseline evaluation. The method chosen at the baseline must be the same throughout 
the study (see Section 7.3.2).

Tumor tissue for central pathology review and biomarker analysis (mandatory)
(see Section 7.6.1): 
o
Fresh tumor tissue (preferred) will be collected between Day -28 and Day -8 
prior to the start of study treatment. Fresh tissue is recommended in patients 
with clinical suspicion of transformed disease. Detailed guidance on fresh 
biopsy sample preparation and storage will be provided to the sites.


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o
Archival tumor tissue will be requested if fresh tissue is not available (the 
latest biopsy available should be provided). Archival tissue may be supplied as 
a block (preferred) or as precut slides. Details on the preparation of slides and 
number of slides to be prepared will be described in separate documents (e.g. 
Sample Handling Sheets or laboratory manual).
Less than 14 days before the first administration of study drug:

Check inclusion and exclusion criteria (see Section 5.1).

Complete medical and surgical history including demographics, relevant medical 
history findings, concomitant illnesses, allergy history, prior surgeries, most recent 
histology of tumor, most recent staging and grading of tumor, FLIPI score (for patients 
with FL), history of anticancer treatments (including type of treatment, type of 
response, date of response and date of subsequent relapse), presence of B symptoms, 
assessment of baseline toxicity and smoking history (see Section 7.2).

Serum beta-2-microglobulin.

Toxicity/AE assessment: any new findings or worsening of any ongoing medical 
history conditions after the patient has signed the informed consent are to be listed as 
AEs (see Section 7.5.1.3).
[...]

Complete physical examination including ECOG performance status (see grading 
definitions in Appendix 14.3), NYHA classification (see Appendix 14.4), height, 
weight, vital signs (temperature, pulse and blood pressure), and a complete review of 
body systems (including physical examination for lymphadenopathy, abdominal 
masses, or organomegaly) (see Section 7.5.3.2).

12-lead ECG including QTcB and QTcF evaluation (see Section 7.5.3.4).

Multiple gated acquisition (MUGA) scan or echocardiogram to measure LVEF. The 
method chosen at Screening must be the same throughout the whole study (see 
Section 7.5.3.5).

Only in patients affected by Lymphoplasmacytoid lymphoma/Waldenström 
macroglobulinemia (LPL/WM):
o Serum protein electrophoresis.
o Immunofixation.
o Serum quantitative IgM test.
o Serum or plasma viscosity (if hyperviscosity syndrome is suspected).
New text:
Screening examinations will be performed after the patient has given written informed 
consent. Certain results from diagnostic testing performed as part of the standard of practice 
prior to the informed consent date and time may be used to fulfill screening criteria. This 


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includes fresh tissue as noted in the protocol as well as results from CT/MRI scans, bone 
marrow sample, MUGA/echocardiogram and hepatitis testing which may also be used 
provided that they fall into the protocol-specified time window. Archival tissue obtained from 
the patients at any time during the course of their iNHL may also be used prior to the 
informed consent date and time if performed as part of the standard of practice. CT/MRI must 
also meet the quality standards of the Imaging Manual. The maximum interval allowed 
between signature of informed consent and start of treatment is 28 days unless written sponsor 
authorization has been obtained for laboratory re-testing (up to additional 14 days permitted).
Less than 28 days before the first administration of study drug:

IVRS/IWRS transaction to register the patient in the system.

Blood test for HBV and HCV: HBsAg, HBcAb and HCV IgG. 
(If HBsAg or HBcAb positive also HBV DNA; if HCV IgG positive also HCV RNA).

12-lead ECG including QTcB and QTcF evaluation (see Section 7.5.3.4).

Multiple gated acquisition (MUGA) scan or echocardiogram to measure LVEF. The 
method chosen at Screening must be the same throughout the whole study (see 
Section 7.5.3.5).

Bone marrow biopsy: mandatory at Screening and to confirm the first complete 
response, if positive at baseline. Biopsy will be performed as per local standard of 
care.

IV (and oral, if indicated, per Imaging Manual) contrast-enhanced CT/MRI of neck, 
chest, abdomen and pelvis (including WM patients). Corticosteroids must be stopped 
or reduced to the allowed dose (less than 15 mg of prednisone or equivalent) at least 7 
days before performing the screening CT/MRI (if a patient is on chronic corticosteroid 
therapy, corticosteroids should be de-escalated to the maximum allowed dose before 
the Screening). The method chosen at the baseline must be the same throughout the 
study (see Section 7.3.2).

Tumor tissue collection will be mandatory at Screening for central pathology review. 
In addition, additional pre-treatment tumor tissue samples will be collected when 
available to investigate or identify biomarkers that may be predictive of copanlisib 
effects/efficacy in NHL and to contribute to better understanding the disease (see 
Section 7.6.1).
Less than 14 days before the first administration of study drug:

Check inclusion and exclusion criteria (see Section 5.1).

Complete medical and surgical history including demographics, relevant medical 
history findings, concomitant illnesses, allergy history, prior surgeries, most recent 
histology of tumor, most recent staging and grading of tumor, FLIPI score (for patients 
with FL), history of anticancer treatments (including type of treatment, type of 


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response, date and duration of response and date of subsequent relapse), presence of B 
symptoms, assessment of baseline toxicity and smoking history (see Section 7.2).

Toxicity/AE assessment: any new findings or worsening of any ongoing medical 
history conditions after the patient has signed the informed consent are to be listed as 
AEs (see Section 7.5.1.3).
[...]

Complete physical examination including ECOG performance status (see grading 
definitions in Appendix 14.3), NYHA classification (see Appendix 14.4), height, 
weight, vital signs (temperature, pulse and blood pressure), and a complete review of 
body systems (see Section 7.5.3.2).

Only in patients affected by Lymphoplasmacytoid lymphoma/Waldenström 
macroglobulinemia (LPL/WM):
o Serum protein electrophoresis.
o Immunofixation.
o Serum quantitative IgM test.
o Serum beta-2-microglobulin.
o Serum or plasma viscosity (if hyperviscosity syndrome is suspected).
13.1.2.32 Section 7.1.2.2 Treatment period
Old text:
The following assessments should be performed both in patients on double-blinded study 
treatment (copanlisib or placebo) as well as those who are randomized to placebo and change 
to copanlisib. After individual patient unblinding, patients receiving placebo who switch to 
open-label copanlisib will have all study assessments and timing reset to the initial schedule 
of study evaluations (i.e. as if the patient was restarting the study at Cycle 1 Day 1).
New text:
The following assessments should be performed both in patients on double-blinded study 
treatment (copanlisib or placebo) as well as those who are randomized to placebo and change 
to copanlisib. After individual patient unblinding, patients receiving placebo who switch to 
open-label copanlisib will have all study assessments and timing reset to the initial schedule 
of study evaluations (i.e. as if the patient was restarting the study at Cycle 1 Day 1). If not 
previously done within 7 days, patients switching to open-label copanlisib must complete the 
following within 7 days prior to the first dose of open-label copanlisib: UPCR measurement, 
GFR measurement, urinalysis, HbA1c, CBC, chemistry and coagulation panels. Dosing 
criteria outlined in Table 6–2 apply also for patients who switch to open-label treatment.


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13.1.2.33 Section 7.1.2.2.1 Treatment – Cycle 1
Old text:
Cycle 1 Day 1
On Cycle 1 Day 1 patients should be fasting for at least 8 h prior to the dose and until 2 h after 
completion of the infusion (see also Section 6.4). During the fasting period, patients may 
drink water and beverages with artificial sweeteners. Approximately 3 h after the start of the 
infusion, the patients should have a low carbohydrate meal. Their pre-dose glucose level 
should be ≤ 125 mg/dL (non-diabetic patients) or < 160 mg/dL (diabetic patients).
Patients can stay overnight at the site, if needed, based on the investigator’s decision.

Quality of life (QoL) questionnaire (FLymSI-18): at the start of a visit, before the 
patient sees the physician. To be completed by electronic patient-reported outcome 
(ePRO) device (see Section 7.6.2).
[...]

Complete physical examination including ECOG performance status, NYHA 
classification, weight, vital signs (temperature, pulse and blood pressure), and 
complete review of body systems (including physical examination for 
lymphadenopathy, abdominal masses, or organomegaly) (see Section 7.5.3.2).

At centers with adequate facilities and equipment: 12-lead ECG including QTcB and 
QTcF evaluation will be recorded pre-infusion and at the end of infusion (Cmax). A PK 
sample is to be drawn after each of these 12-lead ECG recordings (see 
Section 7.5.3.4).

Glucose measurement: on Cycle 1 Day 1 glucose will be measured at pre-dose, and 
3 h, 5 h, 6 h, and 8 h after the start of the infusion. Additional measurements to be 
performed at the clinic as clinically indicated. The first pre-dose glucose sample on 
Cycle 1 Day 1 should be after an 8 h fasting (see Section 6.4).

Home blood glucose monitoring: all patients.

Training on glucose self-monitoring with a glucose meter, if needed.

Blood pressure will be measured every 5-10 min prior to infusion of study drug (no 
more than 4 measurements) until there are 2 consecutive results < 150/90 mmHg. If 
blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention 
or delaying the infusion of study drug. On Cycle 1 Day 1 blood pressure will be 
measured at 0 h (pre-dose), 30 min (mid-infusion), 60 min (end of infusion), 90 min, 
2 h, 3 h, 4 h and 6 h after the start of infusion (deviation of 5 min is allowed). The 
patient should lie down for 5-10 min before blood pressure is recorded.

At centers with adequate facilities and equipment: PK sampling for copanlisib, its 
metabolite M-1 and other metabolites, if needed, will be performed after each 12-lead 
ECG recording pre- infusion and end of infusion (within 5 min prior to the end of 
infusion) (see Section 7.4).


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
Collection of blood for biomarker analyses prior to infusion (see Section 7.6.1):
o
Plasma for genetic biomarker analysis.
o
Plasma for non-genetic biomarker analysis.
[...]
Cycle 1 Day 8
[...]

Glucose test prior to and after study drug IV infusion (see Section 6.4).

Review of the home blood glucose measurements/insulin administration, if applicable. 
Provide strips if necessary (see Section 6.4.2.1).

Home blood glucose monitoring:
o
Diabetic patients: all patients.
o
Non-diabetic patients who experience CTCAE Grade 3 hyperglycemia or 
require insulin administration.

Blood pressure will be measured every 5-10 min prior to infusion of study drug (no 
more than 4 measurements) until there are 2 consecutive results < 150/90 mmHg. If 
blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention 
or delaying the infusion of study drug. From Cycle 1 Day 8 onwards a single blood 
pressure measurement is to be performed prior to each infusion, 30 min after the start 
of infusion and at the end of each infusion. The patient should lie down for 5-10 min 
before blood pressure is recorded.

PK sampling for copanlisib, its metabolite M-1 and other metabolites, if needed: pre-
infusion, 5 to 15 min, 55 min (within 5 min prior to end of infusion) and 1.5 to 5 h 
after start of infusion (see Section 7.4).

Collection of blood for non-genetic biomarker analyses prior to infusion (see 
Section 7.6.1).
[...]
Cycle 1 Day 15
[...]

Glucose test prior to and after study drug IV infusion (see Section 6.4). 

Review of the home blood glucose measurements/insulin administration, if applicable. 
Provide strips if necessary (see Section 6.4.2.1).

Home blood glucose monitoring:
o
Diabetic patients: all patients.


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o
Non-diabetic patients who experience CTCAE Grade 3 hyperglycemia or 
require insulin administration.

Blood pressure will be measured every 5-10 min prior to infusion of study drug (no 
more than 4 measurements) until there are 2 consecutive results < 150/90 mmHg. If 
blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention 
or delaying the infusion of study drug. From Cycle 1 Day 8 onwards a single blood 
pressure measurement is to be performed prior to each infusion, 30 min after the start 
of infusion and at the end of each infusion. The patient should lie down for 5-10 min 
before blood pressure is recorded.

Collection of blood for non-genetic biomarker analyses prior to infusion (see 
Section 7.6.1).
[...]
Cycle 1 Day 22
[...]

Review of the home blood glucose measurements/insulin administration, if applicable. 
Provide strips if necessary (see Section 6.4.2.1).
After Cycle 1, there are no mandatory procedures on Day 22 of subsequent cycles. Day 22 
from Cycle 2 onwards is the earliest time for procedures due at latest on Day 1 of the next 
cycle.
New text:
Cycle 1 Day 1
On Cycle 1 Day 1, patients should be fasting for at least 8 h prior to the pre-dose glucose 
measurement. After pre-dose glucose measurement and approximately within 1 h before the 
start of study drug infusion patients can have a low carbohydrate breakfast. Patient’s fasting
pre-dose glucose level should be ≤ 125 mg/dL (non-diabetic patients) or < 160 mg/dL 
(diabetic patients) (see also Section 6.4).
Patients can stay overnight at the site, if needed, based on the investigator’s decision.

Quality of life (QoL) questionnaire (FLymSI-18): Patient completes the questionnaire
at the start of a visit, before the patient sees the physician. To be completed by 
electronic patient-reported outcome (ePRO) device. A PRO information sheet will be 
provided and completed by the study personnel at each visit at which the FLymSI-18 
questionnaire is to be administered, regardless of whether or not the FLymSI-18 
questionnaire is completed by the patient (see Section 7.6.2).
[...]

Complete physical examination including ECOG performance status, NYHA 
classification, weight, vital signs (temperature, pulse and blood pressure), and 
complete review of body systems (see Section 7.5.3.2).


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
12-lead ECG including QTcB and QTcF evaluation prior to infusion and at the end of 
infusion (window of up to 2 h prior to and post-infusion is allowed) (see 
Section 7.5.3.4).

Glucose measurement: on Cycle 1 Day 1 glucose will be measured at pre-dose and 
after the start of study drug infusion (post-infusion). For patients who had a low 
carbohydrate breakfast prior to the start of infusion, glucose monitoring will be up to 
3 h post-infusion (1 h, 2 h and 3 h). For patients who did not have a low carbohydrate 
breakfast prior to infusion, monitoring will continue for up to 5 h post-infusion (1 h, 
2 h and 5 h). Additional measurements to be performed at the clinic as clinically 
indicated. The pre-dose glucose sample on Cycle 1 Day 1 should be after an 8 h 
fasting (see Section 6.4).

Home blood glucose monitoring: 
o
Diabetic patients: all patients.
o
Non-diabetic patients who experience hyperglycemia > 250 mg/dL or require 
insulin administration.

Training on glucose self-monitoring with a glucose meter, if needed. Patients will be 
provided with glucose meter and supplies (lancets, test strips and diary) to record 
glucose values and insulin doses, if applicable.

Blood pressure will be measured every 5-10 min prior to infusion of study drug (no 
more than 4 measurements) until there are 2 consecutive results < 150/90 mmHg. If 
blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention 
or delaying the infusion of study drug. On Cycle 1 Day 1 blood pressure will be 
measured at 0 h (pre-dose), 30 min (mid-infusion), 60 min (end of infusion), 90 min, 
2 h, 3 h, 4 h and 6 h after the start of infusion (deviation of 5 min is allowed). The 
patient should rest for 5-10 min before blood pressure is recorded.

Collection of blood for biomarker analyses prior to infusion (see Section 7.6.1):
o
Plasma for tumor genetics.
o
Plasma for non-genetic biomarker analysis.
[...]

Cycle 1 Day 8
[...]

Glucose test prior to and after study drug IV infusion. Patients are not required to be 
fasting prior to pre-dose glucose measurement (see Section 6.4).

Review of the home blood glucose measurements/insulin administration, if applicable. 
Provide glucose monitoring supplies if necessary (see Section 6.4.2.1).

Home blood glucose monitoring:
o
Diabetic patients: all patients.


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o
Non-diabetic patients who experience hyperglycemia > 250 mg/dL or require 
insulin administration.

Blood pressure will be measured every 5-10 min prior to infusion of study drug (no 
more than 4 measurements) until there are 2 consecutive results < 150/90 mmHg. If 
blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention 
or delaying the infusion of study drug. From Cycle 1 Day 8 onwards a single blood 
pressure measurement is to be performed prior to each infusion, 30 min after the start 
of infusion and at the end of each infusion (deviation of 5 min is allowed). The 
patient should rest for 5-10 min before blood pressure is recorded.

PK sampling for copanlisib, its metabolite M-1 and other metabolites, if needed: pre-
infusion, 5 to 15 min, 55 min (or within 5 min prior to end of infusion) and 1.5 to 5 h 
after start of 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 7.4).

Collection of plasma for non-genetic biomarker analyses prior to infusion (see 
Section 7.6.1).
[...]

Cycle 1 Day 15
[...]

Glucose test prior to and after study drug IV infusion. Patients are not required to be 
fasting prior to pre-dose glucose measurement (see Section 6.4). 

Review of the home blood glucose measurements/insulin administration, if applicable. 
Provide glucose monitoring supplies if necessary (see Section 6.4.2.1).

Home blood glucose monitoring:
o
Diabetic patients: all patients.
o
Non-diabetic patients who experience hyperglycemia > 250 mg/dL or require 
insulin administration.

Blood pressure will be measured every 5-10 min prior to infusion of study drug (no 
more than 4 measurements) until there are 2 consecutive results < 150/90 mmHg. If 
blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention 
or delaying the infusion of study drug. From Cycle 1 Day 8 onwards a single blood 
pressure measurement is to be performed prior to each infusion, 30 min after the start 
of infusion and at the end of each infusion (deviation of 5 min is allowed). The 
patient should rest for 5-10 min before blood pressure is recorded.

Collection of plasma for non-genetic biomarker analyses prior to infusion (see 
Section 7.6.1).


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[...]
Cycle 1 Day 22
[...]

Review of the home blood glucose measurements/insulin administration, if applicable. 
Provide glucose monitoring supplies if necessary (see Section 6.4.2.1).
13.1.2.34 Section 7.1.2.2.2 Treatment – Cycle 2 and higher
Old text:
Cycle 2 and higher, Day 1

QoL questionnaire (FLymSI-18) on Day 1 of each cycle (i.e. on Day 1 of Cycles 2, 3, 
4 etc.): at the start of a visit, before the patient sees the physician. To be completed by 
ePRO device (see Section 7.6.2).

IVRS/IWRS transaction for medication dispensing.

Serum pregnancy test: after Cycle 1 serum pregnancy test is mandatory at every cycle 
for France, Belgium, Canada and other countries where it is required by local 
regulations.

Toxicity/AE assessment (see Section 7.5.1.3).
[...]

Complete physical examination including ECOG performance status, NYHA 
classification, weight, vital signs (temperature, pulse and blood pressure), and 
complete review of body systems (including physical examination for 
lymphadenopathy, abdominal masses, or organomegaly) (see Section 7.5.3.2).

12-lead ECG including QTcB and QTcF evaluation within 7 days prior to dosing on 
Day 1 of every 3rd cycle (3, 6, 9 etc.) (see Section 7.5.3.4).
[...]

Glucose test prior to and after study drug IV infusion (see Section 6.4). 

Review of the home capillary blood glucose measurements/insulin administration, if 
applicable. Provide strips if necessary (see Section 6.4.2.1).

Home blood glucose monitoring:
o
Diabetic patients: all patients.
o
Non-diabetic patients who experience CTCAE Grade 3 hyperglycemia or 
require insulin administration.


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
Blood pressure will be measured every 5-10 min prior to infusion of study drug (no 
more than 4 measurements) until there are 2 consecutive results < 150/90 mmHg. If 
blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention 
or delaying the infusion of study drug. From Cycle 1 Day 8 onwards a single blood 
pressure measurement is to be performed prior to each infusion, 30 min after the start 
of infusion and at the end of each infusion. The patient should lie down for 5-10 min 
before blood pressure is recorded.

Collection of blood for biomarker analyses prior to infusion (see Section 7.6.1):
o
Plasma for genetic biomarker analysis on Day 1 of every odd cycle 
(3, 5, 7 etc.) starting from Cycle 3.
o
Plasma for non-genetic biomarker analysis.
[...]
Cycle 2 and higher, Day 8
[...]

Glucose test prior to and after study drug IV infusion (see Section 6.4). 

Review of the home blood glucose measurements/insulin administration, if applicable. 
Provide strips if necessary (see Section 6.4.2.1).

Home blood glucose monitoring:
o
Diabetic patients: all patients.
o
Non-diabetic patients who experience CTCAE Grade 3 hyperglycemia or 
require insulin administration.

Blood pressure will be measured every 5-10 min prior to infusion of study drug (no 
more than 4 measurements) until there are 2 consecutive results < 150/90 mmHg. If 
blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention 
or delaying the infusion of study drug. From Cycle 1 Day 8 onwards a single blood 
pressure measurement is to be performed prior to each infusion, 30 min after the start 
of infusion and at the end of each infusion. The patient should lie down for 5-10 min 
before blood pressure is recorded.

Only in Cycle 2: collection of blood for non-genetic biomarker analyses prior to 
infusion (see Section 7.6.1).
[...]
Cycle 2 and higher, Day 15
[...]

At centers with adequate facilities and equipment, 12-lead ECG including QTcB and 
QTcF evaluation will be recorded on Day 15 of every 3rd cycle (3, 6, 9 etc.) pre-


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infusion and at the end of infusion (Cmax). A PK sample is to be drawn after each of 
these 12-lead ECG recordings (see Section 7.5.3.4).

On Cycle 2, blood tests for CBC and chemistry panel (excluding total cholesterol, 
LDL and triglycerides) will be performed. From Cycle 3 onwards, only hemoglobin, 
platelet and ANC counts will be performed prior to each infusion (see Section 6.4 and 
Section 7.5.3.1).

Glucose test prior to and after study drug IV infusion (see Section 6.4). 

Review of the home blood glucose measurements/insulin administration, if applicable. 
Provide strips if necessary (see Section 6.4.2.1).

Home blood glucose monitoring:
o
Diabetic patients: all patients.
o
Non-diabetic patients who experience CTCAE Grade 3 hyperglycemia or 
require insulin administration.

Blood pressure will be measured every 5-10 min prior to infusion of study drug (no 
more than 4 measurements) until there are 2 consecutive results < 150/90 mmHg. If 
blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention 
or delaying the infusion of study drug. From Cycle 1 Day 8 onwards a single blood 
pressure measurement is to be performed prior to each infusion, 30 min after the start 
of infusion and at the end of each infusion. The patient should lie down for 5-10 min 
before blood pressure is recorded.

At centers with adequate facilities and equipment: PK sampling for copanlisib, its 
metabolite M-1 and other metabolites, if needed, will be performed on Day 15 of 
every 3rd cycle (3, 6, 9 etc.) after each 12-lead ECG recording pre- infusion and end of 
infusion (within 5 min prior to the end of infusion) (see Section 7.4).

Only in Cycle 2: collection of blood for non-genetic biomarker analyses prior to 
infusion (see Section 7.6.1)

Study drug IV infusion.


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New text:
Cycle 2 and higher, Day 1
On Day 1 of each subsequent cycle, patients should be fasting for at least 8 h prior to the pre-
dose glucose measurement. After pre-dose glucose measurement patients can have a low 
carbohydrate breakfast. Patient’s fasting pre-dose glucose level should be < 160 mg/dL 
(fasting) or, in case of non-compliance with fasting requirements, < 200 mg/dL (non-fasting) 
(see also Section 6.4).

QoL questionnaire (FLymSI-18) on Day 1 of each cycle (i.e. on Day 1 of Cycles 2, 3, 
4 etc.): Patient completes the questionnaire at the start of a visit, before the patient sees 
the physician. To be completed by ePRO device (see Section 7.6.2).

IVRS/IWRS transaction for medication dispensing.

Serum pregnancy test: after Cycle 1 serum pregnancy test is mandatory at every cycle 
for France, Belgium, Canada and other countries where it is required by local 
regulations.

GFR measurement (see Section 7.5.3.1 and Appendix 14.5).

Toxicity/AE assessment (see Section 7.5.1.3).
[...]

Complete physical examination including ECOG performance status, NYHA 
classification, weight, vital signs (temperature, pulse and blood pressure), and 
complete review of body systems (see Section 7.5.3.2).

12-lead ECG including QTcB and QTcF evaluation on Day 1 of every 3rd cycle 
starting from Cycle 3 (3, 6, 9 etc.) prior to infusion and at the end of infusion (window 
of up to 2 h prior to and post-infusion is allowed) (see Section 7.5.3.4).
[...]

Glucose test prior to and after study drug IV infusion. The pre-dose glucose sample on 
Day 1 of each cycle should be after an 8 hour fasting (see Section 6.4). 

Review of the home blood glucose measurements/insulin administration, if applicable. 
Provide glucose monitoring supplies if necessary (see Section 6.4.2.1).

Home blood glucose monitoring:
o
Diabetic patients: all patients.
o
Non-diabetic patients who experience hyperglycemia > 250 mg/dL or require 
insulin administration.

Blood pressure will be measured every 5-10 min prior to infusion of study drug (no 
more than 4 measurements) until there are 2 consecutive results < 150/90 mmHg. If 
blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention 
or delaying the infusion of study drug. From Cycle 1 Day 8 onwards a single blood 


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pressure measurement is to be performed prior to each infusion, 30 min after the start 
of infusion and at the end of each infusion (deviation of 5 min is allowed). The 
patient should rest for 5-10 min before blood pressure is recorded.

Only in Cycle 2: collection of plasma for non-genetic biomarker analyses prior to 
infusion (see Section 7.6.1).
[...]

Cycle 2 and higher, Day 8
[...]

Glucose test prior to and after study drug IV infusion. Patients are not required to be 
fasting prior to pre-dose glucose measurement (see Section 6.4). 

Review of the home blood glucose measurements/insulin administration, if applicable. 
Provide glucose monitoring supplies if necessary (see Section 6.4.2.1).

Home blood glucose monitoring:
o
Diabetic patients: all patients.
o
Non-diabetic patients who experience hyperglycemia > 250 mg/dL or require 
insulin administration.

Blood pressure will be measured every 5-10 min prior to infusion of study drug (no 
more than 4 measurements) until there are 2 consecutive results < 150/90 mmHg. If 
blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention 
or delaying the infusion of study drug. From Cycle 1 Day 8 onwards a single blood 
pressure measurement is to be performed prior to each infusion, 30 min after the start 
of infusion and at the end of each infusion (deviation of 5 min is allowed). The 
patient should rest for 5-10 min before blood pressure is recorded.

Only in Cycle 2: Collection of plasma for non-genetic biomarker analyses prior to 
infusion (see Section 7.6.1).
[...]
Cycle 2 and higher, Day 15
[...]

On Cycle 2, blood tests for CBC and chemistry panel (excluding total cholesterol, 
LDL and triglycerides) will be performed. From Cycle 3 onwards, only hemoglobin, 
platelet and ANC counts will be performed prior to each infusion (see Section 6.4 and 
Section 7.5.3.1).

Glucose test prior to and after study drug IV infusion. Patients are not required to be 
fasting prior to pre-dose glucose measurement (see Section 6.4). 

Review of the home blood glucose measurements/insulin administration, if applicable. 
Provide glucose monitoring supplies if necessary (see Section 6.4.2.1).


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
Home blood glucose monitoring:
o
Diabetic patients: all patients.
o
Non-diabetic patients who experience hyperglycemia > 250 mg/dL or require 
insulin administration.

Blood pressure will be measured every 5-10 min prior to infusion of study drug (no 
more than 4 measurements) until there are 2 consecutive results < 150/90 mmHg. If 
blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention 
or delaying the infusion of study drug. From Cycle 1 Day 8 onwards a single blood 
pressure measurement is to be performed prior to each infusion, 30 min after the start 
of infusion and at the end of each infusion (deviation of 5 min is allowed). The 
patient should rest for 5-10 min before blood pressure is recorded.

Only in Cycle 2: collection of plasma for non-genetic biomarker analyses prior to 
infusion (see Section 7.6.1).

Study drug IV infusion.
Cycle 2 and higher, Day 22
After Cycle 1, there are no mandatory procedures on Day 22 of subsequent cycles. Tumor 
assessments and related procedures marked for Day 22 will be done according to schedule 
specified in Section 7.1.2.3.
13.1.2.35 Section 7.1.2.3 Tumor assessments
Old text:
7.1.2.2.3 Tumor assessments
Radiological tumor evaluations (IV contrast-enhanced CT/MRI scans of neck, chest, abdomen 
and pelvis) will be performed during the treatment period as well as during the Active follow-
up period at the following intervals. Deviation of ±7 days is allowed. The method chosen at 
the baseline must be the same throughout the study (see also Section 7.3.2):
[...]
Bone marrow biopsy will be mandatory at baseline and if positive at Screening, will be 
repeated for confirmation of the first CR.
In addition, the following procedures will be performed on the days of tumor assessments:

Physical examination for lymphadenopathy, abdominal masses, or organomegaly. 

Collection of B symptoms (fever above 38°C, night sweats, or weight loss of more 
than 10% in the previous 6 months).

Only in patients affected by WM:


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New text:
7.1.2.3 Tumor assessments (changed to level 4 heading)
Radiological tumor evaluations (IV [and oral, if indicated, per Imaging Manual] contrast-
enhanced CT/MRI scans of neck, chest, abdomen and pelvis) will be performed during the 
treatment period as well as during the Active follow-up period at the following intervals. 
Time points for assessments are calculated from Cycle 1 Day 1. The method chosen at the 
baseline must be the same throughout the study (see also Section 7.3.2):
[...]
During treatment, tumor assessments must be performed within 14 days after the last dose 
(Day 15) and before the next dose (Day 1 of the subsequent cycle) starting from Cycle 3.
During Active follow-up, tumor assessments will be done until PD is documented or new 
anti-tumor treatment is administered. Time window of ±14 days is allowed for scheduling the 
visit for response assessment.
Bone marrow biopsy will be mandatory at baseline and if positive at Screening, will be 
repeated for confirmation of the first CR. Biopsy will be performed as per local standard of 
care.
In addition, the following procedures will be performed on the days of tumor assessments 
(deviation of ± 2 days is allowed):

Only in patients affected by WM:
13.1.2.36 Section 7.1.2.4 End-of-treatment visit
Old text:

QoL questionnaire (FLymSI-18): at the start of a visit, before the patient sees the 
physician. To be completed by ePRO device (see Section 7.6.2).
[...]

Complete physical examination including ECOG performance status, NYHA 
classification, weight, vital signs (temperature, pulse and blood pressure), and 
complete review of body systems (including physical examination for 
lymphadenopathy, abdominal masses, or organomegaly) (see Section 7.5.3.2).
[...]

MUGA scan or echocardiogram to measure LVEF. The method chosen at Screening 
must be the same throughout the whole study (see Section 7.5.3.5).
[...]

Review of the home capillary blood glucose measurements/insulin administration, if 
applicable (see Section 6.4.2.1).


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
IV contrast-enhanced CT/MRI of neck, chest, abdomen and pelvis. CT/MRI scans are 
not required, if the patient discontinues due to PD which has been radiologically 
evaluated within the 4 weeks preceding EOT (see Section 7.3.2).

Collection of blood for genetic and non-genetic biomarker analyses (see 
Section 7.6.1).
New text:

QoL questionnaire (FLymSI-18): Patient completes the questionnaire at the start of a 
visit, before the patient sees the physician. To be completed by ePRO device (see 
Section 7.6.2).
[...]

Complete physical examination including ECOG performance status, NYHA 
classification, weight, vital signs (temperature, pulse and blood pressure), and 
complete review of body systems (see Section 7.5.3.2)
[...]

MUGA scan or echocardiogram to measure LVEF if not previously done within 
4 weeks. The method chosen at Screening must be the same throughout the whole 
study (see Section 7.5.3.5).
[...]

Review of the home blood glucose measurements/insulin administration, if applicable 
(see Section 6.4.2.1).

IV (and oral, if indicated, per Imaging Manual) contrast-enhanced CT/MRI of neck, 
chest, abdomen and pelvis. CT/MRI scans are not required, if the patient discontinues 
due to PD which has been radiologically evaluated within the 4 weeks preceding EOT 
(see Section 7.3.2).

A tumor biopsy is encouraged at the time of progression (optional) to allow 
investigation of copanlisib resistance. In addition, if a tumor biopsy/excision occurs 
during the course of the study based on medical need, a sample should be submitted 
(though no biopsy is required during treatment).

Collection of plasma for tumor genetics and non-genetic biomarker analyses (see 
Section 7.6.1).


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13.1.2.37 Section 7.1.2.5 Follow-up periods/Safety follow-up
Old text:
7.1.2.4 Safety follow-up
If a patient discontinues study treatment at any time during the study for any reason (except 
death or lost to follow-up) SFU visit will take place 30-35 days after the last administration 
of study drug. This visit includes:
QoL questionnaire (FLymSI-18): at the start of a visit, before the patient sees the physician. 
To be completed by ePRO device (see Section 7.6.2).
[...]
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.
New text:
7.1.2.5 Follow-up periods (new level 4 heading added)
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 
Safety follow-up, Active follow-up or Survival follow-up (e.g. for a DMC meeting or data 
analysis). 
7.1.2.5.1 Safety follow-up (changed to level 5 heading)
If a patient discontinues study treatment at any time during the study for any reason (except 
death or lost to follow-up) SFU visit will take place 30-35 days after the last administration 
of study drug. This visit includes:
QoL questionnaire (FLymSI-18): Patient completes the questionnaire at the start of a visit, 
before the patient sees the physician. To be completed by ePRO device (see Section 7.6.2).
[...]
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. In this case, 
FLymSI-18 questionnaire does not need to be completed at the SFU evaluation.


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13.1.2.38 Section 7.1.2.5.3 Survival follow-up
Old text:
7.1.2.6 Survival follow-up
All patients will be followed off study for overall survival at 3-month intervals during the 
Survival follow-up period (up to 3 years after the last patient started study treatment), 
independent of the reason for study termination, except for patients who object to follow-up 
data collection. Patients or their healthcare providers will be contacted either in person or by 
telephone.
[...]

Documentation of the first new anticancer treatment regimen, if given.
New text:
7.1.2.5.3 Survival follow-up (changed to level 5 heading)
All patients will be followed off study for overall survival at least at 3-month intervals during 
the Survival follow-up period (up to 3 years after the last patient started study treatment), 
independent of the reason for study termination, except for patients who object to follow-up 
data collection. Patients or their healthcare providers will be contacted either in person or by 
telephone.
[...]

Documentation of the first new anticancer treatment regimen including response, if 
given.
13.1.2.39 Section 7.2.2 Medical history
Old text:

History of anticancer treatments (including type of treatment, type of response, date of 
response and date of subsequent relapse) 
New text:

History of anticancer treatments (including type of treatment, type of response, date 
and duration of response and date of subsequent relapse) 


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13.1.2.40 Section 7.3.2 Radiological tumor assessments
Old text:
Radiological tumor assessments with IV contrast-enhanced CT/MRI will include neck, chest, 
abdomen and pelvis, and will be evaluated locally at the study site and by the central 
independent blinded review. 
The first radiological (IV contrast-enhanced CT/MRI) tumor assessment will be performed at 
Screening. Corticosteroids must be stopped or reduced to the allowed dose (less than 15 mg of 
prednisone or equivalent) at least 7 days before performing the CT/MRI (if a patient is on 
chronic corticosteroid therapy, corticosteroids should be de-escalated to the maximum 
allowed dose before the Screening). Tumor scans done up to 28 days prior to first dose can be 
used as baseline. The method chosen at the baseline must be the same throughout the study.
During the treatment phase as well as during the Active follow-up period, radiological (IV 
contrast-enhanced CT/MRI) tumor assessment will be performed every 12 weeks (±7 days)
during Year 1, every 16 weeks (±7 days) during Year 2, and every 24 weeks (±7 days) during 
Year 3. CT/MRI scans are not required at the EOT visit if the patient discontinues due to PD 
which has been radiologically confirmed within the 4 weeks preceding EOT. The response 
assessment will be done according to the Revised Response Criteria for Malignant 
Lymphoma (1). For patients with WM, additional criteria apply. Detailed instructions on 
tumor assessment are provided in Appendix 14.1. As long as the patient has not experienced 
PD, investigator’s assessment is sufficient for case management. In the event of progression, 
radiological real-time confirmation by central independent blinded evaluation is required 
before a final decision to stop the treatment is made. The final evaluation of treatment 
response (best response: ORR and CRR) will be done by central blinded review 
retrospectively.
Patients who experience PD on placebo treatment (per central independent blinded radiology 
review) can be offered open-label copanlisib upon discretion of the investigator and patient’s 
consent. After individual patient unblinding, patients receiving placebo who switch to open-
label copanlisib will have tumor assessments reset to the initial schedule as if the patient was 
restarting the study at Cycle 1 Day 1.
The same technique (e.g., slice thickness, field of view) should be used for all scans during 
the study treatment period. Preferably all scans should be interpreted by the same 
investigator/radiologist during the study whenever possible. CT/MRI scans must meet the 
standard of care for imaging of lesions in the respective organ system(s). If IV contrast-
enhanced CT is medically contraindicated, sites may acquire contrast-enhanced MRI of the 
neck, abdomen and pelvis, and an unenhanced CT of the chest above lung apices to the 
bottom of the adrenals. Chest CT is preferred. If a patient develops contra-indication to any 
contrast medium during the study, the case examinations should be continued without 
contrast.
A prospective planned central image evaluation by independent radiology experts will be 
performed independent from the conduct of the clinical part of the study in order to facilitate 
an independent evaluation of efficacy in this study. The independent reviewers will be 


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experienced radiologists, who will not have been involved in the clinical part of the study and 
are considered independent from the study. They will be blinded to patient data (excluding 
those which are specified in the Independent Review Charter, e.g. for bone marrow biopsy, 
presence of organomegaly, presence of B symptoms). The primary efficacy variable will be 
analyzed based on the assessment of the central image evaluation, as outlined in the imaging 
manual (or charter).
New text:
Radiological tumor assessments with IV (and oral, if indicated, per Imaging Manual) contrast-
enhanced CT/MRI will include neck, chest, abdomen and pelvis, and will be evaluated locally 
at the study site and by the central independent blinded review.
The first radiological (IV [and oral, if indicated, per Imaging Manual] contrast-enhanced 
CT/MRI) tumor assessment will be performed at Screening (including WM patients). 
Corticosteroids must be stopped or reduced to the allowed dose (less than 15 mg of 
prednisone or equivalent) at least 7 days before performing the screening CT/MRI (if a patient 
is on chronic corticosteroid therapy, corticosteroids should be de-escalated to the maximum 
allowed dose before the Screening). The method chosen at the baseline must be the same 
throughout the study.
During the treatment phase as well as during the Active follow-up period, radiological (IV 
[and oral, if indicated, per Imaging Manual] contrast-enhanced CT/MRI) tumor assessment 
will be performed every 12 weeks during Year 1, every 16 weeks during Year 2, and every 
24 weeks during Year 3 (see Section 7.1.2.3). CT/MRI scans are not required at the EOT visit 
if the patient discontinues due to PD which has been radiologically confirmed within the 4 
weeks preceding EOT.
At each tumor assessment during the course of the study (from baseline to EOT and during 
Active follow-up if applicable) radiological measurement of spleen vertical length (from 
cranial to caudal) must be performed and reported. 
The response assessment will be done according to the Lugano Classification (21). As long as 
the patient has not experienced PD, investigator’s assessment is sufficient for case 
management. In the event of progression, radiological real-time confirmation by central 
independent blinded evaluation is required before a final decision to stop the treatment is 
made. In case of uncertain radiological disease progression the patient may stay on treatment 
at the investigator’s discretion until progression is definitely confirmed on the subsequent 
tumor assessment. The final evaluation of treatment response (best response: ORR and CRR) 
will be done by central blinded review retrospectively.
For patients with WM, response assessment will be performed according to the Owen criteria
(22). However, CT scan will be done and collected for all patients according to the schedule 
specified in the protocol. According to this guidance, disease progression can be confirmed 
based on laboratory parameters. In such case when PD was assessed by an investigator based 
on laboratory parameters alone, no independent confirmation of PD by central independent 
blinded review is necessary. Site must notify the sponsor about disease progression and 
follow procedures outlined in the protocol for patients on study and control arm respectively. 
For patients with WM who had measurable disease at baseline and had PD assessed based on 


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CT scan, scans must be submitted for review to confirm disease progression by central 
blinded review.
Detailed instructions on tumor assessment are provided in Appendix 14.1.
Patients who experience PD on placebo treatment (per central independent blinded radiology 
review) can be offered open-label copanlisib upon discretion of the investigator and patient’s 
consent. After individual patient unblinding, patients receiving placebo who switch to open-
label copanlisib will have tumor assessments reset to the initial schedule as if the patient was 
restarting the study at Cycle 1 Day 1. For further instructions please refer to the Imaging 
Manual.
The same technique (e.g., slice thickness, field of view) should be used for all scans during 
the study treatment period. Preferably all scans should be interpreted by the same 
investigator/radiologist during the study whenever possible. CT/MRI scans must meet the 
standard of care for imaging of lesions in the respective organ system(s). If IV (or oral)
contrast-enhanced CT is medically contraindicated, sites may acquire contrast-enhanced MRI 
of the neck, abdomen and pelvis, and an unenhanced CT of the chest above lung apices to the 
bottom of the adrenals. Chest CT is preferred. If a patient develops contra-indication to any 
contrast medium during the study, the case examinations should be continued without 
contrast. In certain countries MRI should be used based on local regulations.
A prospective planned central image evaluation by independent radiology experts will be 
performed independent from the conduct of the clinical part of the study in order to facilitate 
an independent evaluation of efficacy in this study. All scans obtained for Screening, 
treatment period and Active follow-up including unscheduled scans should be forwarded to 
the designated Imaging Core Laboratory for central review. 
The independent reviewers will be experienced radiologists, who will not have been involved 
in the clinical part of the study and are considered independent from the study. They will be 
blinded to patient data (excluding those which are specified in the Independent Review 
Charter, e.g. for bone marrow biopsy). The primary efficacy variable will be analyzed based 
on the assessment of the central image evaluation, as outlined in the imaging manual (or 
charter).
13.1.2.41 Section 7.4 Pharmacokinetics / pharmacodynamics
Old text:

Cycle 1 Day 8: 
Pre- infusion, 5 to 15 min, 55 min (within 5 min prior to end of infusion) and 
1.5 to 5 h after start of 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.

At centers with adequate facilities and equipment: additional PK samples will be 
drawn after 12-lead ECG recordings at:


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o
Cycle 1 Day 1:
Pre-infusion and end of infusion (within 5 min prior to the end of infusion).
o
Cycle 3, 6, 9 etc. Day 15 (every 3rd cycle):
Pre-infusion and end of infusion (within 5 min prior to the end of infusion).
Patients who experience PD on placebo treatment (per blinded central independent blinded 
radiology review) can be offered open-label copanlisib upon discretion of the investigator and 
patient’s consent.
New text:

Cycle 1 Day 8: 
Pre- infusion, 5 to 15 min, 55 min (or within 5 min prior to end of infusion) and 
1.5 to 5 h after start of 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.
Patients who experience PD on placebo treatment (per blinded central independent blinded 
radiology review) can be offered open-label copanlisib upon discretion of the investigator and 
patient’s consent.
13.1.2.42 Section 7.5.3 Further safety
Old text:
The following assessments should be performed both in patients on double-blinded study 
treatment (copanlisib or placebo) as well as those who are randomized to placebo and change 
to copanlisib. After individual patient unblinding, patients receiving placebo who switch to 
open-label copanlisib will have all study assessments and timing reset to the initial schedule 
of study evaluations (i.e. as if the patient was restarting the study at Cycle 1 Day 1). 
New text:
The following assessments should be performed both in patients on double-blinded study 
treatment (copanlisib or placebo) as well as those who are randomized to placebo and change 
to copanlisib. After individual patient unblinding, patients receiving placebo who switch to 
open-label copanlisib will have all study assessments and timing reset to the initial schedule 
of study evaluations (i.e. as if the patient was restarting the study at Cycle 1 Day 1). If not 
previously done within 7 days, patients switching to open-label copanlisib must complete the 
following within 7 days prior to the first dose of open-label copanlisib: UPCR measurement, 
GFR measurement, urinalysis, HbA1c, CBC, chemistry and coagulation panels. Dosing 
criteria outlined in Table 6-2 apply also for patients who switch to open-label treatment.


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13.1.2.43 Section 7.5.3.1 Laboratory
Old text:
All laboratory analyses will be performed locally. Dipsticks will be provided to be used for 
urinalysis.
[...]

Complete chemistry panel: calcium, sodium, potassium, chloride, phosphorus, 
magnesium, bicarbonate (or carbon dioxide if bicarbonate is not routinely measured at 
the site), total protein, albumin, glucose, blood urea nitrogen (BUN) (or urea if BUN is 
not routinely measured at the site), serum creatinine (SCR), uric acid, total bilirubin, 
creatine phosphokinase, alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), lipase, amylase (or 
pancreatic amylase if total amylase is not routinely measured at the site), cholesterol 
(total, high-density lipoprotein [HDL], low-density lipoprotein [LDL]) and 
triglycerides.
[...]

Urinalysis: turbidity, blood cells, glucose, ketones, bilirubin, protein, and pH 
(dipstick).
Additional microscopic examinations will be performed if clinically indicated.

Quantification of proteinuria by UPCR on a random urine sample preferably taken at 
mid-morning. This should be reported as the ratio of concentrations of total urine 
protein (in mg/dl) to urine creatinine (in g/dl).
New text:
All laboratory analyses will be performed locally. Dipsticks should be available for urinalysis.
[...]

Complete chemistry panel: calcium, sodium, potassium, chloride, phosphorus, 
magnesium, bicarbonate (or carbon dioxide if bicarbonate is not routinely measured at 
the site), total protein, albumin, glucose, blood urea nitrogen (BUN) (or urea if BUN is 
not routinely measured at the site), serum creatinine (SCR), uric acid, total bilirubin, 
creatine phosphokinase, alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), lipase, amylase (or 
pancreatic amylase if total amylase is not routinely measured at the site), cholesterol 
(total, low-density lipoprotein [LDL]) and triglycerides.
[...]

Urinalysis: blood cells, glucose, ketones, bilirubin, protein, and pH (dipstick).
Additional microscopic examinations will be performed if clinically indicated.

Quantification of proteinuria by UPCR on a random urine sample preferably taken at 
mid-morning. This should be reported as the ratio of concentrations of total urine 
protein (in mg/dl) to urine creatinine (in mg/dl).


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13.1.2.44 Section 7.5.3.2 Physical examinations
Old text:
New text:
Physical examinations will be performed according to the schedule summarized in the flow 
chart of Section 7.1.
13.1.2.45 Section 7.5.3.2.1 Complete physical examination
Old text:
Physical examinations will be performed according to the schedule summarized in the flow 
chart of Section 7.1 (sentence transferred to 7.5.3.2).
Complete physical examination includes ECOG performance status assessment (see grading 
definitions in Appendix 14.3), NYHA classification (see Appendix 14.4), height (only at 
Screening), weight, vital signs (see Section 7.5.3.3), and complete review of body systems 
(including physical examination for lymphadenopathy, abdominal masses, or organomegaly).
New text:
Complete physical examination includes ECOG performance status assessment (see grading 
definitions in Appendix 14.3), NYHA classification (see Appendix 14.4), height (only at 
Screening), weight, vital signs (see Section 7.5.3.3), and complete review of body systems.
13.1.2.46 Section 7.5.3.3 Vital signs
Old text:

Blood pressure will be measured every 5-10 min prior to infusion of study drug (no 
more than 4 measurements) until there are 2 consecutive results < 150/90 mmHg. If 
blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention 
or delaying the infusion of study drug. The patient should lie down for 5-10 min 
before blood pressure is recorded.
o
At Cycle 1 Day 1 blood pressure will be measured at 0 h (pre-dose), 30 min 
(mid-infusion), 60 min (end of infusion), 90 min, 2 h, 3 h, 4 h and 6 h after the 
start of infusion (deviation ±5 min).


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o
From Cycle 1 Day 8 onwards a single blood pressure measurement is to be 
performed prior to each infusion, 30 min after the start of infusion and at the 
end of each infusion.
New text:

Blood pressure will be measured every 5-10 min prior to infusion of study drug (no 
more than 4 measurements) until there are 2 consecutive results < 150/90 mmHg. If 
blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention 
or delaying the infusion of study drug. The patient should rest for 5-10 min before 
blood pressure is recorded.
o
At Cycle 1 Day 1 blood pressure will be measured at 0 h (pre-dose), 30 min 
(mid-infusion), 60 min (end of infusion), 90 min, 2 h, 3 h, 4 h and 6 h after the 
start of infusion (deviation ±5 min).
o
From Cycle 1 Day 8 onwards a single blood pressure measurement is to be 
performed prior to each infusion, 30 min after the start of infusion and at the 
end of each infusion (deviation ±5 min).
13.1.2.47 Section 7.5.3.4 12-lead ECG
Old text:
The patient should lie down for 10 min before the ECG is recorded.
New text:
The patient should rest for 10 min before the ECG is recorded.
13.1.2.48 Section 7.6.1 Biomarker investigations
Old text:
There will be several parts to biomarker testing in this study:
1. Tumor-genetic research of fresh (preferred) or archival tumor tissue
2. Non-genetic biomarker testing
3. Genetic biomarker research
[...]


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Collection and use of biomarker specimens
Tumor Tissue (mandatory):

Fresh tumor tissue (preferred) will be collected between Day -28 and Day -8 prior to 
the start of study treatment. Fresh tissue is recommended in patients with clinical 
suspicion of transformed disease. Detailed guidance on fresh biopsy sample 
preparation and storage will be provided to the sites.

A sample of archival tumor tissue will be requested during Screening if fresh tissue is 
not available (the latest biopsy available should be provided). Archival formalin-fixed 
paraffin-embedded (FFPE) tissue may be supplied as a block (preferred) or as precut 
slides. Details on the preparation of slides and number of slides to be prepared will be 
described in separate documents (e.g. Sample Handling Sheets or laboratory manual). 
All tumor tissues may be used as a source of RNA or protein for the study of gene and protein 
expression. The tumor tissue may in addition be used as a source of tumor DNA for the 
evaluation of tumor-associated alterations in genes of interest (e.g., PIK3CA and genes 
associated with NHL). This DNA evaluation may also be performed on the archival tumor 
tissue.
Plasma for genetic biomarker analysis: Blood samples will be obtained and used for plasma 
preparation at the time points as indicated in the study flow chart (see Table 7-1). Plasma may 
be used as a source of circulating tumor DNA for the evaluation of mutations in tumor-related 
genes of interest.
[...] 
Blood (only applicable for patients who provided ‘genetic’ research consent): On Cycle 1 
Day 1, a whole blood sample will be obtained. The blood sample will be used as a source of 
DNA and gene products for the evaluation factors that are associated with the drug or the 
pathomechanisms of the disease. Results will be reported under separate cover, if the 
evaluations are performed.
Patients who experience PD on placebo treatment (per blinded central independent blinded 
radiology review) can be offered open-label copanlisib upon discretion of the investigator and 
patient’s consent. After individual patient unblinding, patients receiving placebo who switch 
to open-label copanlisib will have biomarker assessments reset to the initial schedule as if the 
patient was restarting the study at Cycle 1 Day 1.
New text:
There will be several parts to biomarker testing in this study:
1. Tumor-genetic research of fresh (preferred) or archival tumor tissue, and possibly 
of circulating tumor DNA isolated from plasma.
2. Non-genetic biomarker testing
3. Genetic biomarker research
[...]


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Collection and use of biomarker specimens
Tumor Tissue:
Tumor tissue collection will be mandatory at Screening for central pathology review. Patients 
without historical material or fresh tissue biopsy will not be eligible for randomization.
In addition, one or more of the following pre-treatment tumor tissue samples will be collected 
during Screening when available with the purpose of investigating or identifying biomarkers 
that may be predictive of copanlisib effects/efficacy in NHL and to contribute to better 
understanding the disease. 

Submission of archival tumor tissue from a biopsy performed within 180 days before 
signing of the informed consent.

Submission of fresh tissue from a biopsy performed during Screening (between 
Day -28 and Day -8 prior to the start of study treatment) is highly encouraged when 
the above is not available.

In the absence of either of the above, submission of an older archival tumor tissue 
sample (collected prior to 180 days before signing of the informed consent) is 
mandatory when available.
A tumor biopsy is also encouraged at the time of progression (optional) to allow investigation 
of copanlisib resistance. In addition, if a tumor biopsy/excision occurs during the course of 
the study based on medical need, a sample should be submitted (though no biopsy is required 
during treatment).
Archival formalin-fixed paraffin-embedded (FFPE) tissue may be supplied as a block 
(preferred) or as precut slides. Details on the preparation of slides and number of slides to be 
prepared as well as detailed guidance on fresh biopsy sample preparation and storage will be 
described in separate documents (e.g. Sample Handling Sheets or laboratory manual).
All tumor tissues may be used as a source of RNA or protein for the study of gene and protein 
expression. The tumor tissue may in addition be used as a source of tumor DNA for the 
evaluation of tumor-associated alterations in genes of interest (e.g., PIK3CA and genes 
associated with NHL).
Plasma for tumor genetics biomarker analysis: Blood samples will be obtained and used 
for plasma preparation at the time points as indicated in the study flow chart (see Table 7-1). 
Plasma may be used as a source of circulating tumor DNA for the evaluation of mutations in 
tumor-related genes of interest.
[...] 
Whole blood (only applicable for patients who provided ‘genetic’ research consent): On 
Cycle 1 Day 1, a whole blood sample will be obtained. The blood sample will be used as a 
source of DNA and gene products for the evaluation factors that are associated with the drug 
or the pathomechanisms of the disease. Results will be reported under separate cover, if the 
evaluations are performed.


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Patients who experience PD on placebo treatment (per blinded central independent blinded 
radiology review) can be offered open-label copanlisib upon discretion of the investigator and 
patient’s consent. After individual patient unblinding, patients receiving placebo who switch 
to open-label copanlisib will have biomarker plasma sampling analogous to the initial 
schedule as if the patient was restarting the study at Cycle 1 Day 1.
13.1.2.49 Section 7.6.2 Quality of life questionnaire
Old text:
The main purpose of the symptom assessment in this study is to describe any differences 
between the treatment groups in the time to deterioration in disease-related symptoms –
physical (DRS-P) ≥3 points.
[...]
A patient-reported outcome (PRO) information sheet will be provided and completed by the 
study nurse/investigator at each visit at which the FLymSI-18 questionnaire is to be 
administered, regardless of whether or not the FLymSI-18 questionnaire is completed by the 
patient. This is to document information such as questionnaire completion, date of 
completion, and reasons for non-completed questionnaires.
New text:
The main purpose of the symptom assessment in this study is to describe any differences 
between the treatment groups in the time to deterioration and in time to improvement in 
disease-related symptoms – physical (DRS-P) at least 3 points.
[...]
A patient-reported outcome (PRO) information sheet will be provided and completed by the 
study personnel at each visit at which the FLymSI-18 questionnaire is to be administered, 
regardless of whether or not the FLymSI-18 questionnaire is completed by the patient. This is 
to document information such as questionnaire completion, date of completion, and reasons 
for non-completed questionnaires.
13.1.2.50 Section 7.6.3 Electronic patient-reported outcomes evaluation
Old text:
ePRO devices will be implemented in this study. They will be used to complete the FLymSI-
18 questionnaire and, if needed, may be used to collect data on home blood glucose 
measurements/insulin doses. A Site Manual will be provided to sites and each patient to help 
them understand how the ePRO devices work and how to use them correctly. If, for any 
reason, a device is not available at the site, or technical problems prevent it from working 
properly, a paper PRO questionnaire may be used.
New text:


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ePRO devices will be implemented in this study. They will be used to complete the FLymSI-
18 questionnaire. A Site Manual will be provided to sites and each patient to help them 
understand how the ePRO devices work and how to use them correctly. If, for any reason, a 
device is not available at the site, or technical problems prevent it from working properly, a 
paper PRO questionnaire may be used.
13.1.2.51 Section 7.7 Appropriateness of procedures / measurements
Old text:
The efficacy assessments used in this study include those considered standard of care to 
evaluate objective tumor response rate in patients with iNHL. For patients affected by WM, in 
order to harmonize the response assessment allowing integration into the primary endpoint 
analysis, instead of using the Response Categories published by the VIth International 
Workshop on WM (26) it was decided to adapt the categorical response definitions only for 
complete response (CR), partial response (PR), stable disease, relapsed disease/disease 
progression (RD/PD) including the serum IgM response, and to eliminate the very good 
partial response (VGPR) and the minor response (MR) categories.
The safety assessments are appropriate and standard to monitor safety and assess toxicity.
New text:
The efficacy assessments used in this study include those considered standard of care to 
evaluate objective tumor response rate in patients with iNHL. Although the recently published 
Lugano Classification (21) strongly support the use of PET-CT for staging and response 
assessment of routinely FDG-avid histologies, especially in clinical trials, it was decided to 
use in this study only a CT-based response. CT/MRI-based response remains in fact preferred 
for histologies with low or variable FDG avidity and in regions of the world where PET-CT is 
unavailable. Moreover, in trials exploring new agent in multiply relapsed disease where data 
are lacking regarding PET-CT and where assessment of disease control is more important 
than likelihood of cure, CT/MRI-based response may also be more relevant.
The safety assessments are appropriate and standard to monitor safety and assess toxicity.
13.1.2.52 Section 8.1 General considerations
Old text:
Statistical analyses will be conducted by or under the supervision of the sponsor’s Study 
Statistician, except for the analysis of biomarker data, which will be performed by the 
sponsor’s Genomics and Biomarker Statistical Expert. Statistical analyses will be performed 
using Statistical Analysis System (SAS); the version used will be specified in the statistical 
analysis plan (SAP).
Further details on the statistical analyses will be provided in the SAP that will be approved 
before database release. 


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New text:
Statistical analyses will be conducted by or under the supervision of the sponsor’s Study 
Statistician, except for the analysis of biomarker data, which will be performed by or under 
the direction of the sponsor’s Genomics and Biomarker Statistical Expert. Statistical analyses 
will be performed using Statistical Analysis System (SAS); the version used will be specified 
in the statistical analysis plan (SAP).
Further details on the statistical analyses including handling of missing data will be provided 
in the SAP that will be approved before database release. 
13.1.2.53 Section 8.3.1.2 Secondary efficacy variables
Old text:
Objective tumor response rate (ORR) assessed in all patients up to the time of analysis of 
PFS. ORR is defined as the proportion of patients who have a best response rating over the 
whole duration of the study (i.e. until the time of analysis of PFS) of complete response (CR) 
or partial response (PR) according to the Revised Response Criteria for Malignant 
Lymphoma (1). For patients with WM, additional criteria apply. Detailed instructions on 
tumor assessment are provided in Appendix 14.1.
Duration of response (DOR), defined as the time (in days) from first observed tumor 
response (CR or PR) until PD or death from any cause, whichever is earlier. DOR will only be 
defined for patients with at least one CR or PR. Patients without PD or death at the time of 
analysis will be censored at the date of their last tumor evaluation.
[...]
Time to deterioration in disease-related symptoms – physical (DRS-P) ≥3 points, as 
measured by the FLymSI-18 questionnaire. Patients will be considered as “censored” on their 
last day of visit, if the reason for stopping treatment is not related to PD. Patients dropping out 
due to progression-related reason or experiencing a PD event or death due to any reason will 
be considered as having had their decline in DRS-P on the day of dropout/progression. 
Further sensitivity analyses will be described in the SAP (e.g. might involve different 
handling of the last response status for that patient or considering PD and death as censored). 
Considering ≥3 points decline to be an important change with regard to DRS-P is the current 
assessment. The important change for DRS-P is however under continuing research by the 
developer of the questionnaire. Therefore, the value of 3 points might be updated in the SAP, 
considering forthcoming research findings.
New text:
Objective tumor response rate (ORR) assessed in all patients up to the time of analysis of 
PFS. ORR is defined as the proportion of patients who have a best response rating over the 
whole duration of the study (i.e. until the time of analysis of PFS) of complete response (CR) 
or partial response (PR) according to theLugano Classification (21), and for patients with 
WM, a response rating of CR, very good partial response (VGPR), PR, or minor response


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(MR) according to the Owen criteria (22). Detailed instructions on tumor assessment are 
provided in Appendix 14.1.
Duration of response (DOR), defined as the time (in days) from first observed tumor 
response (CR, VGPR, PR or MR) until PD or death from any cause, whichever is earlier. 
DOR will only be defined for patients with at least one CR, VGPR, PR or MR. Patients 
without PD or death at the time of analysis will be censored at the date of their last tumor 
evaluation.
[...]
Time to deterioration in disease-related symptoms – physical (DRS-P) of at least 
3 points, as measured by the FLymSI-18 questionnaire. Patients will be considered as 
“censored” at the date of their last tumor evaluation, if the reason for stopping treatment is not 
related to PD. Patients dropping out due to progression-related reason or experiencing a PD 
event or death due to any reason will be considered as having had their decline in DRS-P at 
the date of their last tumor evaluation. Due to the symptom-related inclusion criteria (i.e. 
ECOG performance status ≤ 1), a worsening of symptoms can potentially occur in all patients. 
Therefore all patients will be included into this analysis.
Time to improvement in DRS-P of at least 3 points, as measured by the FLymSI-18 
questionnaire, will be evaluated for patients with a baseline DRS-P score of 30 points or less 
(i.e. patients who still have room for improvement in symptoms). Patients will be considered 
as "censored" at the date of their last tumor evaluation, if the reason for stopping treatment is 
not related to PD. Patients dropping out due to progression-related reason or experiencing a 
PD event or deaths due to any reason will be considered censored at the largest observation 
time (of events and censoring in all subjects evaluated for improvement), plus 1 day.
Further sensitivity analyses for the DRS-P will be described in the SAP (e.g. might involve 
different handling of the last response status for that patient or considering PD and death as 
censored). Considering at least 3 points decline or increase, respectively, to be an important 
change with regard to DRS-P is the current assessment. The important change for DRS-P is 
however under continuing research by the developer of the questionnaire. Therefore, the value 
of 3 points might be updated in the SAP, considering forthcoming research findings.
13.1.2.54 Section 8.3.1.3 Other efficacy variables
Old text:

AUC across all data of FLymSI-18 DRS-P subscale score.
New text:

PFS2 defined as the time (in days) from first PD after start of study treatment to 
second PD (both assessed by central review) or death from any cause (if no 
progression is documented). PFS2 will be evaluated only in placebo-treated patients 
who switched to open-label copanlisib treatment after first PD.

AUC across all data of FLymSI-18 DRS-P subscale score.


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13.1.2.55 Section 8.4.1 Population characteristics
Old text:
Demographics and baseline characteristics will be summarized by treatment and total 
population, using descriptive statistics and frequency tables as appropriate. 
New text:
Demographics and baseline characteristics will be summarized by treatment and total 
population, using descriptive statistics and frequency tables as appropriate. In addition, the 
same summaries will be provided separately by FL and other iNHL subgroups.
13.1.2.56 Section 8.4.2 Efficacy
Old text:
All efficacy analyses will be performed when approximately 74 centrally evaluated PFS 
events are observed in the study (see Section 8.6). Evaluations from central blinded review 
will be used for the primary efficacy analyses of primary and secondary variables containing 
radiological tumor assessments. All statistical tests will be one-sided, with a significance level 
of alpha = 0.01.
New text:
All efficacy analyses will be performed when approximately 82 centrally evaluated PFS 
events are observed in the FL subgroup (see Section 8.6). Evaluations from central blinded 
review will be used for the primary efficacy analyses of primary and secondary variables 
containing radiological tumor assessments.
The study-wise alpha of 1% will initially be split, according to the test strategy for this study 
(see Figure 8-1): with 80% * 1% = 0.8% assigned to the one-sided PFS test in the FL 
subgroup, and 20% * 1% = 0.2% to the one-sided PFS test in the total study population.
13.1.2.57 Section 8.4.2.1 Primary efficacy analysis
Old text:
Primary efficacy analysis
The primary efficacy variable is PFS as assessed by central review (for definition see 
Section 8.3.1.1). It will be evaluated whether PFS in copanlisib group is higher compared to 
PFS in the placebo group. 
The following null hypothesis will be tested:
H0, PFS: SCopanlisib(t) = SPlacebo(t) for all time points t ≥ 0
The alternative hypothesis will be:
H1,PFS: SCopanlisib(t) > SPlacebo(t) for at least one time point t ≥ 0, and


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SCopanlisib(t) ≥SPlacebo(t) for all time points t ≥ 0,
where SCopanlisib denotes the survival function of the copanlisib group and SPlacebo denotes the 
survival function of the placebo group.
The following decision rule to test the null hypothesis will be applied:
According to the size of this study it is justified to assume under H0, PFS sufficient close 
approximation of the one-sided log-rank test (27) to the normal distribution. If the z-value 
from the one-sided log-rank test (for the difference SCopanlisib - SPlacebo, stratified by the same 
factors as used for randomization) is larger than the critical quantile from the normal 
distribution (z0.99 = 2.33), the null hypothesis will be rejected in favor of the alternative 
hypothesis. 
Additional analyses of the primary efficacy variable
Kaplan-Meier estimates of median times to PFS (including 98% confidence interval) and 
Kaplan-Meier curves will be presented for each treatment group.
The hazard ratio (including 98% confidence interval) will be derived from a Cox proportional 
hazards model and stratified by the same factors as used for randomization.
[...]
Fixed sequence test hierarchy
If the null hypothesis in the primary efficacy variable is rejected, a fixed sequence testing of 
the secondary efficacy variables ORR and time to ≥ 3 points deterioration in DRS-P subscale 
of FLymSI-18 will be performed. 
In case of success in the primary efficacy variable, the first secondary endpoint being tested in 
this sequence will be ORR. If this succeeds, the next and last endpoint in the hierarchy will be 
the time to ≥ 3 points deterioration in DRS-P subscale of FlymSI-18. In case of the first non-
successful p-value occurring, the hierarchical testing will stop. Further technical details of this 
sequence of tests will be included in the SAP.
OS, CRR, TTP as well as DOR will not be included into the testing hierarchy.
New text:
8.4.2.1 Primary efficacy analysis (level 4 heading added).
The primary efficacy variable is PFS as assessed by central review (for definition see 
Section 8.3.1.1). It will be evaluated whether PFS in the copanlisib group is higher compared 
to PFS in the placebo group for the total study population and separately for the FL subgroup.
The following null hypothesis will be tested:
H0, PFS: SCopanlisib(t) = SPlacebo(t) for all time points t ≥ 0
The alternative hypothesis will be:
H1,PFS: SCopanlisib(t) > SPlacebo(t) for at least one time point t ≥ 0, and


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SCopanlisib(t) ≥SPlacebo(t) for all time points t ≥ 0,
where SCopanlisib denotes the survival function of the copanlisib group and SPlacebo denotes the 
survival function of the placebo group in the total study population or the FL subgroup, 
respectively.
The following decision rule to test the null hypothesis will be applied:
According to the size of this study it is justified to assume that under H0, PFS the one-sided log-
rank test (28) is a sufficiently close approximation to the normal distribution. If the z-value 
from the one-sided log-rank test (for the difference SCopanlisib - SPlacebo, stratified by the same 
factors as used for randomization: FL vs. other iNHL histology [in the test for total study 
population only], the time between last course of systemic anticancer therapy and most recent 
progression [≤ 6 months vs. > 6 months] and previous treatment with PI3K inhibitors [yes vs. 
no]) is larger than the respective critical quantile from the normal distribution (for FL 
subgroup: z0.992 = 2.409, for the total study population: z0.998 = 2.878), the null hypothesis will 
be rejected in favor of the alternative hypothesis. 
Additional analyses of the primary efficacy variable
Kaplan-Meier estimates of median times to PFS (including 98% confidence interval) and 
Kaplan-Meier curves for the total study population and the FL subgroup will be presented for 
each treatment group.
The hazard ratio (including 98% confidence interval) will be derived for the total study 
population and separately for the FL subgroup from Cox proportional hazards models that are 
stratified by the same factors as used for the primary efficacy analysis. 
13.1.2.58 Section 8.4.2.2 Secondary efficacy analysis
Old text:
Secondary efficacy analysis
OS will be analyzed using stratified log-rank tests similar to that for the primary variable, 
PFS. In addition, statistical methods to include the time after change to copanlisib by placebo 
patients in an analysis of OS will be investigated. Further details will be included in the SAP.
For variables other than OS, the data collected after the change from placebo to copanlisib 
will be summarized separately.
TTP, DOR and time to decline in DRS-P of ≥3 points will be analyzed using stratified log-
rank tests similar to that for the primary variable, PFS.
ORR and CRR will be analyzed using the Cochran-Mantel-Haenszel test, adjusted for the 
same stratification factors as used for PFS.


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New text:
8.4.2.2. Secondary efficacy analysis (level 4 heading added).
Depending on study success in the primary efficacy variable in the FL subgroup the 
secondary efficacy variables ORR, time to deterioration and time to improvement in DRS-P 
subscale of FLymSI-18 of at least 3 points will be tested hierarchically in the FL subgroup 
according to the multiple testing strategy outlined in Figure 8-1.
If the study shows success in all secondary endpoints in the FL subgroup and in the primary 
efficacy endpoint for the total study population, then the secondary efficacy endpoints ORR, 
time to deterioration and time to improvement in DRS-P subscale of FLymSI-18 of at least 
3 points will also be tested hierarchically in the total study population.
Despite the initial split of study-wise alpha for the primary efficacy tests of PFS, the applied 
multiple test strategy includes the chance of so-called re-tests at full study-wise alpha-level of 
1% in certain cases. The details are described in Section 8.4.2.3 below.
The ORR will be analyzed using the Cochran-Mantel-Haenszel test (29), stratified for the 
same stratification factors as used for PFS. The null hypothesis is defined as:
H0, ORR: ORRCopanlisib ≤ ORRPlacebo
The alternative hypothesis will be:
H1, ORR: ORRCopanlisib > ORRPlacebo
The following decision rule to test the null hypothesis will be applied:
If the p-value for the two-sided Cochran-Mantel-Haenszel test is smaller than twice the 
available significance level for the respective test and the estimated difference ORRCopanlisib -
ORRPlacebo (comparing copanlisib vs. placebo) is greater than 0.0, the null hypothesis will be 
rejected in favor of the alternative hypothesis.
The time to deterioration and time to improvement in DRS-P subscale of FLymSI-18 will be 
analyzed analogously to the PFS, using similar hypotheses, decision rules, and significance 
level according to the testing strategy.
OS, CRR, TTP as well as DOR will not be included into the confirmatory testing strategy but 
analyzed supportively only.
OS will be analyzed using stratified log-rank tests similar to that for the primary variable, 
PFS. In addition, statistical methods to include the time after change to copanlisib by placebo 
patients in an analysis of OS will be investigated. Further details will be included in the SAP.
For variables other than OS, the data collected after the change from placebo to copanlisib 
will be summarized separately using descriptive statistics and frequency tables. Further details 
will be included in the SAP.
TTP, DOR, time to deterioration and time to improvement in DRS-P of at least 3 points will 
be analyzed using stratified log-rank tests similar to that for the primary variable, PFS.


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CRR will be analyzed using the Cochran-Mantel-Haenszel test analogous to the analysis of 
ORR. The test will be adjusted for the same stratification factors as used for PFS.
13.1.2.59 Section 8.4.2.3 Confirmatory statistical testing strategy
Old text:
Other efficacy evaluations
An additional analysis of the physical symptoms of lymphoma (as measured using the 
FLymSI-18 DRS-P subscale) will be performed to assess differences between treatment arms 
based on AUC. Total FLymSI-18 and subscales will be evaluated descriptively. Further
details on PRO data analysis will be provided in the SAP. 
ECOG performance status will be summarized using descriptive statistics for the original 
score, as well as for the change from baseline score by treatment group.
New text:
8.4.2.3 Confirmatory statistical testing strategy (level 4 heading added)
A graphical summary of the testing strategy is displayed in Figure 8-1, using methodology as 
outlined in "A graphical approach to sequentially rejective multiple test procedures" (30). 
Package "gMCP" for the statistical software R has been used for display (31, 32).
Figure 8-1
Confirmatory statistical testing strategy
FL = follicular lymphoma; ImpDRSP = improvement in disease-related symptoms – physical; ORR = objective 
tumor response rate; PFS = progression-free survival; total = total study population; WorseDRSP = worsening of 
disease-related symptoms – physical.
Note: This design involving ε is a technical construct to potentially allow propagation of alpha to 
secondary endpoints in the total study population, in case all FL secondary endpoints can be rejected. 
The amount ε will be close to zero, and will be exactly defined in the SAP.
PFS is tested in parallel in the FL subgroup (tested at significance level of 0.8%), and in the 
total study population (tested at significance level of 0.2%).


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The secondary endpoints in the FL subgroup and in the total study population, respectively, 
will only be tested if the test for the primary endpoint PFS is successful in the respective 
(sub-) population. A sequentially rejective multiple test procedure (30) will be used for the 
secondary efficacy endpoints in order to control the study-wise alpha level of 1%.
Tests on primary endpoint PFS in the FL subgroup and total study population
As the study is powered to show a success in the FL subgroup, the multiple testing strategy 
also reflects the priority of the FL subgroup by propagating alpha-level first to the FL 
subgroup. After a successful test in the FL subgroup, the alpha-level of 0.8% will be 
propagated to the secondary endpoints in the FL subgroup.
In case of a successful test of PFS in the total study population, the respective alpha-level of 
0.2% will be propagated to the test hierarchy in the FL subgroup except for an amount ε (with 
ε close to zero). The remaining proportion ε of available alpha of 0.2% will be propagated to 
the secondary endpoints in the total study population.
Test hierarchy in secondary endpoints
The secondary endpoints are tested hierarchically both within the FL subgroup and the total 
study population.
Within each (sub-) group, ORR is tested first, followed by worsening in DRS-P, followed by 
improvement in DRS-P according to the pre-defined test sequence.
If both the primary and all secondary efficacy endpoints within the FL subgroup are tested 
successfully, the respective alpha-level is then finally propagated to the test sequence in the 
total study population. This means that for all practical purposes, the secondary endpoints for
the total study population are only tested if all tests in the FL subgroup and the primary 
efficacy endpoint PFS in the total study population were successful.
Potential for re-tests
Therefore, re-tests at (practically) the full study-wise alpha level of 1% could occur, if either:
1. PFS test in the total study population is successful: Then the FL-related test hierarchy, 
starting from PFS in FL subgroup, can be re-tested at full alpha-level (except for the 
small ε part), or
2. Primary as well as all secondary assessments in the FL subgroup are successful: In this 
case, PFS and secondary efficacy hierarchy in the total study population can be tested 
at full alpha.
Other efficacy evaluations
PFS2 will be descriptively evaluated using Kaplan-Meier estimates for quantiles, including 
98% two-sided confidence intervals.


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An additional analysis of the physical symptoms of lymphoma (as measured using the 
FLymSI-18 DRS-P subscale) will be performed to assess differences between treatment arms 
both in the total study population and the FL subgroup based on AUC. Total FLymSI-18 and 
subscales will be evaluated descriptively. Further details on PRO data analysis will be 
provided in the SAP. 
ECOG performance status will be summarized using descriptive statistics for the original 
score, as well as for the change from baseline score by treatment group in the total study 
population and in the FL subgroup.
13.1.2.60 Section 8.4.2.4 Subgroup analyses
Old text:
This section is not included in the original protocol.
New text:
Countries will be combined into regions as US vs. Europe vs. rest of world in order to defined 
regional subgroups.
Subgroup analyses will include forest plots as well as treatment-interaction analyses, both for 
the region subgroups as well as further subgroups (e.g. based on stratification factors and/or 
baseline characteristics) and will be provided both for the primary efficacy endpoint as well as 
other relevant efficacy and/or safety endpoints.
As an efficacious result in the confirmatory multiple testing strategy in the FL subgroup could 
dominate the result for the total population, a pre-defined consistency assessment across 
iNHL subtypes will be pre-specified in the SAP.
13.1.2.61 Section 8.4.3 Safety
Old text:
Safety variables will be summarized by means of descriptive statistics and/or frequency tables 
as appropriate. Summaries will be given by treatment group and total. 
New text:
Safety variables will be summarized by means of descriptive statistics and/or frequency tables 
as appropriate. Summaries will be given by treatment group and total. Summaries will be 
provided for the total study population and separately for the FL subgroup.


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13.1.2.62 Section 8.6 Determination of sample size
Old text:
Sample size is based on the evaluation of the primary efficacy variable, PFS. 
Copanlisib versus placebo treatment groups will be compared.
For the placebo arm, a median PFS of 6 months is assumed, whereas the copanlisib arm will 
be considered to have a median PFS of 14 months.
The study is planned to detect a 132% increase in median PFS in copanlisib versus placebo 
comparison (i.e. to detect a hazard ratio of 0.43), using a stratified log-rank test. Statistical test 
is planned for 90% power and the alpha for the one-sided test is set to be 0.01. Randomization 
ratio will be 1:1 between the two treatment groups.
Using the software PASS 11, it was determined that this study can be evaluated after 
approximately 74 PFS events are observed.
To determine the number of patients required to reach this number of events, a drop-out rate 
of 20% (equally distributed among treatment arms and time), and an accrual time of 
12 months (including 6 month ramp-up phase for study site openings) with a maximum of 
10 month follow-up for last recruited patient was assumed.
PASS 11 calculations (assuming exponential distribution of events) resulted in a required 
number of 60 patients per group (total of 120 patients) for the study.
The required number of events is assumed to be reached after 22 months.
New text:
Sample size estimation is based on the evaluation of the primary efficacy variable, PFS, in the 
primary subgroup of follicular lymphoma (FL). Study recruitment will be closed as soon as 
the required number of evaluable FL patients is reached.
Copanlisib versus placebo treatment groups will be compared. The stratification factor NHL 
histology (FL vs. other iNHL) will be used to derive two subgroups of patients. Superiority of 
the copanlisib arm over the placebo arm will be tested for the total study population and 
separately for the FL subgroup. A study-wise alpha level of 1% will be used to show 
superiority in the FL subgroup and/or the total study population.
For the placebo arm, a median PFS of 6 months is assumed, whereas the copanlisib arm will 
be considered to have a median PFS of 14 months.
The study is planned to detect a 132% increase in median PFS in copanlisib versus placebo 
comparison (i.e. to detect a hazard ratio of 0.43), using a stratified log-rank test. 
Study-wise alpha level of 1% will be split in terms of the test strategy planned (see Figure 8-
1), performing the one-sided primary efficacy test (and successive test hierarchy) with an 
initial alpha level of 0.8% for FL subgroup, and an initial alpha of 0.2% for the one-sided 
efficacy test in PFS for the total study population. Depending on the outcome of the primary 
efficacy tests, respective alpha will be propagated to further hypotheses in accordance with 
the planned test procedure.


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Randomization ratio will be 2:1 between copanlisib group and placebo group, respectively.
Sample size justification for primary efficacy test on PFS in FL patients
Using the software PASS 11 and with the above assumptions (especially alpha level of 0.8%),
it was determined that this study can be evaluated after approximately 82 PFS events are 
observed in the FL subgroup to achieve a statistical power of 90% of observing a significant 
result in the primary efficacy test in the FL subgroup.
In case a re-test in the test strategy is possible, because the test of PFS in the total study 
population was significant at the 0.2% level, the power of showing success in PFS for FL 
patients would increase to 91.4%, which is not considered as an excessive overpowering.
To determine the number of FL patients required to reach this number of events, a drop-out 
rate of 20% (equally distributed among treatment arms and time), and an accrual time of
12 months (including 6 month ramp-up phase for study site openings) with a maximum of 
10 month follow-up for last recruited patient was assumed.
PASS 11 calculations (assuming exponential distribution of events) resulted in a required 
number of patients per group: approximately 96 patients in the copanlisib monotherapy arm 
and approximately 48 patients in the placebo arm (total of 144 FL patients) for the study.
Sample size assumptions for other iNHL patients
Recruitment will be open to several types of iNHL patients. The size of the other iNHL 
subgroup is expected to reach between 20% and 25% of overall patients. Inclusion of these 
patients in addition to FL subgroup was encouraged by advice from EMA Scientific Advice 
Working Party to seek significance in FL subgroup, but to not exclude other subtypes. 
Assuming 23% of patients in the total population have other iNHL histologies, we expect ~45 
other iNHL patients to also be included into the study.
The total study population will thus comprise approximately189 recruited patients.
Sample size justification for primary efficacy test on PFS in the total study population
Under comparable assumptions as for the FL subjects (but using alpha level of 0.2%), the 
power to detect a difference in PFS for the total study population will be 91.3%. In case the 
tests on primary and all secondary efficacy variables are significant in the FL subgroup, the 
total study population can be re-tested with the full study alpha of 1.0% in accordance with 
the test strategy. Under this assumption a power of 96.8% in the primary efficacy test for PFS 
in the total study population is achieved.
As an efficacious result in the FL subgroup could dominate the result for the total population, 
a pre-defined consistency assessment across iNHL subtypes will be pre-specified in the SAP.


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13.1.2.63 Section 11.2 Patient information and consent
Old text:
In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or patient’s clinical record must clearly show that informed 
consent was obtained prior to these procedures.
The ICF and any other written information provided to patients will be revised whenever 
important new information becomes available that may be relevant to the patient’s consent, or 
there is an amendment to the protocol that necessitates a change to the content of the patient 
information and/or the written ICF.
New text:
In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or patient’s clinical record must clearly show that informed 
consent was obtained prior to these procedures. Certain results from diagnostic testing 
performed as part of the standard of practice prior to the informed consent date and time may 
be used to fulfill screening criteria. This includes fresh tissue as noted in the protocol as well 
as results from CT/MRI scans, bone marrow sample, MUGA/echocardiogram and hepatitis 
testing which may also be used provided that they fall into the protocol-specified time 
window. Archival tissue obtained from the patients at any time during the course of their 
iNHL may also be used prior to the informed consent date and time if performed as part of the 
standard of practice. CT/MRI must also meet the quality standards of the Imaging Manual.
The ICF and any other written information provided to patients will be revised whenever 
important new information becomes available that may be relevant to the patient’s consent, or 
there is an amendment to the protocol that necessitates a change to the content of the patient 
information and/or the written ICF.
13.1.2.64 Section 12 Reference list
Old text:
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised 
response criteria for malignant lymphoma. J Clin Oncol. 2007;25:579-86.
New text:
FDA approves Zydelig for three types of blood cancers. FDA news release, Silver Spring, 
MD, USA, July 23, 2014.
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. 
Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and 
Non-Hodgkin Lymphoma: The Lugano Classification. J Clin Oncol. 2014.
Koch GG, Carr GJ, Amara IA, Stokes ME, Uryniak TJ. Categorical Data Analysis in 
Statistical methodology in the pharmaceutical sciences /edited by Berry DA, Marcel Dekker; 
1990.


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Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to sequentially rejective 
multiple test procedures. Stat Med. 2009;28:586-604.
Bretz F, Posch M, Glimm E, Klinglmueller F, Maurer W, Rohmeyer K. Graphical approaches 
for multiple comparison procedures using weighted Bonferroni, Simes or parametric tests. 
Biometrical Journal. 2011;53:894-913.
Rohmeyer K, Klinglmueller F, Bomkamp B. gMCP: Graph Based Multiple Test Procedures, 
R package version 0.8-5.2013. Available from: http://CRAN.R-project.org/package=gMCP.
13.1.2.65 Section 14.1 Evaluation of tumor response
Old text:
Tumor response will be evaluated according to Revised Criteria for Malignant Lymphoma.
Target Lesions 
(lymph node)
Target lesions 
(hepatic/splenic)
Non target 
lesions
Organ 
enlargement
New 
lesion
Bone 
marrow
B 
symptoms
CR
All normal
All disappeared
All normal
Normal size
No
Normal
If not 
assessable:
IHC 
negative
No
PR
Decrease ≥ 50% in 
the SPD
Decrease ≥ 50% in 
the SPD
All normal 
or Stable
Normal size 
or
Stable size
No
Not relevant
Not 
relevant
Stable 
disease
Increase < 50% or
decrease < 50% in 
the SPD
Increase < 50% or
decrease < 50% in 
the SPD
All Normal 
or Stable
Normal size 
or
Stable size
No
Not relevant
Not 
relevant
RD/PD
Increase ≥50% in 
the SPD from nadir
Increase ≥50% in 
the GTD of any 
single previously 
identified node with a 
short axis > 1 cm or, 
for nodes with short 
axis < 1 cm, increase 
≥ 50% in the GTD to 
a final GTD > 1.5 cm
Increase ≥ 50% in 
the SPD from nadir
Increase ≥50% in 
the GTD of any 
single previously 
identified nodule to 
a final size of at 
least 1.5 cm
New or 
increased
Increased 
size
Yes
Lymphoma 
infiltration 
(new or % 
increased 
respect to 
baseline)
Not 
relevant
CR = complete response; GTD = greatest transverse diameter; IHC = Immunohistochemistry; PD = 
progressive disease; PR = partial response; RD = relapsed disease; SPD = sum of the product of the 
diameters.
Source: (1)
Additional response criteria in patients affected by Waldenstrom macroglobulinemia (WM).


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CR
Absence of serum monoclonal IgM by immunofixation ; normal serum IgM level and 
negative bone marrow
PR
At least 50% reduction of serum monoclonal IgM from baseline
RD/PD
At least 25% increase of serum monoclonal IgM from the lowest nadir
Stable 
Disease
A less than 50% reduction and less than 25% increase of serum monoclonal IgM from 
baseline
CR = complete response; IgM = immunoglobulin M; PD = disease progression; PR = partial 
response; RD = relapsed disease.
Source: Adapted from (26)
New text:
Tumor response will be evaluated according to Recommendations for Initial Evaluation, 
Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano 
Classification (21).
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
No
Normal by 
morphology
If not 
assessable:
IHC 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 (=value 
over 13 cm)
No
Not relevant
SD
Decrease < 50% in the SPD 
from baseline
No criteria for PD
All normal or 
stable
Normal size or 
stable size
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 
and be > 13 cm 
Recurrent 
splenomegaly:
the splenic length 
must increase ≥ 2 cm 
from nadir length and 
be > 13 cm 
Progressive 
splenomegaly:
the splenic length 
must increase by > 
50% of the extent 
beyond normal at 
baseline (=value over 
13 cm)
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)
Lymphoma 
infiltration
(new or % 
increased 
respect to 
baseline)


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Target lesions
(nodal)
Target lesions
(extranodal)
Non-target
lesions
Spleen
New lesion
Bone marrow
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
Response criteria in patients affected by Waldenström macroglobulinemia (WM):
CR

Absence of serum monoclonal IgM by immunofixation AND normal serum IgM level

Complete resolution of extramedullary disease

Normal bone marrow
VGPR

IgM M protein still detectable by immunofixation BUT ≥ 90% reduction in serum 
IgM level from baseline

Complete resolution of extramedullary disease

No new sings/symptoms of active disease
PR

IgM M protein still detectable by immunofixation BUT ≥ 50% and < 90% reduction in 
serum IgM level from baseline

Reduction in extramedullary disease

No new signs/symptoms of active disease
MR

IgM M protein still detectable by immunofixation BUT ≥ 25% and < 50% reduction in 
serum IgM level from baseline

No new signs/symptoms of active disease
SD

IgM M protein still detectable by immunofixation BUT < 25% reduction and < 25% 
increase in serum IgM level from baseline

No new signs/symptoms of active disease
PD
After PR:

≥ 25% increase in serum IgM level from lowest nadir (an absolute value of 5 g/L is 
required if IgM level is the only criterion)
OR

Progression in clinical features (signs/symptoms) attributable to disease
After CR:

Reappearance of IgM M protein
OR

Recurrence of bone marrow involvement, extramedullary disease, symptoms 
attributable to disease
CR = complete response; IgM = immunoglobulin M; MR = minor response; PD = progressive 
disease; PR = partial response; SD = stable disease; VGPR = very good partial response
Source: Adapted from (22).


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13.1.2.66 Section 14.5 Glomerular filtration rate
Old text:
The formula is as follows:
GFR (mL/min/1.73m2) = k x 186 x SCR-1.154 x age-0.203
where k = 1 (men) or 0.742 (women), GFR indicates glomerular filtration rate, and serum 
creatinine level (SCR) is measured in mg/dL.
NOTE: This equation should be used only with those creatinine methods that have not been 
recalibrated to be traceable to isotope dilution mass spectroscopy (IDMS).
The above result should be multiplied by 1.212 for African-Americans.
New text:
The formula is as follows:
GFR (mL/min/1.73m2) = k x 186 x SCR-1.154 x age-0.203
where k = 1 (men) or 0.742 (women), GFR indicates glomerular filtration rate, and serum 
creatinine level (SCR) is measured in mg/dL.
NOTE: This equation should be used only with those creatinine methods that have not been 
recalibrated to be traceable to IDMS.
If standardized IDMS-traceable creatinine assay is used, please use the calculator provided in 
the following link: http://www.kidney.org/professionals/kdoqi/gfr_calculator.
The above result should be multiplied by 1.212 for African-Americans.


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13.2
Amendment 3
Amendment 3 is a global amendment dated 16 FEB 2016.
13.2.1
Overview of changes
13.2.1.1
Modification 1 – update of clinical experience with copanlisib
Introductory information on patients treated with copanlisib was updated based on most 
recent data. In addition, the results from copanlisib studies 12871 and 16349 part A were 
updated.
Sections affected by this modification: 1.1.2 Clinical experience, 1.3 Benefit-risk assessment
13.2.1.2
Modification 2 – clarification of rituximab-refractoriness assessment
Inclusion criterion related to rituximab-refractoriness was clarified. The modification was
done because protocol did not provide clear guidance on how the refractoriness assessment 
should be done and some sites were not able to tell whether their patients would qualify as 
“refractory to rituximab”.
Sections affected by this modification: Synopsis, 5.1.1 Inclusion criteria
13.2.1.3
Modification 3 – clarification of inclusion criterion related to WM 
patients
Clarification was added that WM patients who do not have radiologically measurable lesion 
should have a positive immunofixation test result in addition to elevated IgM levels 
(≥2 x ULN) at Screening to indicate the presence of IgM paraprotein. The modification was 
done because IgM level alone does not show that the protein is clonal. Immunofixation 
establishes that the elevated IgM is clonal and therefore a real paraprotein.
Sections affected by this modification: Synopsis, 5.1.1 Inclusion criteria
13.2.1.4
Modification 4 – modification of contraception and pregnancy testing
requirements
Text was added in the inclusion criteria to provide a detailed description of effective 
contraception and to provide definition of a woman of childbearing potential (WOCBP) and a 
post-menopausal state. In addition, it was clarified that the use of condoms by male patients is 
required unless the female partner is permanently sterile to ensure the effective contraception 
for males who appear to mainly confer risk to females (WOCBP) via exposure to copanlisib 
in seminal fluid. 
Serum pregnancy test was added to be performed at the EOT visit in countries where it is 
required by local regulations. The list of specific countries where pregnancy test is mandatory 
after Cycle 1 was removed to avoid confusion and to present a general statement applicable to 
all countries with such a requirement.


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These changes were made according to recommendations related to contraception and 
pregnancy testing in clinical trials by the Clinical Trial Facilitating Group.
Sections affected by this modification: 5.1.1 Inclusion criteria, 7.1.1 Tabulated overview, 
7.1.2.2.2 Treatment – Cycle 2 and higher, 7.1.2.4 End-of-treatment visit.
13.2.1.5
Modification 5 – modification of inclusion criterion related to 
laboratory requirements
The times of ULN requirement for blood total bilirubin during the evaluation of patient’s 
eligibility with proven Gilbert-Meulengracht syndrome were changed considering the study 
patient population with Gilbert-Meulengracht disease and due to feedback from the 
investigators.
Considering the copanlisib safety profile and the fact that serum lipase level alone is sufficient 
to diagnose pancreatitis, amylase was removed from the inclusion criterion since lipase is 
reported to have a higher sensitivity compared to amylase.
Inclusion criterion was updated to clarify that INR should be ≤ 1.5 at Screening. The 
modification was done because previous language (INR ≤ 1.5 x ULN) allowed patients with 
INR of 1.8 to be eligible.
Section affected by this modification: 5.1.1 Inclusion criteria.
13.2.1.6
Modification 6 – modification of exclusion criterion related to arterial 
hypertension 
The conservative requirement for blood pressure levels during the evaluation of patient’s 
eligibility was removed due to feedback from the investigators and lymphoma specialists. 
Appropriate blood pressure levels prior to study treatment and available prophylactic 
treatments are considered to be the most important safety points.
This exclusion criterion was also added to the synopsis as one of the main criteria for 
exclusion.
Sections affected by this modification: Synopsis, 5.1.2 Exclusion criteria
13.2.1.7
Modification 7 – exclusion of patients based on plasma glucose levels 
removed
Exclusion of patients with fasting plasma glucose > 160 mg/dL at Screening was removed to 
implement the advisory board recommendations. The rationale for this change was to 
eliminate the eligibility evaluation requirement for plasma glucose testing considering the 
study patient population and to ensure enrollment of patients with diabetes mellitus in a 
compensation state that will be confirmed by HbA1c testing at Screening.
Sections affected by this modification: Synopsis, 5.1.2 Exclusion criteria


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13.2.1.8
Modification 8 – clarification of exclusion criterion related to 
proteinuria
Exclusion criterion was modified to clarify that laboratory method used to assess proteinuria 
is not limited to UPCR only. 
Following the investigator’s feedback on the study feasibility, the criterion was amended to 
make the patient evaluation more flexible and feasible.
Section affected by this modification: 5.1.2 Exclusion criteria, 6.4 Dosage and administration, 
7.1.1 Tabulated overview, 7.1.2.1 Screening period, 7.1.2.2 Treatment period, 7.5.3 Further 
safety, 7.5.3.1 Laboratory
13.2.1.9
Modification 9 – language on corticosteroid therapy clarified
It was clarified in the protocol that previous corticosteroid therapy must be stopped or reduced 
to the allowed dose at least 7 days prior to the screening tumor scan. This modification was 
made to eliminate a bias in the tumor response assessment; as to not potentially change the 
lesion status from time of baseline scan to study treatment start.
Sections affected by this modification: 5.1.2 Exclusion criteria and 6.9.1 Prohibited 
concomitant therapy
13.2.1.10 Modification 10 – modification of exclusion criterion related to 
evidence of resistance to PI3K inhibitors
Exclusion criterion was modified since the definition of resistance should be progression 
within 6 months starting from the treatment with PI3K inhibitors instead of within 6 months 
from the end of therapy.
Sections affected by this modification: Synopsis, 5.1.2 Exclusion criteria
13.2.1.11 Modification 11 – prior treatment with copanlisib added to the 
exclusion criteria.
Copanlisib was included to the list of prohibited previous therapies and medications. 
Modification was done because prior treatment with copanlisib could jeopardize the clinical 
assessment of the study drug.
Sections affected by this modification: Synopsis, 5.1.2 Exclusion criteria
13.2.1.12 Modification 12 – detailed instructions on copanlisib handling and PK 
blood sampling removed
Detailed information regarding reconstitution and dilution of copanlisib and the storage of 
copanlisib solution was removed from the protocol; this information can be found in the 
Pharmacy Manual or in the IB. 
The required volume of blood samples for PK analysis was removed from the protocol. 
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The rationale for the text deletions was to avoid future protocol amendments in case this 
language would need updating and to avoid the duplication of information that is already 
included in the Pharmacy Manual, Laboratory Manual or in the IB.
Sections affected by this modification: 6.2 Identity of study treatment, 7.4 Pharmacokinetics/ 
pharmacodynamics
13.2.1.13 Modification 13 – updated guidance for management and monitoring 
of glucose increases
An updated guidance for the management of transient glucose increases was provided to 
ensure the patient safety. These changes were made based on updated clinical data and the 
feedback from the investigators. 
Changes include:

Management of transient glucose increases should be based on persistent post-infusion 
blood glucose results.

Additional guidance regarding meal timing was provided.

An updated guidance on dose modification for transient glucose increases was 
provided.

Additional information regarding glucose monitoring at home was provided.

The withdrawal criterion “CTCAE Grade 4 symptomatic hyperglycemia or glucose 
intolerance” was revised to align with a new guidance for the transient glucose 
increases management.Appendix 14.7 was added based on the new guidance for the 
transient glucose increases management and to clarify average glycemic index of 
common foods derived from multiple studies by different laboratories.
Sections affected by this modification: 5.2.1.1 Withdrawal from study treatment, 6.4 Dosage 
and administration, 6.4.1 Dose modification, 6.4.1.2 Non-hematological toxicity, 
6.4.2.1 Management of transient post-infusion glucose increases that can occur with study 
treatment, 7.1.1 Tabulated overview, 7.1.2.2.1 Treatment – Cycle 1, 7.1.2.2.2 Treatment –
Cycle 2 and higher, 7.1.2.4 End-of-treatment visit, 7.5.3.6 Glucose measurements on infusion 
days, Appendix 14.7 The average glycemic index of common foods derived from multiple 
studies by different laboratories
13.2.1.14 Modification 14 – updated guidance for management and monitoring 
of blood pressure increases
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.
Sections affected by this modification: 6.4.1 Dose modification, 6.4.1.2 Non-hematological 
toxicity, 6.4.2.3 Treatment of blood pressure increases associated with study treatment, 


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7.1.1 Tabulated overview, 7.1.2.2.1 Treatment – Cycle 1, 7.1.2.2.2 Treatment – Cycle 2 and 
higher, 7.5.3.3 Vital signs
13.2.1.15
Modification 15 – fasting requirement for lipid panels revised
The 11 h fasting requirement before evaluation of lipid panels was revised; patients must be 
fasting prior to lipid sampling according to local standards. This change was made to allow 
the implementation of local standards for fasting requirements for lipid panel testing.
Sections affected by this modification: 6.4.2.2 Management of hyperlipidemia, 
7.1.1 Tabulated overview, 7.1.2.1, Screening period, 7.1.2.2.2 Treatment – Cycle 2 and 
higher, 7.1.2.4 End-of-treatment visit
13.2.1.16 Modification 16 – clarification of laboratory criteria for patients who
switch to open-label treatment
The language was changed to clarify that certain laboratory parameters as outlined in the 
exclusion and inclusion criteria need to be met for Day 1 of the first open-label cycle. For 
Day 1 of subsequent open-label cycles, dosing criteria outlined in Table 6–2 will apply. The 
purpose of the modification is to document that patients retain certain minimal levels of organ 
function to maximize their safety when switching to open label treatment.
Sections affected by this modification: 6.4 Dosage and administration, 7.1.1 Tabulated 
overview, 7.1.2.2 Treatment period, 7.5.3 Further safety
13.2.1.17 Modification 17 – dose modification guidance of study treatment for 
NIP modified
Guidance regarding differentiation between NIP and other pneumonitis was added to the 
protocol. The addition was made to get an unbiased analysis of the safety profile of copanlisib 
with regards to pneumonitis developed due to a potential hypersensitivity reaction to the 
copanlisib infusion. 
The dose modification guidance of study treatment for NIP was modified: the re-occurrence 
of CTCAE pneumonitis of grade 3 will lead to permanent discontinuation of the study drug. 
This change was made to provide with the guidance how to manage the re-occurrence of 
CTCAE pneumonitis event of grade 3 to ensure patient safety.
Section affected by this modification: 6.4.1.2 Non-hematological toxicity
13.2.1.18 Modification 18 – clarification of tumor evaluation language
The language related to radiological tumor assessments was modified to clarify the process 
for central review that the evaluation of tumor response will be done retrospectively only for 
those patients who did not experience PD. 
Clarification was done that CT/MRI scans need to be re-submitted with the new PID in case 
of re-screening.


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Modifications were also done to harmonize the language across the protocol and with other 
copanlisib protocols, e.g. tumor assessment in patients with WM was added as a separate 
section and was also explained in more detail in synopsis and study design sections. 
In general, CT/MRI needs to be performed with IV contrast agents. A clarification was added 
to explain, in which situations the switch from CT to MRI is required and when to proceed 
after the first treatment without a contrast-enhanced CT/MRI.
Table for the CT and/or MRI response assessment criteria was also clarified:

Original wording from the Lugano Classification 2014 (21) was inserted to the column 
“bone marrow” for PD.

Language in column “spleen” for PD was updated; a rule was added to minimize any 
measurements errors, and the value of ≥ 1 cm was used after advice from professor 
Cheson, the author of the Lugano classification (21). The total value of increase is also 
in line with the total increase required for the bigger lesions, i.e. lesions > 2 cm.

A footnote regarding the longest diameter (LDi) was added to provide more details as 
was outlined in the table; the rule or the content was not changed.

A note was added to further clarify the evaluation provided in the response table, 
which is especially important for patients who do not have a lesion in the spleen.
Sections affected by this modification: Synopsis, 4 Study design, 5.2.1 Withdrawal, 
7.1.1 Tabulated overview, 7.1.2.3 Tumor assessments, 7.3.2 Radiological tumor assessments, 
7.3.3 Tumor assessments in patients with WM, 14.1 Evaluation of tumor response.
13.2.1.19 Modification 19 – usage of verapamil and diltiazem amended
The text was modified to state that verapamil and diltiazem (non-dihydropyridine calcium 
channel blockers) should be used with caution instead of should be avoided because 
itraconazole (a strong CYP 3A4 inhibitor) only increased copanlisib exposure by 1.42 fold.
Sections affected by this modification: 6.4.2.3 Treatment of blood pressure increases 
associated with study treatment
13.2.1.20 Modification 20 – clarification of AE reporting language
The statement was added that death should generally not be recorded as an AE but as the 
outcome of underlying AE(s) instead. If death is reported without any associated AE (s), it 
should be reported as SAE. The statement was added for increased clarity and to ensure 
consistency in how deaths should be reported.
It was also emphasized that disease progression should be clearly mentioned on the SAE 
form as an alternative explanation in case disease progression leads to signs and symptoms 
that meet the criteria for seriousness.
Sections affected by this modification: 7.5.1.3 Assessments and documentation of adverse 
events, 7.5.1.4 Reporting of serious adverse events


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13.2.1.21 Modification 21 – language related to hemoglobin A1c measurements 
clarified
It was clarified in the protocol that test for HbA1c is not required at the EOT visit if the 
previous test was performed within 4 weeks preceding EOT visit. The rationale for this 
change was to implement the consideration of erythrocyte lifecycle. 
HbA1c was added to the list of laboratory evaluations in further safety section for 
consistency.
Sections affected by this modification: 7.1.1 Tabulated overview, 7.1.2.4 End-of-treatment 
visit, 7.5.3.1 Laboratory
13.2.1.22 Modification 22 – assessment of hydration status added
Language on clinical assessment of hydration status was included to be part of complete and 
brief physical examinations. This change was made to emphasize the importance to check a 
hydration status during patient physical examination.
Sections affected by this modification: 7.5.3.2.1 Complete physical examination and 
7.5.3.2.2 Brief physical examination
13.2.1.23 Modification 23 – paper PRO questionnaire removed
The possibility to use paper PRO surveys was removed since only electronic devices will be 
used in this study. If electronic device is not available at the site, or technical problems 
prevent it from working properly, the PRO questionnaire will not be completed at that visit.
Section affected by this modification: 7.6.3 Electronic patient-reported outcomes evaluation
13.2.1.24 Modification 24 – reference to the Declaration of Objection form 
removed
The reference to the Declaration of Objection to the Collection of Study Data after 
Withdrawal of Consent was removed from the study protocol since this form is not used 
anymore according to sponsor’s standard operating procedures. Patient information and 
content section was updated based on current protocol template text.
Sections affected by this modification: 5.2.1.1 Withdrawal from study treatment, 11.2 Patient 
information and consent
13.2.1.25 Modification 25 – other clarifications and corrections
In addition to the modifications specified above there have been minor corrections for better 
clarity and consistency.

The sentence regarding the institution of DMC for this study was modified for further 
clarity.


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
The clarification was made that the study drug is to be administered in an approximate 
timeframe of 1 h to allow for a little time window. The change was done following the 
feedback from the investigators.

It was clarified that the laboratory test results can be assessed by the investigator 
and/or appropriate site personnel before administration of study drug.

The symbol “≥” was added to dosing criteria section to clarify that criteria apply to 
anemia, neutrophil count decreased and platelet count decreased of CTCAE grade ≥3, 
not only for events of CTCAE grade 3.

The symbol “≥” was added to dose modification Table 6–4 to ensure that dose 
modification guidance is provided for anemia of CTCAE grade ≥ 3. A footnote was 
added to the same table clarifying that treatment with transfusion or growth factors is 
allowed at the investigator’s discretion.

Clarification was added that also doses scheduled for Days 1 after Cycle 1 Day 1 may 
be delayed by up to 2 days (in addition to doses scheduled on Days 8 and 15 or each 
cycle).

Cyclosporin was removed from the list of permitted concomitant medications since the 
protocol prohibits concomitant therapy with immunosuppressive agents. 

PRO information sheet was added to Table 7–1 for clarification.

It was clarified in the timing of assessment section that for the assessments scheduled 
for the treatment period, deviations of -1 day and +2 days are acceptable unless 
otherwise specified in the protocol.

It was clarified in the screening period section that procedures need to be performed 
within x days before start of study treatment instead of less than x days.
Sections affected by this modification: 3 Investigator and other study personnel, 4 Study 
design 6.4 Dosage and administration, 6.4.1.1 Hematological toxicity, 6.9.2 Permitted 
concomitant therapy, 7.1.1 Tabulated overview, 7.1.2 Timing of assessments, 
7.1.2.1 Screening period
13.2.2
Changes to the protocol text
In this section, all affected protocol sections are detailed; the sequence of the sections follows 
the structure of the original protocol. In the display of modifications, the “old text” refers to 
the protocol version preceding this amendment. Deletions are crossed out in the “old text”. 
Additions are underlined in the “new text”. Corrections of typing errors or omissions are not 
highlighted in this amendment.


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13.2.2.1
Synopsis
Old text:
Diagnosis and main criteria 
for inclusion
[…]
Prior therapy must include rituximab and alkylating agent(s). Prior 
exposure to idelalisib or other PI3K inhibitors is acceptable provided that 
there is no resistance (modified by amendment 1).
Patients must be refractory to the last rituximab-based treatment (no 
response or response lasting < 6 months).
[…]
Patients affected by WM, who do not have at least one bi-dimensionally 
measurable lesion in the baseline radiologic assessment, must have 
measurable disease, defined as presence of immunoglobulin M (IgM) 
paraprotein with a minimum IgM level ≥ 2 x upper limit of normal (ULN) 
(changed by amendment 1). 
[…]
Main criteria for exclusion
[…]
Known lymphomatous involvement of the central nervous system.
Type I or II diabetes mellitus with HbA1c > 8.5% or fasting plasma 
glucose > 160 mg/dL at Screening.
[…]

Progression (PD) after any response (PR/CR) or after stable disease 
(SD) within 6 months from the end of the therapy with a PI3K 
inhibitor.
Patients who discontinued treatment due to other reason than disease 
progression, and did not exhibit any signs of PD, will be allowed to enroll 
in this study after discussion with the sponsor.
Methodology
[…]
The final evaluation of treatment response (best response: ORR and CRR) 
will be done by central blinded review retrospectively.


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New text:
Diagnosis and main criteria 
for inclusion
[…]
Prior therapy must include rituximab and alkylating agent(s). Prior 
exposure to idelalisib or other PI3K inhibitors is acceptable (except to 
copanlisib) provided that there is no resistance (modified by amendment 
1).
Patients must be refractory to the last rituximab-based treatment, defined 
as no response or response lasting < 6 months after completion of 
treatment. Time interval to assess refractoriness will be calculated between 
the end date (last day) of the last rituximab-containing regimen and the 
day of diagnosis confirmation of the subsequent relapse.
[…].
Patients affected by WM, who do not have at least one bi-dimensionally 
measurable lesion in the baseline radiologic assessment, must have 
measurable disease, defined as presence of immunoglobulin M (IgM) 
paraprotein with a minimum IgM level ≥ 2 x upper limit of normal (ULN) 
and positive immunofixation test (changed by amendment 1). 
[…]
Main criteria for exclusion
Known lymphomatous involvement of the central nervous system.
Uncontrolled arterial hypertension despite optimal medical management 
(per investigator’s assessment).
Type I or II diabetes mellitus with HbA1c > 8.5% at Screening.
[…]

Progression (PD) after any response (PR/CR) or after stable disease 
(SD) within 6 months from the start of the therapy with a PI3K 
inhibitor.
Patients who discontinued treatment due to other reason than 
disease progression, and did not exhibit any signs of PD, will be 
allowed to enroll in this study after discussion with the sponsor.
Prior treatment with copanlisib.
Methodology
[…]
The final evaluation of treatment response (best response: ORR and CRR) 
will be done by central blinded review and for those not undergoing PD-
confirmation in retrospective setting.
WM patients who do not have radiologically measurable lesion at 
Screening will not have further radiological assessments as per protocol. 
Their tumor response will be measured only by laboratory/clinical tests. 
However, in cases when WM patients will develop disease progression 
confirmed radiologically by presenting with measurable lesion(s) without 
simultaneous increase in IgM, the imaging scans should be submitted for 
central review and PD confirmation. WM patients who have radiologically 
measurable lesion at Screening will continue having radiological 
assessments and, in addition, will have laboratory tests performed on the 


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same days.
Bone marrow biopsy will be mandatory at Screening. If the baseline 
biopsy is positive for lymphoma infiltration, it will be mandatory to 
perform it again to confirm the first complete response (CR).
13.2.2.2
List of abbreviations
New abbreviations were added:
BP
Blood pressure
DPP4
Dipeptidyl peptidase-4
FSH
Follicle stimulating hormone
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
SGLT-2
Sodium/glucose co-transporter 2
WOCBP
Woman of childbearing potential
13.2.2.3
Section 1.1.2 Clinical experience
Old text:
Copanlisib is currently under investigation in various trials enrolling cancer patients. As of 
30 NOV 2013, approximately 240 patients with advanced cancer have been treated with 
copanlisib in five different Phase 1 studies and one Phase 2 study. 
As of 30 NOV 2013, a total of 57 cancer patients were treated in the Phase I monotherapy 
study 12871, with 17 patients in the dose escalation cohorts and 34 patients in the maximum 
tolerated dose (MTD) expansion cohorts (two cohorts including 9 patients with NHL and 
25 patients with solid tumors), as well as 6 patients with Type II diabetes mellitus in the 
diabetic expansion cohort at 0.4 mg/kg. The MTD of copanlisib, when administered 
intravenously (IV) over 1 h, on Days 1, 8 and 15 of every 28 days given as a single agent, was 
determined to be 0.8 mg/kg, with a maximum dose of 65 mg in order to control copanlisib 
exposure in obese patients. 
Preliminary efficacy data are available from the NHL expansion cohort of Study 12871. 
A total of 6 non-diabetic patients with FL and 3 patients with diffuse large B-cell lymphoma 
(DLBCL) were treated, all initially dosed at 0.8 mg/kg. All 6 patients with FL reached 
a partial response (PR). As of 30 NOV 2013, 2 patients with FL were still on treatment, both 
having an ongoing PR since 978 and 507 days, respectively. Two patients had disease 
progression (PD) after 281 and 447 days of treatment, and 2 patients withdrew from the study 
due to treatment-related AEs (interstitial pneumonitis at the end of Cycle 2 and persisting 
mucositis at Cycle 8).
Preliminary analysis of the 9 NHL patients showed that the most common treatment-emergent 
adverse events (TEAEs), irrespective of relationship to study drug and grade, occurring in 


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> 20% of the patients, were hyperglycemia (89%), nausea (78%), diarrhea (67%), 
hypokalemia (56%), any infection, rash and cough (44% each), fatigue, vomiting, 
hypertension, pruritus, mucositis and constipation (33% each), thrombocytopenia, decreased 
appetite, dehydration, dizziness, anxiety and pneumonitis (22% each). The most common 
study drug-related TEAEs that occurred in > 20% of the patients were hyperglycemia (89%), 
nausea (78%), diarrhea, hypertension, mucositis and fatigue (33.3% each), pneumonitis, rash, 
pruritus and thrombocytopenia (22% each).
[…]
In the ongoing study 16349 (part A), a total of 67 patients with various indolent and 
aggressive lymphomas were treated at a starting dose of 0.8 mg/kg. The objective of the study 
was to identify activity signals in various histologic NHL subtypes and to further explore the 
safety profile of copanlisib. In the group of patients with iNHL, the following histologies 
were represented: FL (16 patients), CLL/SLL (14 patients), and MZL (3 patients). Median age 
was 68 years and 61% of the patients had ≥4 previous lines of systemic treatment. At the cut-
off date of 04 NOV 2013 the median duration of treatment was 4 cycles in the indolent group. 
The objective response rate (ORR) was 47% in FL, 38% in CLL, 100% in SLL and 67% in 
MZL (paragraph updated by amendment 1).
As of 04 NOV 2013, the most frequent TEAEs, regardless of relationship to study drug, 
occurring in > 20% of the whole study population were hyperglycemia (62.7%), hypertension 
(61.2%), fatigue (44.8%), diarrhea (40.3%), nausea (34.3%), neutrophil count decreased 
(31.3%), anemia (26.9%), and oral mucositis (20.9%). The two most common study drug-
related TEAEs were hyperglycemia (61.2%) and hypertension (58.2%). A total of 50 patients 
(19 with indolent, and 31 with aggressive lymphomas) discontinued the study treatment. 
Altogether 25.4% of patients stopped treatment because of AEs. No conspicuous cluster of 
AEs causing treatment discontinuation emerged. Overall 13 out of 67 patients received 
treatment with short-acting insulin (paragraph updated by amendment 1).


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New text:
Copanlisib is currently under investigation in various trials enrolling cancer patients. As of 
01 FEB 2015, approximately 377 patients with advanced cancer have been treated with 
copanlisib in Phase 1and Phase 2 clinical trials as a single agent or in combination with other 
agents. 
As of 10 FEB 2014, a total of 57 cancer patients were treated in the Phase I monotherapy 
study 12871, with 17 patients in the dose escalation cohorts and 34 patients in the maximum 
tolerated dose (MTD) expansion cohorts (two cohorts including 9 patients with NHL and 
25 patients with solid tumors), as well as 6 patients with Type II diabetes mellitus in the 
diabetic expansion cohort at 0.4 mg/kg. In AUG 2013, the enrollment in study 12871 was 
completed. Dose-limiting toxicity was observed at 1.2 mg/kg with MTD established at 
0.8 mg/kg when administered intravenously (IV) over 1 h, on Days 1, 8 and 15 of every 
28 days given as a single agent. The flat dose of 65 mg correlates with 0.8 mg/kg (MTD level) 
dose and was selected in order to control copanlisib exposure in obese patients.
In the NHL expansion cohort of Study 12871, a total of 6 non-diabetic patients with FL and 3 
patients with diffuse large B-cell lymphoma (DLBCL) were treated, all initially dosed at 
0.8 mg/kg. As of 01 FEB 2014, according to investigator’s assessment, 7 patients (77.8%) with 
NHL experienced partial response (PR) as best overall response and 2 patients (22.2%) had 
progressive disease. Partial responders included 6 patients with FL and 1 patient with DLBCL. 
A retrospective independent review performed in 8 of the 9 NHL patients (excluding the
clinical assessment) concluded that a complete response (CR) was the best overall response in
the 2 FL long-term responders (assessed as partial responders by the investigators).
The most common treatment-emergent adverse events (TEAEs), regardless of seriousness, 
severity, and causality, occurring in ≥20% of the 57 subjects were hyperglycemia (64.9%), 
nausea (52.6%), fatigue (40.4%), diarrhea (33.3%), hypokalemia (31.6%), hemoglobin 
(decreased) and hypertension (29.8% each), rash/desquamation and vomiting (28.1%, each), 
anorexia (26.3%), constipation (24.6%), cough and dehydration (22.8%, each), and dyspnea 
(21.1%).
[…]
As of 28 FEB 2015, a total of 81 patients with various indolent and aggressive lymphomas 
were treated at a starting dose of 0.8 mg/kg in the ongoing study 16349 (part A). The 
objective of the study was to identify activity signals in various histologic NHL subtypes and 
to further explore the safety profile of copanlisib. In the group of patients with iNHL, the 
following histologies were represented: FL (16 patients), CLL/SLL (14 patients), and MZL 
(3 patients). Median age was 68 years and 61% of the patients had ≥4 previous lines of 
systemic treatment. As of the cut-off date the median duration of copanlisib treatment was 
6 cycles in the indolent group. The objective response rate (ORR) was 40% in FL, 38% in 
CLL, 100% in SLL and 67% in MZL (paragraph updated by amendment 1).
The most frequent TEAEs, regardless of relationship to study drug, occurring in > 20% of the 
whole study population were hyperglycemia (59.3%), hypertension (56.8%), diarrhea 
(40.7%), fatigue (35.8%), nausea (32.1%), neutropenia (28.4%) and anemia (27.2%). The two 
most common study drug-related TEAEs were hyperglycemia (56.8%) and hypertension 


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(53.1%). At the time of the cut-off, a total of 75 patients (92.6%), 30 with indolent, and 
45 with aggressive lymphomas, had discontinued the study treatment. Altogether 20 patients 
(24.7%) stopped treatment because of AEs. No conspicuous cluster of AEs causing treatment 
discontinuation emerged. Overall 17 out of 81 patients received treatment with short-acting 
insulin (paragraph updated by amendment 1).
13.2.2.4
Section 1.3 Benefit-risk assessment
Old text:
[…]
Copanlisib has showed activity in patients with iNHL. In the Phase I study 12871 all 
6 patients with FL responded (please see Section 1.1.2). In the Phase II study 16349 (part A), 
response rates in patients with iNHL of various histologies were: 47% in FL, 67% in MZL, 
and 100% in SLL. Responses included complete remissions. Patients with iNHL were heavily 
pretreated, with 82% having received ≥3, and 36% ≥5 lines of treatment prior to study start 
(updated by amendment 1).
New text:
[…]
Copanlisib has showed activity in patients with iNHL. In the Phase I study 12871 all 
6 patients with FL responded (please see Section 1.1.2). In the Phase II study 16349 (part A), 
response rates in patients with iNHL of various histologies were: 40% in FL, 67% in MZL, 
and 100% in SLL. Responses included complete remissions. Patients with iNHL were heavily 
pretreated, with 82% having received ≥3, and 36% ≥5 lines of treatment prior to study start 
(updated by amendment 1).
13.2.2.5
Section 3 Investigator and other study personnel
Data Monitoring Committee
Old text:
[…]
A Data Monitoring Committee (DMC) will be established which will closely interact with the 
sponsor’s Global Pharmacovigilance (GPV) department in order to assess all safety-relevant 
information. 


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Data Monitoring Committee
New text:
[…]
A Data Monitoring Committee (DMC) will be established for this study (according to a 
separate DMC charter) in order to ensure ongoing safety of study patients. 
13.2.2.6
Section 4 Study design
Old text:
Design overview
[…]
The start of the treatment period is defined by first administration of study drug (copanlisib or 
placebo). Copanlisib will be administered IV over 1 h at starting dose of 60 mg on Days 1, 8 
and 15 of each 28-day treatment cycle.
[…]
The final evaluation of treatment response (best response: objective tumor response rate 
[ORR] and complete response rate [CRR]) will be done by central blinded review 
retrospectively.
Bone marrow biopsy will be mandatory at Screening. Biopsies taken up to 28 days prior to 
treatment start are acceptable. If the baseline biopsy is positive for lymphoma infiltration, it 
will be mandatory to perform it again to confirm the first complete response (CR).
New text:
Design overview
[…]
The start of the treatment period is defined by first administration of study drug (copanlisib or 
placebo). Copanlisib will be administered IV over approximately 1 h at starting dose of 60 mg 
on Days 1, 8 and 15 of each 28-day treatment cycle.
[…]
The final evaluation of treatment response (best response: objective tumor response rate 
[ORR] and complete response rate [CRR]) will be done by central blinded review and for 
those not undergoing PD-confirmation in retrospective setting.
WM patients who do not have radiologically measurable lesion at Screening will not have 
further radiological assessments as per protocol. Their tumor response will be measured only 
by laboratory/clinical tests. However, in cases when WM patients will develop disease 
progression confirmed radiologically by presenting with measurable lesion(s) without 
simultaneous increase in IgM, the imaging scans should be submitted for central review and
PD confirmation. WM patients who have radiologically measurable lesion at Screening will 


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continue having radiological assessments and, in addition, will have laboratory tests 
performed on the same days.
Bone marrow biopsy will be mandatory at Screening. Biopsies taken up to 28 days prior to 
treatment start are acceptable. If the baseline biopsy is positive for lymphoma infiltration, it 
will be mandatory to perform it again to confirm the first complete response (CR).
13.2.2.7
Section 5.1.1 Inclusion criteria
Old text:
[…]
4. Prior therapy must include rituximab and alkylating agent(s). Prior exposure to 
idelalisib or other PI3K inhibitors is acceptable provided that there is no resistance 
(modified by amendment 1).
5. Patients must be refractory to the last rituximab-based treatment (no response or 
response lasting < 6 months).
[…]
7. Patients affected by WM, who do not have at least one bi-dimensionally measurable 
lesion in the baseline radiologic assessment, must have measurable disease, defined as 
presence of immunoglobulin M (IgM) paraprotein with a minimum IgM level ≥ 2 x 
upper limit of normal (ULN) (changed by amendment 1).
[…]
12. Women of childbearing potential and men must agree to use adequate contraception 
when sexually active. This applies since signing of the ICF until at least 3 months after 
the last study drug administration. The investigator or a designated associate is 
requested to advise the patient how to achieve an adequate birth control. Adequate 
contraception is defined in the study as any medically recommend method (or 
combination of methods) as per standard of care.
[…]
o
Total bilirubin ≤1.5 x ULN 
(≤3 x ULN for patients with Gilbert-Meulengracht syndrome or for patients with 
cholestasis due to compressive adenopathies of the hepatic hilum).
[…]
o
Amylase and lipase ≤1.5 x the ULN.
[…]
o
International normalized ratio (INR) and partial thromboplastin time (PTT) 
≤1.5 x ULN.


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New text:
[…]
4. Prior therapy must include rituximab and alkylating agent(s). Prior exposure to 
idelalisib or other PI3K inhibitors is acceptable (except to copanlisib) provided that 
there is no resistance (modified by amendment 1).
5. Patients must be refractory to the last rituximab-based treatment, defined as no 
response or response lasting < 6 months after completion of treatment. Time interval 
to assess refractoriness will be calculated between the end date (last day) of the last 
rituximab-containing regimen and the day of diagnosis confirmation of the subsequent 
relapse.
[…]
7. Patients affected by WM, who do not have at least one bi-dimensionally measurable 
lesion in the baseline radiologic assessment, must have measurable disease, defined as 
presence of immunoglobulin M (IgM) paraprotein with a minimum IgM level ≥ 2 x 
upper limit of normal (ULN) and positive immunofixation test (changed by 
amendment 1).
[…]
12. Women of childbearing potential (WOCBP) and men must agree to use effective
contraception when sexually active. This applies for the time period between signing 
of the ICF and 3 months after the last administration of study treatment. A woman 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 women not using hormonal contraception or hormonal 
replacement therapy.
o
The investigator or a designated associate is requested to advise the patient how to 
achieve highly effective birth control (failure rate of less than 1%), e.g. 
intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral 
tubal occlusion, vasectomized partner and sexual abstinence.
o
The use of condoms by male patients is required unless the female partner is 
permanently sterile.
[…]
o
Total bilirubin ≤1.5 x ULN 
(≤5 x ULN for patients with proven Gilbert-Meulengracht syndrome or 
≤3 x ULN for patients with cholestasis due to compressive adenopathies of the 
hepatic hilum).


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[…]
o
Lipase ≤1.5 x the ULN.
[…]
o
International normalized ratio (INR) ≤1.5 and 
partial thromboplastin time (PTT) ≤1.5 x ULN.
13.2.2.8
Section 5.1.2 Exclusion criteria
Old text:
[…]
14. Uncontrolled arterial hypertension (systolic blood pressure > 150 mmHg or diastolic 
blood pressure > 90 mmHg despite optimal medical management).
15. Type I or II diabetes mellitus with HbA1c > 8.5% or fasting plasma glucose 
> 160 mg/dL at Screening.
[…]
24. Proteinuria as measured by urine protein/creatinine ratio (UPCR) > 3.5 on a random 
urine sample.
[…]
39. Ongoing systemic corticosteroid therapy at a daily dose higher than 15 mg prednisone 
or equivalent. Previous corticosteroid therapy must be stopped or reduced to the 
allowed dose 7 days before performing the screening CT/MRI and again prior to the 
first study drug administration. If a patient is on chronic corticosteroid therapy, 
corticosteroids should be de-escalated to the maximum allowed dose before the 
Screening. Patients may be using topical or inhaled corticosteroids.
[…]
45. Documented evidence of resistance to a prior treatment with idelalisib or other PI3K 
inhibitors defined as (exclusion criterion added by amendment 1):
o
No response (response defined as PR or CR) at any time during therapy, or
o
Progression (PD) after any response (PR/CR) or after stable disease (SD) 
within 6 months from the end of the therapy with a PI3K inhibitor.
Patients who discontinued treatment due to other reason than disease 
progression, and did not exhibit any signs of PD, will be allowed to enroll in 
this study after discussion with the sponsor.


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New text:
[…]
14. Uncontrolled arterial hypertension despite optimal medical management (per 
investigator’s assessment).
15. Type I or II diabetes mellitus with HbA1c > 8.5% at Screening.
[…]
24. Proteinuria ≥ CTCAE Grade 3 as assessed by either a 24 h total urine protein 
quantification or a urine protein to creatinine ratio (UPCR) > 3.5 on a random urine 
sample.
[…]
39. Ongoing systemic corticosteroid therapy at a daily dose higher than 15 mg prednisone 
or equivalent. Previous corticosteroid therapy must be stopped or reduced to the 
allowed dose at least 7 days before performing the screening CT/MRI. If a patient is 
on chronic corticosteroid therapy, corticosteroids should be de-escalated to the 
maximum allowed dose before the Screening. Patients may be using topical or inhaled 
corticosteroids.
[…]
45. Documented evidence of resistance to a prior treatment with idelalisib or other PI3K 
inhibitors defined as (exclusion criterion added by amendment 1):
o
No response (response defined as PR or CR) at any time during therapy, or
o
Progression (PD) after any response (PR/CR) or after stable disease (SD) 
within 6 months from the start of the therapy with a PI3K inhibitor.
Patients who discontinued treatment due to other reason than disease 
progression, and did not exhibit any signs of PD, will be allowed to enroll in 
this study after discussion with the sponsor.
46. Prior treatment with copanlisib.
13.2.2.9
Section 5.2.1 Withdrawal
Old text:
[…]
Diagnostic testing performed as part of the original screening or standard of practice (e.g. 
including fresh tumor tissue, CT/MRI scans, bone marrow sample, MUGA/echocardiogram 
and hepatitis testing) will not need to be repeated during the 14 day re-testing period.
New text:
[…]


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Diagnostic testing performed as part of the original screening or standard of practice (e.g. 
including fresh tumor tissue, CT/MRI scans, bone marrow sample, MUGA/echocardiogram 
and hepatitis testing) will not need to be repeated during the 14 day re-testing period. CT/MRI 
scans need to be resubmitted with the new PID.
13.2.2.10 Section 5.2.1.1 Withdrawal from study treatment
Old text:
[…]

Patients who withdraw consent from treatment will still participate in the Active or 
Survival follow-up unless they object to follow-up data collection. In this case the 
patient has to expressively inform the investigator and sign the Declaration of 
Objection to the Collection of Study Data after Withdrawal of Consent. The objection 
is also valid, if the declaration is not in place for any reason, but the investigator 
documented the objection in the files.
[…]

CTCAE Grade 4 symptomatic hyperglycemia or glucose intolerance (modified by 
amendment 1).
New text:
[…]

Patients who withdraw consent from treatment will still participate in the Active or 
Survival follow-up unless they object to follow-up data collection (see Section 11.2).
[…]

Persistent occurrence of post-infusion blood glucose > 400 mg/dL based on laboratory 
analysis which occurred at the lowest study drug dose level despite optimal glucose 
lowering therapy (after at least one cycle of treatment) with consultation of a diabetes 
specialist (e.g. diabetologist or endocrinologist). 
Definition of persistent occurrence is based on repeated post-infusion blood glucose 
laboratory analysis taken at different time during the whole cycle of treatment.
13.2.2.11 Section 6.2 Identity of study treatment
Old text:
Copanlisib
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 infusions is obtained after reconstitution 
of the lyophilisate with normal saline solution. Reconstitution and dilution should be 
performed according to separate handling instructions specified in the Pharmacy Manual 
(reference added by amendment 1). 


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The lyophilisate in each vial is to be reconstituted with 3.0 mL of normal saline solution, 
resulting in a concentration of 20 mg/mL of BAY 80-6946, and the extractable volume of not 
less than 3.0 mL for the starting dose (60 mg). For a dose modification of 45 mg (dose 
level -1) the volume to be extracted is 2.25 mL, and for a dose modification of 30 mg (dose 
level -2) the volume to be extracted is 1.5 mL. The required amount of reconstituted solution 
is to be further diluted with saline solution according to handling instructions. The resulting 
solution contains the excipients (lyophilisate) of mannitol, sodium hydroxide (NaOH) and 
citric acid in addition to active substance. 
The diluted solution is physically and chemically stable for 24 h at room temperature. 
However, for microbiological consideration, diluted solution should be stored between 2°C 
(36°F) and 8°C (46°F) if not administered immediately. 
Refer to IB for copanlisib for more details regarding drug properties and formulation 
(modified by amendment 1).
New text:
Copanlisib
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 infusions is obtained after reconstitution 
of the lyophilisate with normal saline 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 
(modified by amendment 1).


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13.2.2.12 Section 6.4 Dosage and administration
Old text:
Study drug (copanlisib or placebo) is administered in a normal saline solution, intravenously, 
over 1 h. No intravenous glucose preparations should be administered on the days of infusion.
See Pharmacy Manual for additional details (modified by amendment 1).
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). 
The requirements for fasting and pre-dose glucose levels are presented in Table 6-1 (table 
added by amendment 1).
Table 6-1
Fasting requirements and pre-dose glucose levels
Period
Fasting ≥ 8 h required 
before first glucose 
measurement
Pre-dose glucose levels
Fasting required before 
study drug infusion
Day 1 of
cycle 1
Yes
≤125 mg/dL (non-diabetic patients)
<160 mg/dL (diabetic patients)
No a
Day 1 of 
subsequent 
cycles
Yes
<160 mg/dL (fasting)
< 200 mg/dL (non-fasting) c
No b
Days 8 and 15 
of each cycle
No
<160 mg/dL (fasting)
<200 mg/dL (non-fasting)
No b
a: Within 1 h before the start of study drug infusion patients may have a low carbohydrate 
breakfast (e.g. eggs, cheese, plain yoghurt, vegetables, meat).
b: Patients may have a low carbohydrate breakfast (e.g. eggs, cheese, plain yoghurt, vegetables, 
meat) at any time after pre-dose glucose measurement.
c: In case of non-compliance with the fasting requirement.
The investigator will accurately document fasting/non-fasting for each glucose measurement 
done at the site. Fasting for this purpose refers to a ≥ 8 h fast. (fasting requirements changed 
by amendment 1).
From Cycle 1 Day 1 onwards, glucose measurements at the site may be done either by 
laboratory analysis or in capillary blood using a handheld glucose meter. If handheld glucose 
meters are chosen, the appropriate calibration of glucose meters will be documented.
Patients will continue study treatment until PD (per central independent blinded radiology 
review) or they meet the criteria described in Section 5.2.
[…]
If not previously done within 7 days, patients switching to open-label copanlisib must 
complete the following within 7 days prior to the first dose of open-label copanlisib: UPCR 
measurement, GFR measurement, urinalysis, HbA1c, CBC, chemistry and coagulation panels 
Dosing criteria outlined in Table 6-2 apply also for patients who switch to open-label 
treatment.
[…]


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Dosing criteria
Starting from Cycle 1 Day 8, 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 prior to administration of planned dose. On Day 1 of each subsequent cycle, the 
dose of study drug will be given only if the laboratory test criteria described in Table 6-2 are 
met.
[…]
A blood count will be performed and assessed prior to infusion on Days 8 and 15 of each 
cycle. The study drug will not be administered if, on the day of scheduled dosing, any of the 
following criteria is met:

CTCAE Grade 3 neutrophil count decreased (ANC < 1,000/mm3)

CTCAE Grade 3 platelet count decreased (platelets < 50,000/mm3)

CTCAE Grade 3 anemia (hemoglobin < 8 g/dL)
Doses scheduled for Days 8 and 15 may be delayed by up to 2 days. A delay of more than 
2 days will be considered a missed dose. Missed doses will not be replaced. The minimum 
interval needed between two infusions of study drugs is 5 days.
New text:
Study drug (copanlisib or placebo) is administered in a normal saline solution, intravenously, 
over approximately 1 h. See Pharmacy Manual for additional details (modified by 
amendment 1). No intravenous glucose preparations should be administered on the days of 
infusion.
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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The requirements for fasting and pre-dose glucose levels are presented in Table 6-1 (table 
added by amendment 1).
Table 6-1
Fasting requirements and pre-dose glucose levels
Period
Fasting ≥ 8 h required 
before first glucose 
measurement
Pre-dose glucose levels
(first glucose measurement)
Fasting required before 
study drug infusion
Day 1 of
cycle 1
Yes
≤125 mg/dL (non-diabetic patients)
<160 mg/dL (diabetic patients)
Yes a
Day 1 of 
subsequent 
cycles
Yes
<160 mg/dL (fasting)
< 200 mg/dL (non-fasting) c
Conditional a, b, d
Days 8 and 15 
of each cycle
No
<160 mg/dL (fasting)
<200 mg/dL (non-fasting)
Conditional a, b, d
a: Diabetic patients who take insulin treatment at any cycle visit: Timing and content of caloric 
intake on infusion days will be managed and monitored by the investigator. Consultation with 
treating physician or diabetes specialist is advised.
b: The decision regarding meal timing and fasting can be made by the investigator based on 
glucose response patterns during prior treatment days (see text below “Recommendations on 
meal timing on infusion days” for further details).
c: In case of non-compliance with the fasting requirement.
d: A low glycemic index meal may be taken at least 4 h before the start of the study drug infusion 
for patients who have their infusions scheduled at a later hour, or due to their age or medical 
condition when fasting prior to infusion is not viable.
The investigator will accurately document fasting/non-fasting for each glucose measurement 
done at the site. 

Fasting refers to a ≥ 8 h fast. (fasting requirements changed by amendment 1).

Non-fasting status includes any caloric intake such as meals and also juice, snacks, 
and other caloric intake not consistently called a meal.
From Cycle 1 Day 1 onwards, glucose measurements at the site may be done either by 
laboratory analysis or in capillary blood using a handheld glucose meter. If handheld glucose 
meters are chosen, the appropriate calibration of glucose meters will be documented.
Any capillary or plasma glucose levels > 250 mg/dL should be confirmed by repeated 
laboratory analysis.
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 and content of caloric intake on infusion days is managed and 
monitored by the investigators. Consultation with treating physician or diabetes specialist 
(e.g. diabetologist or endocrinologist) is advised.
The investigator will review the glucose profile during and post the study drug infusions. 


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The investigator may manage the timing of post-infusion meals based on the glucose profile 
during prior infusion(s) to minimize glucose increases. This is in addition to glucose lowering 
medication. Low glycemic index meals (see Appendix 14.7) should be provided for patients 
who are kept in clinic for continued observation.
A low glycemic index diet is recommended for the first 48 h after study drug infusion. 
However, caloric restriction is not intended for the population under study.
All glucose measurements, oral glucose lowering medication and/or insulin administration, if 
applicable, and meal timing will be collected as part of the clinical source documentation. 
Note: Caloric intake and timing recommendations for diabetic patients who require insulin 
treatment prior to the infusion at any cycle visit should be managed and monitored by the 
investigator based on consultation with treating physician or diabetes specialist.

On infusion days at any cycle:
The decision regarding meal timing and fasting can be made by the investigator based 
on glucose response patterns during prior treatment days.
Note: If patient needs to take a low glycemic meal, then glucose test should be taken 
prior to meal intake and at 1 h and 2 h after the meal (see Section 7.5.3.6).

Cycle 1 Day 1:  
Fasting is required before start of infusion. 
A low glycemic index meal (see Appendix 14.7) may be taken 3 h after start of 
infusion.

Day 1 of each subsequent cycle after Cycle 1 Day 1:
Fasting is required before the first glucose measurement.
After Cycle 1, a low glycemic index meal may be taken at least 4 h before the start of
the study drug infusion for patients who have their infusions scheduled at a later hour, 
or due to their age or medical condition when fasting prior to infusion is not viable.

Day 8 and Day 15 of each cycle:
Fasting is not required before start of infusion.
A low glycemic index meal may be taken at least 4 h before the start of the study drug 
infusion for patients who have their infusions scheduled at a later hour, or due to their 
age or medical condition when fasting prior to infusion is not viable.
Patients will continue study treatment until PD (per central independent blinded radiology 
review) or they meet the criteria described in Section 5.2.
[…]
If not previously done within 7 days, patients switching to open-label copanlisib must 
complete the following within 7 days prior to the first dose of open-label copanlisib: 
UPCR/24 h total urine protein quantification, GFR measurement, urinalysis, HbA1c, CBC, 
chemistry and coagulation panels. For Day 1 of the first open-label cycle, laboratory 


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parameters as outlined in inclusion criterion 13 and exclusion criteria 15 and 24 will apply. 
For Day 1 of subsequent open-label cycles, dosing criteria outlined in Table 6-2 will apply for 
patients who switch to open-label treatment.
[…]
Dosing criteria
Starting from Cycle 1 Day 8, 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. On Day 
1 of each subsequent cycle, the dose of study drug will be given only if the laboratory test 
criteria described in Table 6-2 are met.
[…]
A blood count will be performed and assessed prior to infusion on Days 8 and 15 of each 
cycle. The study drug will not be administered if, on the day of scheduled dosing, any of the 
following criteria is met:

CTCAE Grade ≥3 neutrophil count decreased (ANC < 1,000/mm3)

CTCAE Grade ≥3 platelet count decreased (platelets < 50,000/mm3)

CTCAE Grade ≥3 anemia (hemoglobin < 8 g/dL)
Doses scheduled for Days 1 (after Cycle 1 Day 1), 8 and 15 may be delayed by up to 2 days. 
A delay of more than 2 days will be considered a missed dose. Missed doses will not be 
replaced. The minimum interval needed between two infusions of study drugs is 5 days.
13.2.2.13 Section 6.4.1 Dose modification
Old text:
It is recognized that attribution of causality of any AE to the test drug specifically may be 
difficult. However, certain toxicities were seen only in relation to copanlisib in Phase I trials: 
e.g., hyperglycemia and arterial hypertension. Based on this knowledge the investigator may 
decide on the necessary dose modifications. 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.
New text:
It is recognized that attribution of causality of any AE to the test drug specifically may be 
difficult. However, certain toxicities were seen only in relation to copanlisib in Phase I trials: 
e.g., transient increases in glucose and blood pressure. Based on this knowledge the 
investigator may decide on the necessary dose modifications. 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.


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13.2.2.14 Section 6.4.1.1 Hematological toxicity
Old text:
[…]
Table 6-4
Dose modification of study treatment for hematological toxicity
Note: This table should not be used to determine patient eligibility for infusion on days 1, 8 and 15. 
Please follow specific guidance given for laboratory test criteria on days 1, 8 and 15 (note added by 
amendment 1)
Hematological toxicity of CTCAE Grade
(any of the following)
Study drug action (for all toxicities)
Grade 4 thrombocytopenia (platelet < 25,000/mm3) 
or Grade 3 (platelet < 50,000/mm3) with bleeding.
Febrile neutropenia.
Grade 4 neutropenia (ANC < 500/mm3).a
INR or PTT of Grade ≥3 with bleeding.
Grade 3 anemia (Hb < 8 g/dL).
Delay infusion until criteria displayed in 
Table 6-2 are met. Patient can be treated at 
one dose level lower at the investigator’s 
discretion.b If more dose reductions are 
required than allowed per protocol, 
discontinue study treatment permanently. 
The lowest dose level is 30 mg.
[…]
After having fully recovered from toxicity and in the absence of any criteria for further dose reduction 
or study drug discontinuation, re-escalation to dose level -1 or 1 will be allowed at the investigator’s 
discretion.
New text:
[…]
Table 6-4
Dose modification of study treatment for hematological toxicity
Note: This table should not be used to determine patient eligibility for infusion on days 1, 8 and 15. 
Please follow specific guidance given for laboratory test criteria on days 1, 8 and 15 (note added by 
amendment 1)
Hematological toxicity of CTCAE Grade
(any of the following)
Study drug action (for all toxicities)
Grade 4 thrombocytopenia (platelet < 25,000/mm3) 
or Grade 3 (platelet < 50,000/mm3) with bleeding.
Febrile neutropenia.
Grade 4 neutropenia (ANC < 500/mm3).a
INR or PTT of Grade ≥3 with bleeding.
Grade ≥3 anemia (Hb < 8 g/dL).
Delay infusion until criteria displayed in 
Table 6-2 are met.c Patient can be treated 
at one dose level lower at the investigator’s 
discretion.b If more dose reductions are 
required than allowed per protocol, 
discontinue study treatment permanently. 
The lowest dose level is 30 mg.
[…]
After having fully recovered from toxicity and in the absence of any criteria for further dose reduction 
or study drug discontinuation, re-escalation to dose level -1 or 1 will be allowed at the investigator’s 
discretion.
Treatment with transfusion or growth factors is allowed at the investigator’s discretion.


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13.2.2.15 Section 6.4.1.2 Non-hematological toxicity
Old text:
Dose modifications for non-hematologic toxicities except hyperglycemia, dermatologic 
toxicity, NIP and arterial hypertension are outlined in Table 6-5.
Table 6-5
Dose modification of study treatment for non-hematological toxicity
(except hyperglycemia, dermatologic toxicity, non-infectious pneumonitis 
and arterial hypertension)
[…]
[…]
Non-infectious pneumonitis 
In the event of NIP, an adjustment as described in Table 6-7 must be applied.
Table 6-7
Dose modification of study treatment for non-infectious pneumonitis (NIP)
Study drug action
Suspected or confirmed
NIP of CTCAE
For current course of therapy
Re-initiation of study drug 
(if recovered within 14 days)
Grade 1
No change
Not applicable
Grade 2
Interruption
Decrease by one dose levela
Grade 2 re-occurrence
Permanent discontinuation
No
Grade 3
Interruption
Case by case decision (after 
consulting the sponsor)
Grade 4
Permanent discontinuation
No
NIP = Non-infectious pneumonitis; CTCAE = Common Terminology Criteria for Adverse Events.
a: Not applicable for 30 mg dose level. No re-escalation is allowed after the dose reduction.
The lowest dose level is 30 mg; if a patient is already on the 30 mg 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. 
Hyperglycemia and arterial hypertension
a)
Hyperglycemia
Section modified by amendment 1.
Patients who develop transient post-infusion hyperglycemia (glucose intolerance) of
> 250 mg/dL after study drug administration may continue treatment. However, the next 
infusion must be delayed until the patient’s pre-infusion glucose levels return to < 160 mg/dL 
(fasting) or < 200 mg/dL (non-fasting). Guidelines for the treatment of hyperglycemia are 
given in Section 6.4.2.1.
A dose reduction of study drug by one dose level is mandatory in the event of asymptomatic 
hyperglycemia > 500 mg/dL. No further dose reductions will be allowed in the event of re-
occurrence of asymptomatic hyperglycemia > 500 mg/dL and the treatment will be 
permanently discontinued.


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If CTCAE Grade 4 glucose intolerance occurs, permanent discontinuation of the study drug is 
mandatory.
b)
Arterial hypertension
No dose should be given if blood pressure is ≥150/90 mmHg. Instructions for blood pressure 
measurement are given in Section 7.5.3.3. Antihypertensive medication may be given to 
control the arterial hypertension. Dosing can proceed on the scheduled day if there are at least 
2 consecutive measurements < 150/90 mmHg. Otherwise dosing must be delayed. 
If drug-related arterial hypertension (post-dose blood pressure of CTCAE Grade 3 or 
160/100 mmHg) is not manageable with optimal antihypertensive treatment, the dose for 
the subsequent study drug administrations may be reduced by 1 or 2 dose levels at the 
investigator’s discretion. Guidelines for the treatment of arterial hypertension are given in 
Section 6.4.2.3. Patients with a post-dose blood pressure of CTCAE Grade 4, i.e., a post-dose 
blood pressure that may have life-threatening consequences (e.g., malignant arterial 
hypertension, transient or permanent neurologic deficit, hypertensive crisis), or patients who 
require urgent intervention, must permanently discontinue the study drug.
New text:
Dose modifications for non-hematologic toxicities except glucose increases, dermatologic 
toxicity, NIP and arterial hypertension are outlined in Table 6-5.
Table 6-5
Dose modification of study treatment for non-hematological toxicity
(except glucose increases, dermatologic toxicity, non-infectious pneumonitis 
and arterial hypertension)
[…]
[…]


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Non-infectious pneumonitis 
In the event of NIP, an adjustment as described in Table 6-7 must be applied.
Table 6-7
Dose modification of study treatment for non-infectious pneumonitis (NIP)
Study drug action
Suspected or confirmed
NIP of CTCAE
For current course of therapy
Re-initiation of study drug 
(if recovered within 14 days)
Grade 1
No change
Not applicable
Grade 2
Interruption
Decrease by one dose levela
Grade 2 re-occurrence
Permanent discontinuation
No
Grade 3
Interruption
Case by case decision (after 
consulting the sponsor)
Grade 3 re-occurrence
Permanent discontinuation
No
Grade 4
Permanent discontinuation
No
NIP = Non-infectious pneumonitis; CTCAE = Common Terminology Criteria for Adverse Events.
a: Not applicable for 30 mg dose level. No re-escalation is allowed after the dose reduction.
The lowest dose level is 30 mg; if a patient is already on the 30 mg 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”.
Glucose increases and arterial hypertension
a)
Glucose increases
Section modified by amendment 1.
Patients who develop transient post-infusion glucose > 250 mg/dL after study drug 
administration may continue treatment. However, the next infusion must be delayed until the 
patient’s pre-infusion glucose levels return to < 160 mg/dL (fasting) or < 200 mg/dL (non-
fasting). Guidelines for the management of glucose increases are given in Section 6.4.2.1.

Continuing occurrence of post-infusion blood glucose > 400 mg/dL based on repeated 
laboratory analysis despite optimal glucose lowering therapy after 2 infusions of study 
drug will require dose reduction by one dose level.

Further dose reduction is allowed as long as discontinuation criteria was not met.

Dose re-escalation is allowed when a patient has achieved controlled glucose levels 
per investigator’s judgment.

Persistent occurrence of post-infusion blood glucose > 400 mg/dL based on laboratory 
analysis which occurred at the lowest study drug dose level despite optimal glucose 


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lowering therapy (after at least one cycle of treatment) with consultation of a diabetes 
specialist requires permanent discontinuation of the study treatment (see 
Section 5.2.1.1).
b)
Arterial hypertension
The guidelines for dose modifications of study drug in case of arterial hypertension are given 
in Table 6-8.
No dose should be given if blood pressure is ≥150/90 mmHg. Instructions for blood pressure 
measurement are given in Section 7.5.3.3. Antihypertensive medication may be given to 
control the arterial hypertension. Dosing can proceed on the scheduled day if there are at least 
2 consecutive measurements < 150/90 mmHg. Otherwise dosing must be delayed. 
If drug-related arterial hypertension (post-dose blood pressure of CTCAE Grade 3 or 
160/100 mmHg) is not manageable with optimal antihypertensive treatment, the dose for 
the subsequent study drug administrations may be reduced by 1 or 2 dose levels at the 
investigator’s discretion. Guidelines for the treatment of blood pressure increases are given in 
Section 6.4.2.3. Patients with a blood pressure of CTCAE Grade 4 must permanently 
discontinue the study drug (see Section 5.2.1.1).


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Table 6-8
Dose modification of study treatment for arterial hypertension
Toxicity (CTCAE)
Study drug action
Recommendation
Pre-dose measurements
BP ≥150/90 mmHg
No dose should be given until 
recovery to < 150/90 mmHg.
Consider BP lowering medication. Dosing 
can proceed on the scheduled day if after at 
least 2 consecutive measurements BP 
returns to < 150/90 mmHg. If BP doesn’t 
return to < 150/90 mmHg, delay dosing until 
next visit.
During infusion:
CTCAE hypertension of 
grade 3 
or ≥160/100 mmHg
Infusion can be interrupted or 
slowed down and administration 
of BP lowering therapy should 
be initiated.
Infusion may be resumed immediately when 
BP has returned to < 150/90 mmHg or 
skipped.
Subsequent study drug administrations may 
be reduced by 1 dose level at the 
investigator’s discretion.b
Post-dose:
Drug-related
CTCAE hypertension of 
grade 3
or ≥160/100 mmHga
–
Administration of BP lowering therapy should 
be initiated according to local standard of 
care.  
Additional measurements to be performed as 
clinically indicated until recovery to 
< 150/90 mmHg.
Subsequent study drug administrations may 
be reduced by 1 dose level at the 
investigator’s discretion.b
CTCAE hypertension of 
grade 4
Permanent discontinuation
–
CTCAE = Common Terminology Criteria for Adverse Events; BP = Blood pressure
a: Not manageable despite optimal antihypertensive treatment.
b: The lowest dose level is 30 mg. If a patient is already on the 30 mg dose level and experiences 
post-dose hypertension of CTCAE Grade 3 or ≥160/100 mmHg, consider more intensive 
therapy than previously used.
13.2.2.16 Section 6.4.2.1 Management of transient post-infusion glucose increases 
that can occur with study treatment
Old text:
Management of hyperglycemia that can occur with study treatment
a)
Management of transient post-infusion hyperglycemia
Section modified by amendment 1.
Only the use of rapid or short acting (regular) insulin is allowed for the treatment of transient 
hyperglycemia (glucose intolerance). The prophylactic administration of rapid or short acting 
(regular) insulin prior to study drug infusion is not permitted.
In the event of post-dose glucose > 250 mg/dL on the day of infusion, the administration of 
rapid or short acting (regular) insulin is recommended according the institution’s insulin 
sliding scale regimen.


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All patients (diabetic and non-diabetic) should be kept under close observation if the glucose 
level is > 250 mg/dL until the glucose level decreases to < 160 mg/dL at any cycle. In the 
event of rapid or short acting (regular) insulin administration at any cycle, a 3 h close 
observation time is required post-administration. Meals should be provided for patients who 
are kept for continued observation. A low dose carbohydrate diet is recommended for the first 
48 h after study drug infusion. However, carbohydrate restriction is not meant as caloric 
restriction in the population under study.
Patients will be trained to measure their capillary blood glucose levels at home starting at 
Screening and will be provided with glucose meter and supplies (lancets, test strips and diary) 
to register measured values and record insulin administration, if applicable. The appropriate 
calibration of glucose meters will be documented.
Patients who might need treatment with rapid or short acting insulin not only on the day of 
infusion should be referred to the local diabetes center/endocrinologist, to be trained to self-
administer rapid or short acting insulin and to be provided with insulin prescription and an 
insulin sliding scale regimen. Alternatively, the investigator will be free to adequately manage 
these patients in the same way as indicated above. A domiciliary support by specialized 
nurses (public or private) should be arranged for patients not able to co-operate (old age, no 
caregivers available) or who cannot be adequately trained to self-monitor home blood glucose 
or self-administer short acting insulin for any reason.
Monitoring of non-diabetic patients
Section modified by amendment 1.
All non-diabetic patients who experience hyperglycemia > 250 mg/dL or require insulin 
administration will be instructed to check blood glucose at home at least 3 times per full day 
for at least 72 h after the start of infusion. This includes fasting glucose (morning before 
breakfast) and 2 further random non-fasting measurements approximately 2 h after intake of 
food. If after the required 72 h the glucose values are not at goal (fasting glucose ≤125 mg/dL 
or random non-fasting glucose ≤160 mg/dL), this monitoring will continue until blood 
glucose values are at goal.
Monitoring of diabetic patients
Section clarified by amendment 1.
All diabetic patients will be instructed to check blood glucose at home at least 3 times per full 
day for at least 72 h after start of each infusion. This includes fasting glucose (morning before 
breakfast) and 2 further random non-fasting measurements approximately 2 h after intake of 
food. If after the required 72 h the glucose values are not at goal (fasting glucose < 160 mg/dL 
or random non fasting glucose < 200 mg/dL), this monitoring will continue until blood 
glucose values are at goal, and the patient should be immediately referred to the local diabetes 
center/endocrinologist to adjust treatment.
If the patient already monitors his/her blood glucose as part of routine antidiabetic care, the 
routine measurements should not be replaced by the study specific measurements. In this 
situation, patients should add the study specific measurements to their routine, if applicable. 


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After the required 72 h, if blood glucose values are at goal (fasting glucose < 160 mg/dL or
random non-fasting glucose < 200 mg/dL) after each infusion, patients can then stop only the 
study specific measurements until the next day of infusion, but should keep their routine 
measurements unchanged and ongoing as usual.
Sites recruiting patients with diabetes should have the option to extend glucose monitoring 
overnight.
b)
Management of diabetic patients (non-transient hyperglycemia) for the duration of 
the study
It is generally recommended that patients with a pre-existing or new onset diagnosis of 
diabetes mellitus adhere to their regular medication schedule, and take their usual doses on the 
days of study drug infusion. Modifications are recommended if deemed necessary for changes 
in uptake of food. 
To monitor non-transient hyperglycemia fasting glucose is recommended. Glucose 
measurement prior to the infusion on Day 1 of each cycle is needed for the management of 
non-transient hyperglycemia (modified by amendment 1). The following guideline applies:
The anti-diabetic regimen is to be continued if glucose values are at goal (fasting glucose 
< 160 mg/dL and random non-fasting glucose < 200 mg/dL).
If fasting glucose is ≥ 160 mg/dL or random non-fasting glucose is ≥ 200 mg/dL the patient 
should be immediately referred to the local diabetes center/endocrinologist to adjust 
treatment.
New text:
Management of transient post-infusion glucose increases that can occur with 
study treatment
Management of transient post-infusion glucose increases on infusion days
Section modified by amendment 1.
Mild to moderate asymptomatic increases of blood glucose may occur with copanlisib 
infusion, and with larger increases potentially occurring post-prandially.
The guidelines for management of transient post-infusion glucose increases on infusion days 
are given in Table 6-9.


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Table 6-9
Management of transient post-infusion glucose increases
Criteria 
Recommendation
Suggested Treatment
On infusion days: 
Asymptomatic glucose 
increases ≤ 250 mg/dL
Does not generally require treatment 
with glucose lowering medication
None
Asymptomatic glucose 
increases > 250 mg/dL
Should have repeated laboratory 
glucose determination
If the repeated glucose value is 
decreasing, the glucose may be 
followed without glucose lowering 
medication treatment if hydration 
status is normal as clinically 
assessed
Consultation with diabetes specialist 
is recommended
Hydration if appropriate 
When planning next infusion 
consider prophylaxis with oral 
glucose lowering medication
Symptomatic or persisting 
glucose increases 
> 250 mg/dL
Hydration status should be clinically 
assessed
If clinical assessment is consistent 
with dehydration, fluids should be 
given as clinically appropriate (orally 
or IV).
Laboratory test confirming increase 
should be repeated. If the repeated 
glucose value is > 250 mg/dL and/or 
patient is symptomatic and/or the 
hydration status indicate the need for 
hydration, glucose lowering 
medication should be administered
Prompt input from a diabetes 
specialist should be obtained. 
Hydration if appropriate 
Rapid/short acting insulin may 
be given for glucose persisting 
at > 250 mg/dL, or if the patient 
is symptomatic during the 
infusion day.
Rapid/short acting insulin 
according to the institution 
sliding scale coverage of 
glucose persisting at > 250 
mg/dL is recommended, with 
oral or IV hydration as clinically 
appropriate.
When planning next infusion 
consider prophylaxis with oral 
glucose lowering medication
On subsequent days:
Max post-infusion glucose 
> 200 mg/dL noted on 
subsequent days
Oral glucose lowering medication 
recommended on subsequent days
Consultation with diabetes specialist 
is recommended
The use of 
sulphonylurea/metaglinides 
insulin secretagogues 
medications to manage 
increased glucose levels post 
drug infusions is not 
recommended.
Treatment with glucose lowering 
medication suggested according 
the local standards of practice. 
Based on mechanisms of action 
and decreased risk of 
hypoglycemia, metformin, 
SGLT-2-inhibitor or DPP4-
inhibitor might be useful 
treatment options
DPP4 = Dipeptidyl peptidase-4; IV = intravenous; SGLT-2 = Sodium/glucose co-transporter 2


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Glucose monitoring at home
At least 3 times per full day including fasting glucose (morning before breakfast) and 
2 further measurements approximately 2 h after intake of food for at least 72 h after the start 
of infusion is required for: 

All diabetic patients regardless of glucose level on infusion day

Non-diabetic patients who experience persisting glucose > 250 mg/dL or who require 
insulin administration post-infusion. Consultation with diabetes specialist is 
recommended.
Patients will be trained how to measure their capillary blood glucose levels at home. If 
applicable, patients will be provided with glucose meter and supplies (lancets, test strips and 
diary) to register measured values and record meal timing, oral glucose lowering medication 
and/or insulin administration. The appropriate calibration of glucose meters will be 
documented.
Monitoring of diabetic patients
Section clarified by amendment 1.
If the patient already monitors his/her blood glucose as part of routine antidiabetic care, the 
routine measurements should not be replaced by the study specific measurements. In this 
situation, patients should add the study specific measurements to their routine, if applicable. 
After the required 72 h, if blood glucose values are at goal (random non-fasting glucose < 
200 mg/dL) after each infusion, patients can then stop only the study specific measurements 
until the next day of infusion, but should keep their routine measurements unchanged and 
ongoing as usual.
Sites recruiting patients with diabetes should have the option to extend glucose monitoring 
overnight.
13.2.2.17 Section 6.4.2.2 Management of hyperlipidemia
Old text:
Although there is a paucity of data on the effects of hyperlipidemia and cancer outcomes, 
these goals have been chosen to decrease risk of established complications of 
hypertriglyceridemia (pancreatitis) and hypercholesterolemia (cardiovascular events). For 
evaluation of lipid-panels including triglycerides the patient would be required to be fasted for 
11 h prior to sampling. For patients who cannot adhere to these fasting requirements the 
evaluation of lipid-panels including triglycerides and determination of treatment is considered 
as not feasible.
New text:
Although there is a paucity of data on the effects of hyperlipidemia and cancer outcomes, 
these goals have been chosen to decrease risk of established complications of 


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hypertriglyceridemia (pancreatitis) and hypercholesterolemia (cardiovascular events). For 
evaluation of lipid-panels including triglycerides, patients must be fasting prior to sampling 
according to local standards. For patients who cannot adhere to fasting requirements the 
evaluation of lipid-panels including triglycerides is considered as not feasible.
13.2.2.18 Section 6.4.2.3 Treatment of blood pressure increases associated with 
study treatment
Old text:
Treatment of arterial hypertension associated with study treatment
[…]
Topical nitrates should also be considered. Verapamil and diltiazem (non-dihydropyridine 
calcium channel blockers) should be avoided due to a potential CYP3A4 interaction. In 
general, it is advisable for sites to be prepared so that antihypertensive medication is readily 
available in case of need.
New text:
Treatment of blood pressure increases associated with study treatment
[…]
Topical nitrates should also be considered. Verapamil and diltiazem (non-dihydropyridine 
calcium channel blockers and moderate inhibitors of CYP 3A4) should be used with caution
due to a potential CYP3A4 interaction. In general, it is advisable for sites to be prepared so 
that antihypertensive medication is readily available in case of need.
13.2.2.19 Section 6.9.1 Prohibited concomitant therapy
Old text:
[…]

Systemic corticosteroid therapy at a daily dose higher than 15 mg prednisone or 
equivalent. Previous corticosteroid therapy must be stopped or reduced to the allowed 
dose 7 days prior to the screening CT/MRI and again prior to the first administration 
of study drug.
New text:
[…]

Systemic corticosteroid therapy at a daily dose higher than 15 mg prednisone or 
equivalent. Previous corticosteroid therapy must be stopped or reduced to the allowed 
dose at least 7 days prior to the screening CT/MRI.


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13.2.2.20 Section 6.9.2 Permitted concomitant therapy
Old text:
[…]

Patients taking narrow therapeutic index medications should be monitored proactively, 
if these medications cannot be avoided. These medications may include quinidine, 
cyclosporine and digoxin.
New text:
[…]

Patients taking narrow therapeutic index medications should be monitored proactively, 
if these medications cannot be avoided. These medications may include quinidine and 
digoxin.


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13.2.2.21 Section 7.1.1 Tabulated overview
Old text:
Screening 
maximum days 
before C1D1
Treatment *
EOT
SFU
Active 
follow-
up aa
Survival
follow-
up bb
Cycle 1
Cycle 2 and higher
Within (days) after
Days
-28 -14
-7
D1
D4
D8
D15
D22
D1
D8
D15
D22 y
7
30-35 z
every 3 
months
Acceptable deviation (in days)
-1 to +2 days
-1 to +2 days
Decision 
to stop
Last 
dose
14 days
[…]
Serum pregnancy test (if applicable) c
X
Xc
UPCR
X
[…]
Quality of life questionnaire (FLymSI-18) q 
X
X
X
X
[…]
*
NOTE: Patients who experience PD on placebo treatment (per central independent blinded radiology review) can be offered open-label copanlisib upon 
discretion of the investigator and patient’s consent. After individual patient unblinding, patients receiving placebo who switch to open-label copanlisib will 
have all study assessments and timing reset to the initial schedule of study evaluations (i.e. as if the patient was restarting the study at Cycle 1 Day 1). If not 
previously done within 7 days, patients switching to open-label copanlisib must complete the following within 7 days prior to the first dose of open-label 
copanlisib: UPCR measurement, GFR measurement, urinalysis, HbA1c, CBC, chemistry and coagulation panels (see dosing criteria in Table 6-3) (clarified 
by amendment 1).
[…]
c
After Cycle 1 serum pregnancy test is mandatory at every cycle for France, Belgium, Canada and other countries where it is required by local 
regulations.
[…]
i
HbA1c at Screening, on Day 1 of every odd cycle (3, 5, 7, etc.) starting from Cycle 3 and at the EOT visit.
[…]
k
Chemistry panel: calcium, sodium, potassium, chloride, phosphorous, magnesium, bicarbonate (or carbon dioxide, if bicarbonate is not 
routinely measured at the site), total protein, albumin, glucose, BUN (or urea if BUN is not routinely measured at the site), SCR, uric acid, 


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total bilirubin, creatine phosphokinase, ALT, AST, LDH, ALP, lipase, amylase (or pancreatic amylase, if total amylase is not routinely 
measured at the site), cholesterol (total and LDL) and triglycerides (modified by amendment 1). 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 
for 11 h prior to sampling. If a patient can’t adhere to fasting requirements, the evaluation of lipid-panels including triglycerides is considered 
not feasible.
l
On Cycle 1 Day 1, glucose will be measured at pre-dose and after the start of study drug infusion (post-infusion). For patients who had a low 
carbohydrate breakfast prior to the start of infusion, glucose monitoring will be up to 3 h post-infusion (1 h, 2 h and 3 h). For patients who did 
not have a low carbohydrate breakfast prior to infusion, monitoring will continue for up to 5 h post-infusion (1 h, 2 h and 5 h). Additional 
measurements to be performed at the clinic as clinically indicated. On subsequent infusions, glucose will be measured prior to and after 
infusion. The pre-dose glucose sample on Day 1 of each cycle should be after an 8 h fasting. On Cycle 1 Day 1, patient’s fasting pre-dose 
glucose level should be ≤125 mg/dL (non-diabetic patients) or < 160 mg/dL (diabetic patients) before the infusion. Pre-dose glucose levels 
for subsequent infusions should be < 160 mg/dL (fasting) or < 200 mg/dL (non-fasting). For fasting requirements, see Section 6.4 (footnote 
changed by amendment 1).
m
Home glucose monitoring is required for all diabetic patients after each infusion. For non-diabetic patients home glucose measurement is 
required if patients develop hyperglycemia > 250 mg/dL or require insulin administration after any infusion. Measurements should be taken at 
least 3 times per full day for at least 72 h after the start of infusion. This includes fasting glucose (morning before breakfast) and 2 further 
random non-fasting measurements approximately 2 h after intake of food. If after the required 72 h the glucose values are not at goal (fasting 
glucose ≤125 mg/dL/< 160 mg/dL or random non-fasting glucose ≤160 mg/dL/< 200 mg/dL for non-diabetic/diabetic patients, respectively), 
this monitoring will continue until blood glucose values are at goal. Patients will be trained to measure their capillary blood glucose levels at 
home starting at Screening. On Cycle 1 Day 1, patients will be provided with glucose meter and supplies, (lancets, test strips and diary) to 
record glucose values and insulin doses, if applicable (footnote changed by amendment 1). For details see Section 6.4.2.1.
n
Blood pressure will be measured every 5-10 min prior to infusion of study drug (no more than 4 measurements) until there are 2 consecutive 
results < 150/90 mmHg. If blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention or delaying the infusion of 
study drug. At Cycle 1 Day 1 blood pressure will be measured at 0 h (pre-dose), 30 min (mid-infusion), 60 min (end of infusion), 90 min, 2 h, 3 
h, 4 h and 6 h after the start of infusion (deviation 5 min). From Cycle 1 Day 8 onwards a single blood pressure measurement is to be 
performed prior to each infusion, 30 min after the start of infusion and at the end of each infusion (deviation of 5 min is allowed). The patient 
should rest for 5-10 min before blood pressure is recorded (modified by amendment 1).
[…]
p
[…] 
During Active follow-up period patients will have radiological assessments at same intervals as during treatment (time window of ±14 days is 
allowed) until PD is documented or new anti-tumor treatment is administered (see Section 7.1.2.3 and Section 7.3.2) (footnote changed by 
amendment 1).


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New text:
Screening 
maximum days 
before C1D1
Treatment *
EOT
SFU
Active 
follow-
up aa
Survival
follow-
up bb
Cycle 1
Cycle 2 and higher
Within (days) after
Days
-28 -14
-7
D1
D4
D8
D15
D22
D1
D8
D15
D22 y
7
30-35 z
every 3 
months
Acceptable deviation (in days)
-1 to +2 days
-1 to +2 days
Decision 
to stop
Last 
dose
14 days
[…]
Serum pregnancy test (if applicable) c
X
Xc
Xc, ee
UPCR / 24 h total urine protein 
quantification ee
X
[…]
Quality of life questionnaire (FLymSI-18) and 
PRO information sheet q, ee
X
X
X
X
[…]
*
NOTE: Patients who experience PD on placebo treatment (per central independent blinded radiology review) can be offered open-label copanlisib upon 
discretion of the investigator and patient’s consent. After individual patient unblinding, patients receiving placebo who switch to open-label copanlisib will 
have all study assessments and timing reset to the initial schedule of study evaluations (i.e. as if the patient was restarting the study at Cycle 1 Day 1). For 
further information on laboratory requirements for patients who switch to open-label treatment, please see Section 7.1.2.2 (clarified by amendment 1).
[…]
c
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.
[…]
i
HbA1c at Screening, on Day 1 of every odd cycle (3, 5, 7, etc.) starting from Cycle 3 and at the EOT visit. The testing is not required if the 
previous test was performed within 4 weeks preceding EOT visit.
[…]
k
Chemistry panel: calcium, sodium, potassium, chloride, phosphorous, magnesium, bicarbonate (or carbon dioxide, if bicarbonate is not 
routinely measured at the site), total protein, albumin, glucose, BUN (or urea if BUN is not routinely measured at the site), SCR, uric acid, 
total bilirubin, creatine phosphokinase, ALT, AST, LDH, ALP, lipase, amylase (or pancreatic amylase, if total amylase is not routinely 
measured at the site), cholesterol (total and LDL) and triglycerides (modified by amendment 1). 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 


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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.
l
On Cycle 1 Day 1, glucose will be measured at pre-dose and post-dose after the end of study drug infusion (0), 1 h and 2 h. Additional 
measurements to be performed at the clinic as clinically indicated. On subsequent infusions, glucose will be measured prior to and 1 h after 
the end of infusion. Deviation of ± 5 min is allowed for glucose measurements, except for the pre-dose measurement. The pre-dose glucose 
sample on Day 1 of each cycle should be after an 8 h fasting. For details on fasting requirements and pre-dose glucose levels, see 
Section 6.4. Glucose is also measured as part of the chemistry panel (footnote changed by amendment 1).
m
Home glucose monitoring is required for all diabetic patients after each infusion. For non-diabetic patients home glucose measurement is 
required if patients experience persisting glucose > 250 mg/dL or require insulin administration post-infusion. Measurements should be 
performed according to guidance provided in Section 6.4.2.1. Patients will be trained to measure their capillary blood glucose levels at home 
starting at Screening. On Cycle 1 Day 1, patients will be provided with glucose meter and supplies, (lancets, test strips and diary) to record 
glucose values, meal timing, oral glucose lowering medication and/or insulin administration, if applicable (footnote changed by amendment 
1).
n
Blood pressure will be measured every 5-10 min prior to infusion of study drug (no more than 4 measurements) until there are 2 consecutive 
results < 150/90 mmHg. If blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention or delaying the infusion of 
study drug. On infusion days, blood pressure will be measured at 0 h (pre-dose), 30 min (mid-infusion), 60 min (end of infusion); and 1 h and 
2 h after the end of infusion. Time window of ± 10 min is allowed for all blood pressure measurements except for 0 h (pre-dose). The patient 
should rest for 5-10 min before blood pressure is recorded (modified by amendment 1).
[…]
p
[…]
During Active follow-up period patients will have radiological assessments at same intervals as during treatment (time window of ±14 days is allowed) until 
PD is documented or new anti-tumor treatment is administered (see Section 7.1.2.3 and Section 7.3.2). For tumor assessments in patients with WM, see 
Section 7.3.3 (footnote changed by amendment 1).


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13.2.2.22 Section 7.1.2 Timing of assessments
Old text:
[…]
All procedures during the treatment period should be done according to the relative days 
mentioned in this CSP. Deviations of -1 day and +2 days are acceptable with the exception of 
blood glucose (or capillary glucose sampling via glucose meter) and blood pressure 
measurement before study drug infusion (modified by amendment 1).
New text:
[…]
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 (modified by amendment 1).
13.2.2.23 Section 7.1.2.1 Screening period
Old text:
[…]
Less than 28/14 days before the first administration of study drug:
[…]
Less than 7 days before the first administration of study drug:
[…]

UPCR measurement (see Section 7.5.3.1).

GFR measurement (see Section 7.5.3.1 and Appendix 14.5).

Blood tests for HbA1c, CBC, chemistry and coagulation panels (see Section 7.5.3.1). 
Patients must be fasting for 11 h prior to sampling. If a patient can’t adhere to fasting 
requirements, the evaluation of lipid-panels including triglycerides is considered not 
feasible.
New text:
[…]
Within 28/14 days before the first administration of study drug:
[…]
Within 7 days before the first administration of study drug:
[…]

UPCR/24 h total urine protein quantification (see Section 7.5.3.1).

GFR measurement (see Section 7.5.3.1 and Appendix 14.5).


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
Blood tests for HbA1c, CBC, chemistry and coagulation panels (see Section 7.5.3.1). 
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.
13.2.2.24 Section 7.1.2.2 Treatment period
Old text:
[…]
If not previously done within 7 days, patients switching to open-label copanlisib must 
complete the following within 7 days prior to the first dose of open-label copanlisib: UPCR 
measurement, GFR measurement, urinalysis, HbA1c, CBC, chemistry and coagulation panels. 
Dosing criteria outlined in Table 6-2 apply also for patients who switch to open-label 
treatment (clarified by amendment 1).
New text:
[…]
If not previously done within 7 days, patients switching to open-label copanlisib must 
complete the following within 7 days prior to the first dose of open-label copanlisib: 
UPCR/24 h total urine protein quantification, GFR measurement, urinalysis, HbA1c, CBC, 
chemistry and coagulation panels. For Day 1 of the first open-label cycle, laboratory 
parameters as outlined in inclusion criterion 13 and exclusion criteria 15 and 24 will apply. 
For Day 1 of subsequent open-label cycles, dosing criteria outlined in Table 6-2 will apply for 
patients who switch to open-label treatment (clarified by amendment 1).
13.2.2.25 Section 7.1.2.2.1 Treatment – Cycle 1
Old text:
Cycle 1 Day 1
On Cycle 1 Day 1, patients should be fasting for at least 8 h prior to the pre-dose glucose 
measurement. After pre-dose glucose measurement and approximately within 1 h before the 
start of study drug infusion patients can have a low carbohydrate breakfast. Patient’s fasting 
pre-dose glucose level should be ≤ 125 mg/dL (non-diabetic patients) or < 160 mg/dL 
(diabetic patients) (fasting requirements changed by amendment 1) (see also Section 6.4).
[…]

Glucose measurement: on Cycle 1 Day 1, glucose will be measured at pre-dose and 
after the start of study drug infusion (post-infusion). For patients who had a low 
carbohydrate breakfast prior to the start of infusion, glucose monitoring will be up to 
3 h post-infusion (1 h, 2 h and 3 h). For patients who did not have a low carbohydrate 
breakfast prior to infusion, monitoring will continue for up to 5 h post-infusion (1 h, 
2 h and 5 h). Additional measurements to be performed at the clinic as clinically 
indicated. The pre-dose glucose sample on Cycle 1 Day 1 should be after an 8 h 
fasting (changed by amendment 1) (see Section 6.4).


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
Home blood glucose monitoring (modified by amendment 1): 
o
Diabetic patients: all patients.
o
Non-diabetic patients who experience hyperglycemia > 250 mg/dL or require 
insulin administration.

Training on glucose self-monitoring with a glucose meter, if needed. Patients will be 
provided with glucose meter and supplies (lancets, test strips and diary) to record 
glucose values and insulin doses, if applicable (changed by amendment 1).

Blood pressure will be measured every 5-10 min prior to infusion of study drug (no 
more than 4 measurements) until there are 2 consecutive results < 150/90 mmHg. If 
blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention 
or delaying the infusion of study drug. On Cycle 1 Day 1 blood pressure will be 
measured at 0 h (pre-dose), 30 min (mid-infusion), 60 min (end of infusion), 90 min,
2 h, 3 h, 4 h and 6 h after the start of infusion (deviation of 5 min is allowed). The 
patient should rest for 5-10 min before blood pressure is recorded (modified by 
amendment 1).
Cycle 1 Day 4

Review of blood glucose measurements, if applicable. Patients, who might need 
treatment with insulin not only on the day of infusion, should be referred to the local 
diabetes center/endocrinologist to be trained to self- administer insulin, and to be 
provided with insulin prescription and an insulin sliding scale regimen. Investigators 
will be free to manage hyperglycemic patients in the same way. If indicated, 
domiciliary support will be arranged.
Cycle 1 Day 8 and 15
[…]

Glucose test prior to and after study drug IV infusion. Patients are not required to be 
fasting prior to pre-dose glucose measurement (changed by amendment 1) (see 
Section 6.4).

Review of the home blood glucose measurements/insulin administration, if applicable. 
Provide glucose monitoring supplies if necessary (changed by amendment 1) (see 
Section 6.4.2.1).

Home blood glucose monitoring:
o
Diabetic patients: all patients.
o
Non-diabetic patients who experience hyperglycemia > 250 mg/dL or require 
insulin administration (modified by amendment 1).

Blood pressure will be measured every 5-10 min prior to infusion of study drug (no 
more than 4 measurements) until there are 2 consecutive results < 150/90 mmHg. If 
blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention 


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or delaying the infusion of study drug. From Cycle 1 Day 8 onwards a single blood 
pressure measurement is to be performed prior to each infusion, 30 min after the start 
of infusion and at the end of each infusion (deviation of 5 min is allowed). The 
patient should rest for 5-10 min before blood pressure is recorded (modified by 
amendment 1).
[…]
Cycle 1 Day 22
[…]

Review of the home blood glucose measurements/insulin administration, if applicable. 
Provide glucose monitoring supplies if necessary (changed by amendment 1) (see 
Section 6.4.2.1).
New text:
Cycle 1 Day 1
On Cycle 1 Day 1, patients should be fasting for at least 8 h prior to the pre-dose glucose 
measurement. For details on fasting requirements and pre-dose glucose levels, see Section 6.4
(fasting requirements changed by amendment 1).
[…]

Glucose will be measured at pre-dose and post-dose after the end of study drug 
infusion (0), 1 h and 2 h (deviation of 5 min is allowed, except for the pre-dose 
measurement). Additional measurements to be performed at the clinic as clinically 
indicated.
Note: If patient needs to take a low glycemic meal, then glucose test should be taken 
prior to meal intake and at 1 h and 2 h after the meal (see Section 6.4 and 
Section 7.5.3.6) (changed by amendment 1).

Home blood glucose monitoring (modified by amendment 1): 
o
All diabetic patients regardless of glucose level on infusion day.
o
Non-diabetic patients who experience persisting glucose > 250 mg/dL or who 
require insulin administration post-infusion.

Training on glucose self-monitoring with a glucose meter, if needed. Patients will be 
provided with glucose meter and supplies (lancets, test strips and diary) to record 
glucose values, meal timing, oral glucose lowering medication and/or insulin 
administration, if applicable (see Section 6.4.2.1) (changed by amendment 1).

Blood pressure will be measured every 5-10 min prior to infusion of study drug (no 
more than 4 measurements) until there are 2 consecutive results < 150/90 mmHg. If 
blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention 
or delaying the infusion of study drug. Blood pressure will be measured at 0 h (pre-
dose), 30 min (mid-infusion), 60 min (end of infusion); and 1 h and 2 h after the end
of infusion. Time window of ± 10 min is allowed for all measurements except for 0 h 


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(pre-dose). The patient should rest for 5-10 min before blood pressure is recorded 
(modified by amendment 1).
[…]
Cycle 1 Day 4

Review of blood glucose measurements, meal timing, oral glucose lowering 
medication and/or insulin administration, if applicable. Patients, who might need 
treatment with glucose lowering medications not only on the day of infusion, may be 
referred to the local diabetes center/endocrinologist for glucose management if 
appropriate e.g. to be trained to self- administer insulin or oral glucose lowering 
medication, and to be provided with glucose lowering medication prescription and an 
insulin sliding scale regimen, if applicable. Investigators will be free to manage 
patients in the same way as described in Section 6.4.2.1. If indicated, domiciliary 
support will be arranged.
Cycle 1 Day 8 and 15
[…]

Glucose test prior to study drug infusion and 1 h after the end of study drug infusion 
(deviation of 5 min is allowed, except for the pre-dose measurement). Patients are 
not required to be fasting prior to pre-dose glucose measurement.
Note: If patient needs to take a low glycemic meal, then glucose test should be taken 
prior to meal intake and at 1 h and 2 h after the meal (see Section 6.4 and 
Section 7.5.3.6) (changed by amendment 1).

Review of the home blood glucose measurements/meal timing/oral glucose lowering 
medication/insulin administration, if applicable. Provide glucose monitoring supplies 
if necessary (changed by amendment 1) (see Section 6.4.2.1).

Home blood glucose monitoring:
o
All diabetic patients regardless of glucose level on infusion day.
o
Non-diabetic patients who experience persisting glucose > 250 mg/dL or who
require insulin administration post-infusion (modified by amendment 1).

Blood pressure will be measured every 5-10 min prior to infusion of study drug (no 
more than 4 measurements) until there are 2 consecutive results < 150/90 mmHg. If 
blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention 
or delaying the infusion of study drug. Blood pressure will be measured at 0 h (pre-
dose), 30 min (mid-infusion), 60 min (end of infusion); and 1 h and 2 h after the end 
of infusion. Time window of ± 10 min is allowed for all measurements except for 0 h 
(pre-dose). The patient should rest for 5-10 min before blood pressure is recorded 
(modified by amendment 1).
[…]


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Cycle 1 Day 22
[…]

Review of the home blood glucose measurements/meal timing/oral glucose lowering 
medication/insulin administration, if applicable. Provide glucose monitoring supplies 
if necessary (changed by amendment 1) (see Section 6.4.2.1).
13.2.2.26 Section 7.1.2.2.2 Treatment – Cycle 2 and higher
Old text:
Cycle 2 and higher, Day 1
On Day 1 of each subsequent cycle, patients should be fasting for at least 8 h prior to the pre-
dose glucose measurement. After pre-dose glucose measurement patients can have a low 
carbohydrate breakfast. Patient’s fasting pre-dose glucose level should be < 160 mg/dL 
(fasting) or, in case of non-compliance with fasting requirements, < 200 mg/dL (non-fasting)
(added by amendment 1) (see also Section 6.4).
[…]
Serum pregnancy test: after Cycle 1 serum pregnancy test is mandatory at every cycle for 
France, Belgium, Canada and other countries where it is required by local regulations.
[…]

Blood tests for CBC, chemistry and coagulation panels (see Section 6.4 and 
Section 7.5.3.1). Total cholesterol, LDL and triglycerides will be determined on Day 1 
of every 2nd cycle starting from Cycle 2. On these days patients must be fasting for 
11 h prior to sampling. If a patient can’t adhere to fasting requirements, the evaluation 
of lipid-panels including triglycerides is considered not feasible.

[…]

Glucose test prior to and after study drug IV infusion. The pre-dose glucose sample on 
Day 1 of each cycle should be after an 8 hour fasting (changed by amendment 1) (see 
Section 6.4). 

Review of the home blood glucose measurements/insulin administration, if applicable. 
Provide glucose monitoring supplies if necessary (changed by amendment 1) (see 
Section 6.4.2.1).

Home blood glucose monitoring:
o
Diabetic patients: all patients.
o
Non-diabetic patients who experience hyperglycemia > 250 mg/dL or require 
insulin administration (modified by amendment 1).

Blood pressure will be measured every 5-10 min prior to infusion of study drug (no 
more than 4 measurements) until there are 2 consecutive results < 150/90 mmHg. If 
blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention 
or delaying the infusion of study drug. From Cycle 1 Day 8 onwards a single blood 


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pressure measurement is to be performed prior to each infusion, 30 min after the start 
of infusion and at the end of each infusion (deviation of 5 min is allowed). The 
patient should rest for 5-10 min before blood pressure is recorded (modified by 
amendment 1).
[…]
Cycle 2 and higher, Day 8 and 15
[…]

Glucose test prior to and after study drug IV infusion. Patients are not required to be 
fasting prior to pre-dose glucose measurement (changed by amendment 1) (see 
Section 6.4). 

Review of the home blood glucose measurements/insulin administration, if applicable. 
Provide glucose monitoring supplies if necessary (changed by amendment 1) (see 
Section 6.4.2.1).

Home blood glucose monitoring:
o
Diabetic patients: all patients.
o
Non-diabetic patients who experience hyperglycemia > 250 mg/dL or require 
insulin administration (modified by amendment 1).

Blood pressure will be measured every 5-10 min prior to infusion of study drug (no 
more than 4 measurements) until there are 2 consecutive results < 150/90 mmHg. If 
blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention 
or delaying the infusion of study drug. From Cycle 1 Day 8 onwards a single blood 
pressure measurement is to be performed prior to each infusion, 30 min after the start 
of infusion and at the end of each infusion (deviation of 5 min is allowed). The 
patient should rest for 5-10 min before blood pressure is recorded (modified by 
amendment 1).
New text:
Cycle 2 and higher, Day 1
On Day 1 of each subsequent cycle, patients should be fasting for at least 8 h prior to the pre-
dose glucose measurement. For details on fasting requirements and pre-dose glucose levels, 
see Section 6.4 (added by amendment 1).
[…]
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.
[…]

Blood tests for CBC, chemistry and coagulation panels (see Section 6.4 and 
Section 7.5.3.1). Total cholesterol, LDL and triglycerides will be determined on Day 1 
of every 2nd cycle starting from Cycle 2. On these days patients must be fasting prior 


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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.

[…]

Glucose test prior to study drug infusion and 1 h after the end of study drug infusion 
(deviation of 5 min is allowed, except for the pre-dose measurement). The pre-dose 
glucose sample on Day 1 of each cycle should be after an 8 h fasting
Note: If patient needs to take a low glycemic meal, then glucose test should be taken 
prior to meal intake and at 1 h and 2 ho after the meal (see Section 6.4 and 
Section 7.5.3.6) (changed by amendment 1). 

Review of the home blood glucose measurements/meal timing/oral glucose lowering 
medication/insulin administration, if applicable. Provide glucose monitoring supplies 
if necessary (changed by amendment 1) (see Section 6.4.2.1).

Home blood glucose monitoring:
o
All diabetic patients regardless of glucose level on infusion day.
o
Non-diabetic patients who experience persisting glucose > 250 mg/dL or who
require insulin administration post-infusion (modified by amendment 1).

Blood pressure will be measured every 5-10 min prior to infusion of study drug (no 
more than 4 measurements) until there are 2 consecutive results < 150/90 mmHg. If 
blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention 
or delaying the infusion of study drug. Blood pressure will be measured at 0 h (pre-
dose), 30 min (mid-infusion), 60 min (end of infusion); and 1 h and 2 h after the end 
of infusion. Time window of ± 10 min is allowed for all measurements except for 0 h 
(pre-dose). The patient should rest for 5-10 min before blood pressure is recorded 
(modified by amendment 1).
[…]
Cycle 2 and higher, Day 8 and 15
[…]

Glucose test prior to study drug infusion and 1 h after the end of study drug infusion 
(deviation of 5 min is allowed, except for the pre-dose measurement). Patients are 
not required to be fasting prior to pre-dose glucose measurement 
Note: If patient needs to take a low glycemic meal, then glucose test should be taken 
prior to meal intake and at 1 h and 2 h after the meal (see Section 6.4 and 
Section 7.5.3.6) (changed by amendment 1). 

Review of the home blood glucose measurements/meal timing/oral glucose lowering 
medication/insulin administration, if applicable. Provide glucose monitoring supplies 
if necessary (changed by amendment 1) (see Section 6.4.2.1).

Home blood glucose monitoring:


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o
All diabetic patients regardless of glucose level on infusion day.
o
Non-diabetic patients who experience persisting glucose > 250 mg/dL or who
require insulin administration post-infusion (modified by amendment 1).

Blood pressure will be measured every 5-10 min prior to infusion of study drug (no 
more than 4 measurements) until there are 2 consecutive results < 150/90 mmHg. If 
blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention 
or delaying the infusion of study drug. Blood pressure will be measured at 0 h (pre-
dose), 30 min (mid-infusion), 60 min (end of infusion); and 1 h and 2 h after the end 
of infusion. Time window of ± 10 min is allowed for all measurements except for 0 h 
(pre-dose). The patient should rest for 5-10 min before blood pressure is recorded 
(modified by amendment 1).
13.2.2.27 Section 7.1.2.3 Tumor assessments
Old text:
[…]
o Serum quantitative IgM test.
New text:
[…]
o Serum quantitative IgM test.
For further details on tumor assessments in patients with WM, see Section 7.3.3.
13.2.2.28 Section 7.1.2.4 End-of-treatment visit
Old text:
[…]

IVRS/IWRS transaction to register end of treatment.

Toxicity/AE assessment (see Section 7.5.1.3).
[…]

Blood tests for HbA1c, CBC, chemistry and coagulation panels (see Section 7.5.3.1). 
Patients must be fasting for 11 h prior to sampling. If a patient can’t adhere to fasting 
requirements, the evaluation of lipid-panels including triglycerides is considered not 
feasible.
[…]

Review of the home blood glucose measurements/insulin administration, if applicable 
(modified by amendment 1) (see Section 6.4.2.1).


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New text:
[…]

IVRS/IWRS transaction to register end of treatment.

Serum pregnancy test (if applicable): mandatory for countries where it is required by 
local regulations (see Section 7.5.3.1).

Toxicity/AE assessment (see Section 7.5.1.3).
[…]

Blood tests for HbA1c, CBC, chemistry and coagulation panels (see Section 7.5.3.1). 
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 (see Section 6.4.2.2).
The testing for HbA1c is not required if the previous test was performed within 
4 weeks preceding EOT visit.
[…]

Review of the home blood glucose measurements/meal timing/oral glucose lowering 
medication/insulin administration, if applicable (modified by amendment 1) (see 
Section 6.4.2.1).
13.2.2.29 Section 7.3.2 Radiological tumor assessments
Old text:
[…]
The method chosen at the baseline must be the same throughout the study.
[…]
The response assessment will be done according to the Lugano Classification (21). As long as 
the patient has not experienced PD, investigator’s assessment is sufficient for case 
management. In the event of progression, radiological real-time confirmation by central 
independent blinded evaluation is required before a final decision to stop the treatment is 
made. In case of uncertain radiological disease progression the patient may stay on treatment 
at the investigator’s discretion until progression is definitely confirmed on the subsequent 
tumor assessment. The final evaluation of treatment response (best response: ORR and CRR) 
will be done by central blinded review retrospectively.
For patients with WM, response assessment will be performed according to the Owen 
criteria (22). However, CT scan will be done and collected for all patients according to the 
schedule specified in the protocol. According to this guidance, disease progression can be 
confirmed based on laboratory parameters. In such case when PD was assessed by an 
investigator based on laboratory parameters alone, no independent confirmation of PD by 
central independent blinded review is necessary. Site must notify the sponsor about disease 
progression and follow procedures outlined in the protocol for patients on study and control 
arm respectively. For patients with WM who had measurable disease at baseline and had PD 


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assessed based on CT scan, scans must be submitted for review to confirm disease 
progression by central blinded review.
Detailed instructions on tumor assessment are provided in Appendix 14.1.
[…]
The same technique (e.g., slice thickness, field of view) should be used for all scans during
the study treatment period. Preferably all scans should be interpreted by the same 
investigator/radiologist during the study whenever possible. CT/MRI scans must meet the 
standard of care for imaging of lesions in the respective organ system(s). If IV (or oral) 
contrast-enhanced CT is medically contraindicated, sites may acquire contrast-enhanced MRI 
of the neck, abdomen and pelvis, and an unenhanced CT of the chest above lung apices to the 
bottom of the adrenals. Chest CT is preferred. If a patient develops contra-indication to any
contrast medium during the study, the case examinations should be continued without 
contrast. In certain countries MRI should be used based on local regulations.
New text:
[…]
The method chosen at the baseline must be the same throughout the study. MRI shall be 
performed instead of CT when local regulations do not permit the use of CT as requested per 
protocol schedule.
[…]
As long as the patient has not experienced PD, investigator’s assessment is sufficient for case 
management. In the event of progression, radiological real-time confirmation by central 
independent blinded evaluation is required before a final decision to stop the treatment is 
made. In case of uncertain radiological disease progression the patient may stay on treatment 
at the investigator’s discretion until progression is definitely confirmed on the subsequent 
tumor assessment. The final evaluation of treatment response (best response: ORR and CRR) 
will be done by central blinded review and for those not undergoing PD-confirmation in
retrospective setting.
The response assessment will be done according to the Lugano Classification (21). For 
patients with WM, additional criteria apply (see Section 7.3.3). 
Detailed instructions on tumor assessment are provided in Appendix 14.1.
[…]
The same technique (e.g., slice thickness, field of view) should be used for all scans during 
the study treatment period. Preferably all scans should be interpreted by the same 
investigator/radiologist during the study whenever possible. CT/MRI scans must be 
performed with contrast agents and must meet the standard of care for imaging of lesions in 
the respective organ system(s). If IV (and oral, if indicated, per Imaging Manual) contrast-
enhanced CT is medically contraindicated, sites may acquire contrast-enhanced MRI of the 
neck, abdomen and pelvis, and an unenhanced CT of the chest above lung apices to the 
bottom of the adrenals. Chest CT is preferred. Only if a patient develops contra-indication to 
both CT and MRI contrast medium during the treatment phase of the study, the case 


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examinations should be continued without contrast. In certain countries MRI should be used 
based on local regulations.
13.2.2.30 Section 7.3.3 Tumor assessments in patients with WM
New section was added:
WM patients who do not have radiologically measurable lesion at Screening will not have 
further radiological assessments as per protocol. Their tumor response will be measured only 
by laboratory/clinical tests, and response assessment will be done according to the Owen 
Criteria. If PD was assessed by an investigator based on laboratory parameters alone, no 
independent confirmation of PD by independent blinded review is necessary. However, in 
cases when WM patients will develop disease progression confirmed radiologically by 
presenting with measurable lesion(s) without simultaneous increase in IgM, the imaging scans
should be submitted for central review and PD confirmation. 
WM patients who have radiologically measurable lesion at Screening will continue having 
radiological assessments and, in addition, will have laboratory tests performed on the same 
days. CT/MRI scans will be done and collected according to the schedule specified in the 
protocol (see Section 7.1.2.3). For patients who have PD assessed based on CT/MRI, scans 
must be submitted for review to confirm disease progression by an independent blinded 
radiology review.
Sites must notify the sponsor about disease progression and follow procedures outlined in the 
protocol.
Detailed instructions on tumor assessment are provided in Appendix 14.1.
13.2.2.31 Section 7.4 Pharmacokinetics / pharmacodynamics
Old text:
[…]
Deviations from the specified time points will be documented and taken into account when 
calculating the PK parameters. Those deviations do not qualify as protocol violation. All 
blood samples (5 mL at each sampling time point) should be collected, processed, stored, and 
shipped according to procedures outlined in the Laboratory Manual.
New text:
[…]
Deviations from the specified time points will be documented and taken into account when 
calculating the PK parameters. Those deviations do not qualify as protocol violation. All 
blood samples should be collected, processed, stored, and shipped according to procedures 
outlined in the Laboratory Manual.


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13.2.2.32 Section 7.5.1.3 Assessments and documentation of adverse events
Old text:
[…]
If any patient dies during the observation phase for AEs, the investigator will inform the 
sponsor and record the cause of death in detail within 24 h on an SAE form.
New text:
[…]
If any patient dies during the observation phase for AEs, the investigator will inform the 
sponsor and record the cause of death in detail within 24 h on an SAE form. “Death” should 
generally not be recorded as an AE on the AE page. Instead, “death” should be recorded as 
the outcome of underlying AE(s). If death is reported without any associated AE (s), it should 
be reported as SAE.
13.2.2.33 Section 7.5.1.4 Reporting of serious adverse events
Old text:
If disease progression leads to signs and symptoms that meet the criteria for seriousness (see 
Section 7.5.1.1), the associated signs and symptoms, not the underlying cause, should be 
reported as SAE, (i.e. progressive disease should not be recorded as SAE). In this case, 
disease progression should be mentioned on the SAE form as an “alternative 
explanation”.
New text:
If disease progression leads to signs and symptoms that meet the criteria for seriousness (see 
Section 7.5.1.1), the associated signs and symptoms, not the underlying cause, should be 
reported as SAE, (i.e. progressive disease should not be recorded as SAE). In this case, 
disease progression should be clearly mentioned on the SAE form as an “alternative 
explanation”.
13.2.2.34 Section 7.5.3 Further safety
Old text:
[…]
If not previously done within 7 days, patients switching to open-label copanlisib must 
complete the following within 7 days prior to the first dose of open-label copanlisib: UPCR 
measurement, GFR measurement, urinalysis, HbA1c, CBC, chemistry and coagulation panels. 
Dosing criteria outlined in Table 6-2 apply also for patients who switch to open-label 
treatment (clarified by amendment 1). 
New text:
[…]


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If not previously done within 7 days, patients switching to open-label copanlisib must 
complete the following within 7 days prior to the first dose of open-label copanlisib: 
UPCR/24 h total urine protein quantification, GFR measurement, urinalysis, HbA1c, CBC, 
chemistry and coagulation panels. For further information on laboratory requirements for 
patients who switch to open-label treatment, please see Section 7.1.2.2 (clarified by 
amendment 1). 
13.2.2.35 Section 7.5.3.1 Laboratory
Old text:
All laboratory analyses will be performed locally. Dipsticks should be available for urinalysis 
(modified by amendment 1).
[…]

Quantification of proteinuria by UPCR on a random urine sample preferably taken at 
mid-morning. This should be reported as the ratio of concentrations of total urine 
protein (in mg/dl) to urine creatinine (in mg/dl).
[…]

Serum pregnancy test in women of childbearing potential. Postmenopausal women 
who have not had periods for more than 1 year or surgically sterilized women will not 
be required to undergo a pregnancy test (this information should be recorded under 
medical history on the eCRF). 
New text:
All laboratory analyses will be performed locally according to the schedule summarized in the 
flow chart of Section 7.1.1. Dipsticks should be available for urinalysis (modified by 
amendment 1).
[…]

Quantification of proteinuria by either a 24 h total urine protein quantification or by 
UPCR on a random urine sample preferably taken at mid-morning. This should be 
reported as the ratio of concentrations of total urine protein (in mg/dl) to urine 
creatinine (in mg/dl), both done on the same sample. Dipstick analysis is not 
acceptable to assess proteinuria.
[…]

Serum pregnancy test in women of childbearing potential. Postmenopausal women 
who have not had periods for more than 1 year or surgically sterilized women will not 
be required to undergo a pregnancy test (this information should be recorded under 
medical history on the eCRF). 

Hemoglobin A1c.
13.2.2.36 Section 7.5.3.2.1 Complete physical examination
Old text:


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[…]

Skin (paleness, jaundice, redness/rush, acneiforme changes)
[…]

Ears, nose, throat (presence of petechial bleedings, gingival bleeding)
New text:
[…]

Skin (paleness, jaundice, redness/rash, acneiforme changes) including clinical 
assessment of hydration status via hand extensor surface skin turgor
[…]

Ears, nose, throat (presence of petechial bleeding, gingival bleeding) including 
inspection of oral mucosa for hydration status
13.2.2.37 Section 7.5.3.2.2 Brief physical examination
[…]

Skin (paleness, jaundice, redness/rush, acneiforme changes)
[…]

Throat (presence of petechial bleedings, gingival bleeding)
New text:
[…]

Skin (paleness, jaundice, redness/rash, acneiforme changes) including clinical 
assessment of hydration status via hand extensor surface skin turgor
[…]

Throat (presence of petechial bleeding, gingival bleeding) including inspection of oral 
mucosa for hydration status
13.2.2.38 Section 7.5.3.3 Vital signs
Old text:
Pulse, blood pressure and temperature will be assessed according to the schedule summarized 
in the flow chart of Section 7.1. If clinically indicated, it is at the investigator’s discretion to 
perform these measurements more frequently. 

Blood pressure will be measured every 5-10 min prior to infusion of study drug (no 
more than 4 measurements) until there are 2 consecutive results < 150/90 mmHg. If 
blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention 
or delaying the infusion of study drug. The patient should rest for 5-10 min before 
blood pressure is recorded (modified by amendment 1).


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o
At Cycle 1 Day 1 blood pressure will be measured at 0 h (pre-dose), 30 min 
(mid-infusion), 60 min (end of infusion), 90 min, 2 h, 3 h, 4 h and 6 h after the 
start of infusion (deviation ±5 min). 
o
From Cycle 1 Day 8 onwards a single blood pressure measurement is to be 
performed prior to each infusion, 30 min after the start of infusion and at the 
end of each infusion (deviation ±5 min) (modified by amendment 1).
New text:
Pulse, blood pressure and temperature will be assessed according to the schedule summarized 
in the flow chart of Section 7.1. If clinically indicated, it is at the investigator’s discretion to 
perform these measurements more frequently. 
Blood pressure measurement on infusion days
Blood pressure will be measured every 5-10 min prior to infusion of study drug (no more than 
4 measurements) until there are 2 consecutive results < 150/90 mmHg. If blood pressure is 
≥150/90 mmHg, the investigator can consider a medical intervention or delaying the infusion 
of study drug. The patient should rest for 5-10 min before blood pressure is recorded 
(modified by amendment 1).

On infusion days: blood pressure will be measured at 0 h (pre-dose), 30 min (mid-
infusion), 60 min (end of infusion); and 1 h and 2 h after the end of infusion.

Note: time window of ± 10 min is allowed for all blood pressure measurements except 
for 0 h (pre-dose) 
13.2.2.39 Section 7.5.3.6 Glucose measurement on infusion days
New section was added:

On Cycle 1 Day 1: glucose will be measured at pre-dose and post-dose after the end of 
study drug infusion (0), 1 h and 2 h. Additional measurements to be performed at the 
clinic as clinically indicated.

On subsequent infusion days: glucose will be measured prior to study drug infusion 
and 1 h after the end of study drug infusion. 

On all infusion days: time window of ± 5 min is allowed for glucose measurements, 
except for the pre-dose measurement. If patient needs to take a low glycemic meal, 
then glucose test should be taken prior to meal intake and at 1 h and 2 h after the meal.
13.2.2.40 Section 7.6.3 Electronic patient-reported outcomes evaluation
Old text:
ePRO devices will be implemented in this study. They will be used to complete the FLymSI-
18 questionnaire (modified by amendment 1). A Site Manual will be provided to sites and 
each patient to help them understand how the ePRO devices work and how to use them 
correctly. If, for any reason, a device is not available at the site, or technical problems prevent 
it from working properly, a paper PRO questionnaire may be used.


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New text:
ePRO devices will be implemented in this study. They will be used to complete the FLymSI-
18 questionnaire (modified by amendment 1). A Site Manual will be provided to sites and 
each patient to help them understand how the ePRO devices work and how to use them 
correctly. If, for any reason, a device is not available at the site, or technical problems prevent 
it from working properly, the FLymSI-18 questionnaire will not be completed at that visit.
13.2.2.41 Section 11.2 Patient information and consent
Old text:
[…]
The investigator will also mention that written approval of the IEC/IRB has been obtained.
Each patient will have ample time and opportunity to ask questions and will be informed 
about the right to withdraw from the study at any time without any disadvantage and without 
having to provide reasons for this decision.
Only if the patient voluntarily agrees to sign the ICF and has done so, may he/she enter the 
study.
New text:
[…]
The investigator will also mention that written approval of the IEC/IRB has been obtained.
Each patient 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 data that have been collected until the time of withdrawal will be 
retained and statistically analyzed in accordance with the SAP.

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 SAP. The patient has the right to object to the generation and 
processing of this post-withdrawal data. The patient’s oral objection may be 
documented in the patient’s source data.
Each patient will have ample time and opportunity to ask questions.
Only if the patient voluntarily agrees to sign the ICF and has done so, may he/she enter the 
study.
13.2.2.42 Section 12 Reference list
Reference 38 was added.


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38.
Atkinson FS, Foster-Powell K, Brand-Miller JC. International Tables of Glycemic 
Index and Glycemic Load Values: 2008. Diabetes Care 2008;31:2281-2283.
13.2.2.43 Section 14.1 Evaluation of tumor response
Old text:
Tumor response will be evaluated according to Recommendations for Initial Evaluation, 
Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano 
Classification (21).
Target lesions
(nodal)
Target lesions
(extranodal)
Non-target
lesions
Spleen
New lesion
Bone marrow
[…]
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
and be > 13 cm 
Recurrent 
splenomegaly:
the splenic length 
must increase ≥ 2 cm 
from nadir length and 
be > 13 cm 
Progressive 
splenomegaly:
the splenic length 
must increase by > 
50% of the extent 
beyond normal at 
baseline (=value over 
13 cm)
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)
Lymphoma 
infiltration
(new or % 
increased 
respect to 
baseline)
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


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New text:
Tumor response will be evaluated according to Recommendations for Initial Evaluation, 
Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano 
Classification (21).
Target lesions
(nodal)
Target lesions
(extranodal)
Non-target
lesions
Spleen
New lesion
Bone marrow
[…]
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
and be > 13 cm 
Recurrent 
splenomegaly:
the splenic length 
must increase ≥ 2 cm 
from nadir length and 
be > 13 cm 
Progressive 
splenomegaly:
the splenic length 
must increase by > 
50% of the extent 
beyond normal at 
baseline (=value 
over 13 cm) 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
* 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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13.2.2.44 Section 14.7 The average glycemic index of common foods derived from 
multiple studies by different laboratories
New appendix was added:
Foods are categorized as having a low-glycemic index if the glucose reference index is ≤ 55. 
The summary table below contains glucose reference for common foods, please see 
reference 38 for additional information.
GI = glycemic index.
Source: (38)


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13.3
Amendment 4
Amendment 4 is a global amendment dated 21 JUL 2016.
13.3.1
Overview of changes
13.3.1.1
Modification 1 - clarification of bone marrow biopsy sample to be 
reviewed by central pathology
To align with other CHRONOS protocols, the statement was added when bone marrow 
biopsy samples must be sent to central pathology for review. Also it is at the investigator’s 
discretion to perform a bone marrow biopsy if there is suspicion of bone marrow infiltration.
It was emphasized that the bone marrow biopsy is mandatory at screening, which is up to 28 
days before the first study drug infusion.
Sections affected by this modification: Synopsis, 4 Study design, 7.1.1 Tabulated overview, 
7.1.2.1 Screening period and 7.1.2.3 Tumor assessments.
13.3.1.2
Modification 2– update of clinical experience with copanlisib
Introductory information on the number of patients treated with copanlisib was updated based 
on most recent data.
Section affected by this modification: 1.1.2 Clinical experience.
13.3.1.3
Modification 3– clarification of inclusion criterion related to platelets
To clarify the requirements for platelet count in patients with confirmed lymphomatous bone 
marrow infiltration.
Section affected by this modification: 5.1.1 Inclusion criteria.
13.3.1.4
Modification 4 – exclusion of patients with Cytomegalovirus (CMV) 
An additional exclusion criterion was added to exclude patients with positive CMV infection
at baseline.
Sections affected by this modification: 5.1.2 Exclusion criteria, 7.1.1 Tabulated overview and 
7.1.2.1 Screening period.
13.3.1.5
Modification 5 – clarification when a patient withdraws study 
treatment due to CMV infection
If a patient experiences reactivation of CMV infection and study drug is delayed up to 2 
cycles, the patient should withdraw from study treatment. Reactivation means that acute 
infection needs treatment. Patients with chronic infection could be eligible as long as they do 
not exhibit symptoms of acute infection which should be confirmed by negative CMV PCR 
test at baseline.
Section affected by this modification: 5.2.1.1 Withdrawal from study treatment.


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13.3.1.6
Modification 6 – addition of guidance for monitoring and prophylaxis 
of opportunistic infections (OI)
Following Health Authority alerts related to safety issues with Zydelig (idelalisib, a PI3K 
inhibitor) treatment in clinical trials, Section 6.4.2.6 was added to provide guidance for 
monitoring and prophylaxis of opportunistic infections in patients who are at risk for 
opportunistic infection development while on study treatment. 
The guidance includes additional CD4, CD8, CMV and blood culture laboratory tests, and 
lung examinations to be monitored during study treatment in patients who are at risk of 
development of infections. Schedule of procedures were modified to be consistent with the OI 
guidance.
Sections affected by this modification: 6.4.2.6 Guidance for monitoring and prophylaxis of 
opportunistic infection (OI) (new section), 7.1.1 Tabulated overview, 7.1.2.2 Treatment 
period, 7.1.2.2.1 Treatment – Cycle 1, 7.1.2.2.2 Treatment – Cycle 2 and higher, 7.5.3.1
Laboratory, 7.5.3.2.1 Complete physical examination, and 7.5.3.2.2 Brief physical 
examination.
13.3.1.7
Modification 7 – modification to management of hypertension
Dose modification guidance for the management of hypertension was clarified for incidence 
of grade 3 event.
Section affected by this modification: 6.4.1.2 Non-hematological toxicity.
13.3.1.8
Modification 8 – clarification of observation period for adverse events
AEs are to be documented upon signing the ICF until 30 days after the last dose of study drug. 
The period for TEAEs was clarified to be after start of study drug administration until 30 days 
after last study drug intake.
Sections affected by this modification: 7.1.1 Tabulated overview, 7.5.1.3 Assessments and 
documentation of adverse events and 8.3.2 Safety variables.
13.3.1.9
Modification 9 – modification to definition of complete response
In addition to a negative IHC confirmation for CR, a negative PCR is also acceptable.
Section affected by this modification: 14.1 Evaluation of tumor response.
13.3.1.10 Modification 10 – other clarifications and corrections
In addition to the modifications specified above there have been minor corrections for better 
clarity and consistency.

Due to sponsor name change, sponsor information and sponsor logo were changed.

Due to Study 
 change, the sponsor information was changed. 
PPD


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
The Safety follow-up visit window was clarified to be 30 days after last administration 
of study drug, with an additional +5 days allowed

Minor updates were made to clarify that only ePRO devices would be used in this 
study.

A minor inconsistency was corrected in Section 5.2.1 “Withdrawal” to clarify that 
baseline glucose test is not required for patient’s eligibility evaluation.

Text was modified in Section 7.5.3.1 Laboratory and in Table 7–1 footnote j to allow 
site to provide differential blood count in percentage when absolute count is not 
available per standard of care of the local lab.
Sections affected by this modification: Title Page, Synopsis, 3 Investigator and other 
study personnel, 4 Study Design, 5.2.1 Withdrawal, 7.1.1 Tabulated overview, 7.1.2.5.1
Safety follow-up, 7.5.1.3 Assessments and documentation of adverse events, 7.5.3.1
Laboratory, 7.6.3 Electronic patient-reported outcomes evaluation, and header on every 
page of the document.


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13.3.2
Changes to the protocol text
13.3.2.1
Title page
Old text:
Sponsor:
Bayer HealthCare AG,  D-51368 Leverkusen,  Germany
Sponsor’s 
:
 MD
100 Bayer Blvd
PO Box 915
Whippany, NJ 07981, USA
Telephone no.:
New text:
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 
:
 MD, PhD
Bayer S.A.
Rua Domingos Jorge, 1100, Predio 9301, 2º andar
CEP 04779-900, Sao Paulo-SP, Brazil
Telephone no.: 
PPD
PPD
PPD
PPD
PPD
PPD


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13.3.2.2
Synopsis
Old text:
Methodology
[…]
An End-of-treatment (EOT) visit will be performed within 7 days after the 
decision is made to discontinue study treatment. Following completion of 
the EOT visit, patients will enter either the Safety follow-up or the Active 
follow-up period, if applicable. In both cases, the Safety follow-up (SFU) 
visit will take place 30-35 days after the last administration of study drug.
[…]
Bone marrow biopsy will be mandatory at Screening. If the baseline 
biopsy is positive for lymphoma infiltration, it will be mandatory to 
perform it again to confirm the first complete response (CR) (paragraph 
added to synopsis by amendment 3).
New text:
Methodology
[…]
An End-of-treatment (EOT) visit will be performed within 7 days after the 
decision is made to discontinue study treatment. Following completion of 
the EOT visit, patients will enter either the Safety follow-up or the Active 
follow-up period, if applicable. In both cases, the Safety follow-up (SFU) 
visit will take place 30 days (window of +5 days allowed) after the last 
administration of study drug.
[…]
Bone marrow biopsy will be mandatory at Screening. Bone marrow tissue 
biopsy will be done within 28 days before first study drug infusion and 
must be provided at screening. Bone marrow biopsy must be performed 
again to confirm the first complete response (CR) on patients with 
previous bone marrow infiltration at baseline, and may also be performed 
at the investigator discretion if there is clinical suspicion of bone marrow 
infiltration. All specimens must be sent to central pathology review 
(paragraph added to synopsis by amendment 3).


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13.3.2.3
List of abbreviations
New abbreviations were added:
CD4
Cluster of differentiation 4
CD8
Cluster of differentiation 8
CMV
Cytomegalovirus
CRP
C-reactive protein
OI
Opportunistic Infection
PCR
Polymerase chain reaction
13.3.2.4
Section 1.1.2 Clinical experience
Old text:
Copanlisib is currently under investigation in various trials enrolling cancer patients. As of 
01 FEB 2015, approximately 377 patients with advanced cancer have been treated with 
copanlisib in Phase 1and Phase 2 clinical trials as a single agent or in combination with other 
agents.
New text:
Copanlisib is currently under investigation in various trials enrolling cancer patients. As of 
01 FEB 2016, approximately 627 patients with advanced cancer have been treated with 
copanlisib in Phase 1, Phase 2, and Phase 3 clinical trials (please refer to IB) as a single agent 
or in combination with other agents.
13.3.2.5
Section 3 Investigator and other study personnel
Old text:
Sponsor’s 
Name: 
 MD
Title:
 Oncology
Address: 100 Bayer Blvd
PO Box 915
Whippany, NJ 07981, USA
Telephone no.:
PPD
PPD
PPD
PPD


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New text:
Sponsor’s 
Name:
 MD, PhD
Title:
 Oncology
Address: Rua Domingos Jorge, 1100, Predio 9301, 2º andar
CEP 04779-900, Sao Paulo-SP, Brazil
Telephone no.:
13.3.2.6
Section 4 Study design
Old text:
An End-of-treatment (EOT) visit will be performed within 7 days after the decision is made to 
discontinue study treatment. Following completion of the EOT visit, patients will enter either 
the Safety follow-up or the Active follow-up period, if applicable. In both cases, the Safety 
follow-up (SFU) visit will take place 30-35 days after the last administration of study drug.
[…]
Bone marrow biopsy will be mandatory at Screening. Biopsies taken up to 28 days prior to 
treatment start are acceptable. If the baseline biopsy is positive for lymphoma infiltration, it 
will be mandatory to perform it again to confirm the first complete response (CR). 
New text:
An End-of-treatment (EOT) visit will be performed within 7 days after the decision is made to 
discontinue study treatment. Following completion of the EOT visit, patients will enter either 
the Safety follow-up or the Active follow-up period, if applicable. In both cases, the Safety 
follow-up (SFU) visit will take place 30days (window of +5 days allowed) after the last 
administration of study drug.
[…]
Bone marrow biopsy will be mandatory at Screening. Bone marrow tissue biopsy will be 
performed within 28 days before first study drug infusion and must be provided at screening. 
Bone marrow biopsy must be performed again to confirm the first complete response (CR) on 
patients with bone marrow infiltration at baseline, and may also be performed at the 
investigator discretion if there is clinical suspicion of bone marrow infiltration. All specimens 
must be sent to central pathology review. 
13.3.2.7
Section 5.1.1 Inclusion criteria
Old text:
[…]
PPD
PPD
PPD
PPD


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13. Adequate bone marrow, liver and renal function as assessed by the following laboratory 
requirements conducted within 7 days before start of study treatment:
[…]
o
Platelet count ≥ 75,000/mm3.
New text:
[…]
13. Adequate bone marrow, liver and renal function as assessed by the following laboratory 
requirements conducted within 7 days before start of study treatment:
[…]
o
Platelet count ≥ 75,000/mm3. For patients with confirmed lymphomatous bone 
marrow infiltration, platelet count ≥ 50,000 /mm3. Platelet transfusion should not 
be given less than 7 days before the exam collection.
13.3.2.8
Section 5.1.2 Exclusion criteria 
Old text:
[…]
Excluded medical conditions
[…]
Excluded previous therapies and medications
New text:
[…]
Excluded medical conditions, previous therapies and medications
[…]
47. Positive cytomegalovirus (CMV) PCR test at baseline.
13.3.2.9
Section 5.2.1 Withdrawal
Old text:
For patients with newly diagnosed diabetes mellitus that cannot meet protocol requirements, a 
single re-screening (which includes all screening procedures) should be performed when the 
patient’s diabetes is controlled and can meet protocol requirements for glucose and HbA1c.


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New text:
For patients with newly diagnosed diabetes mellitus that cannot meet protocol requirements, a 
single re-screening (which includes all screening procedures) should be performed when the 
patient’s diabetes is controlled and can meet protocol requirements for HbA1c.
13.3.2.10 Section 5.2.1.1 Withdrawal from study treatment
Old text:

Delay in study drug administration due to toxicities for > 21 days (this does not 
include the required 1 week break), a delay of study drug dosing due to reasons other 
than toxicity is not included in this definition (clarified by amendment 1).
New text:

Delay in study drug administration due to toxicities for > 21 days (this does not 
include the required 1 week break), a delay of study drug dosing due to reasons other 
than toxicity is not included in this definition (clarified by amendment 1). Except in 
case of delays due to reactivation of CMV where delay could be up to 2 cycles.
13.3.2.11 Section 6.4.1.2 Non-hematological toxicity
Old text:
Table 6-8
Dose modification of study treatment for arterial hypertension
Toxicity (CTCAE)
Study drug action
Recommendation
[…]
During infusion:
CTCAE hypertension of 
grade 3 
or ≥160/100 mmHg
Infusion can be interrupted or 
slowed down and administration 
of BP lowering therapy should 
be initiated.
Infusion may be resumed immediately when 
BP has returned to < 150/90 mmHg or 
skipped.
Subsequent study drug administrations may 
be reduced by 1 dose level at the 
investigator’s discretion.b
[…]
New text:
Table 6-8
Dose modification of study treatment for arterial hypertension
Toxicity (CTCAE)
Study drug action
Recommendation
[…]
During infusion:
CTCAE hypertension of 
grade 3 
or ≥160/100 mmHg
Infusion can be interrupted or 
slowed down and administration 
of BP lowering therapy should 
be initiated.
Infusion may be resumed immediately when 
BP has returned to < 150/90 mmHg or 
skipped otherwise.
Subsequent study drug administrations may 
be reduced by 1 dose level at the 
investigator’s discretion.b
[…]


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13.3.2.12 Section 6.4.2.6 Guidance for monitoring and prophylaxis of 
opportunistic infection (OI) 
New section was added:
6.4.2.6.1 Monitoring guidelines for OI
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 an examination at each visit prior to infusion.

Laboratory tests: cluster of differentiation 4  (CD4) for patients with signs of infection 
i.e. cough, dyspnea or fever, blood cultures when low ANC of CTCAE Grade 4, PCR 
for CMV (monthly for the first 6 months of study treatment and every 3 months 
thereafter).
o
Note: If PCR test is positive for CMV, treatment should be delayed until 
recovery. Treatment of CMV should be initiated based on local standard of 
care (SOC). Retreatment with copanlisib will be allowed without dose 
reduction once PCR test for CMV is negative.
Enhanced monitoring when prior medical history or laboratory parameters could be associated 
with one of the following risk factors:

Intensive chemotherapy (≥2 lines of myelosupressive cytotoxic therapy)

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 developed OI on study treatment, 
additional assessments will include:

CD4 and Cluster of differentiation 8 (CD8) count and ratio, C-reactive protein (CRP), 
blood cultures

Any additional laboratory and diagnostic methods according to local SOC reported as 
unscheduled laboratory and diagnostic methods of assessment 

Radiological imaging (i.e. chest X-ray or CT scan)
o
Note: Treatment of opportunistic infections should be based on local SOC.


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6.4.2.6.2 Prophylaxis of OI
Mandatory prophylactic therapy is not recommended in all patients:

Review of copanlisib data does not support risk benefit ratio favoring prophylaxis in 
all patients

Mandatory prophylaxis may cause a higher risk of side effects associated with 
supportive treatment where no risk factors are present

Currently implemented schedule of assessments and additional enhancements provide 
frequent monitoring and flexibility for prophylaxis based on local SOC.
Although not mandated in all patients, 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 initiated based on local SOC in patients when high 
risk factors are identified (see protocol Section 6.4.2.6.1). For example: Bactrim or 
equivalent, Acyclovir or equivalent.


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13.3.2.13 Section 7.1.1 Tabulated overview
Old text:
Table 7-1
Study flow chart
Screening 
maximum days 
before C1D1
Treatment *
EOT
SFU
Active 
follow-
up aa
Survival
follow-
up bb
Cycle 1
Cycle 2 and higher
Within (days) after
Days
-28 -14
-7
D1
D4
D8
D15
D22
D1
D8
D15
D22 y
7
30-35 z
every 3 
months
Acceptable deviation (in days)
-1 to +2 days
-1 to +2 days
Decision 
to stop
Last 
dose
14 days
[…]
[…]
d
After Screening: AE assessment and concomitant medication review must be updated before each dose and 30-35 days after last dose. 
After the patient signs the informed consent, any new finding discovered not present in the patient’s medical history or a worsening of a 
prior medical history finding must be recorded as an AE. Contrast media does not need to be recorded as concomitant medication unless 
there is an AE related to its administration (e.g. allergic reaction). During the Active follow-up period, AEs and SAEs assessed as related to 
study procedures by the investigator will be reported in the usual manner.
e
Complete physical examination to include: ECOG performance status, NYHA classification, height (only at Screening), weight, vital signs 
(temperature, pulse and blood pressure), and a complete review of body systems (changed by amendment 1).
f
Brief physical examination to include: ECOG performance status, vital signs (temperature, pulse and blood pressure), examination of 
pertinent organ systems, and brief interim history (change of symptoms).
[…]
j
CBC: Hemoglobin, hematocrit, RBC, WBC (with differential to include absolute neutrophil, lymphocyte, monocyte, basophil and eosinophil 
counts and platelet count). From Cycle 3 onwards, only hemoglobin, platelet and ANC counts will be performed on Day 8 and Day 15 prior 
to each infusion.
[…]
o
Bone marrow biopsy is mandatory at Screening (biopsy done up to 28 days prior to first dose can be used as baseline evaluation) and to 
confirm the first complete response, if positive at baseline. Biopsy will be performed as per local standard of care (clarified by amendment 
1).
[…]


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z
The post-treatment follow-up 30-35 days after the last administration of study drug can be conducted via telephone if the patient is no 
longer being actively seen at the clinic or has started another therapy. In this case, FLymSI-18 questionnaire does not need to be 
completed at the SFU evaluation (modified by amendment 1). Procedures marked with “(X)” are only to be performed, if clinically indicated.
[…]
New text:
Table 7-1
Study flow chart
Screening 
maximum days 
before C1D1
Treatment *
EOT
SFU
Active 
follow-
up aa
Survival
follow-
up bb
Cycle 1
Cycle 2 and higher
Within (days) after
Days
-28 -14
-7
D1
D4
D8
D15
D22
D1
D8
D15
D22 y
7
30 + 5
days 
windowz
every 3 
months
Acceptable deviation (in days)
-1 to +2 days
-1 to +2 days
Decision 
to stop
Last 
dose
14 days
[…]
CMV PCR testff, ii
X
Xff
Xff
[…]
CD4 (for patients with signs of infection) and 
blood cultures when low ANC of CTCAE
Grade 4 gg, hh, ii
[…]
] CD4 = Cluster of differentiation 4; CMV = cytomegalovirus; […] eCRF= Electronic case report form; […] OI = Opportunistic infection; PCR = 
polymerase chain reaction; 
[…]
d
After Screening: AE assessment and concomitant medication review must be updated before each dose and all AEs starting within 30 days 
after the last dose of study drug should be collected and recorded in eCRF. After the patient signs the informed consent, any new finding 
discovered not present in the patient’s medical history or a worsening of a prior medical history finding must be recorded as an AE. Contrast 
media does not need to be recorded as concomitant medication unless there is an AE related to its administration (e.g. allergic reaction). 
During the Active follow-up period, AEs and SAEs assessed as related to study procedures by the investigator will be reported in the usual 
manner.
e
Complete physical examination to include: ECOG performance status, NYHA classification, height (only at Screening), weight, vital signs 
(temperature, pulse and blood pressure), and a complete review of body systems (changed by amendment 1), including lung examination.


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f
Brief physical examination to include: ECOG performance status, vital signs (temperature, pulse and blood pressure), examination of 
pertinent organ systems, and brief interim history (change of symptoms), including lung examination.
[…]
j
CBC: Hemoglobin, hematocrit, RBC, WBC (with differential to include absolute neutrophil, lymphocyte, monocyte, basophil and eosinophil 
counts and platelet count). From Cycle 3 onwards, only hemoglobin, platelet and ANC counts will be performed on Day 8 and Day 15 prior 
to each infusion. Differential blood count in percentage can be provided when absolute count is not available per standard of care of the 
local lab.
[…]
o
Bone marrow biopsy must be performed within 28 days before first study drug infusion, and to confirm the first complete response if there is 
bone marrow infiltration at baseline, and also at the investigator discretion if there is clinical suspicion of bone marrow infiltration. All 
specimens must be sent to central pathology review(clarified by amendment 1).
[…]
z
The post-treatment follow-up 30days (window of +5 days allowed) after the last administration of study drug can be conducted via 
telephone if the patient is no longer being actively seen at the clinic or has started another therapy. In this case, FLymSI-18 questionnaire 
does not need to be completed at the SFU evaluation(modified by amendment 1). Procedures marked with “(X)” are only to be performed, if 
clinically indicated.
[…]
ff
Blood test for CMV. Should be performed in all patients prior to IV infusion of copanlisib. Every month for the first 6 months of treatment and 
every 3 months thereafter. If PCR test is positive for CMV, treatment should be delayed until recovery. Treatment of CMV should be 
initiated based on local SOC. Re-treatment with copanlisib will be allowed without dose reduction once PCR test for CMV is negative.
gg For patients with identified risk factors and those who developed OI on study treatment, additional assessments will include: (1) CD4 and 
CD8 count and ratio, CRP, blood cultures (2) any additional laboratory and diagnostic methods according to local SOC should be reported 
as unscheduled laboratory and diagnostic methods of assessments (3) Radiological imaging (i.e. chest X-ray or CT scans) (Note: 
Treatment of developed OI should be based on local SOC).
hh Blood cultures should be performed as per local SOC if the patient develops low ANC of CTCAE Grade 4. CD4 count should be performed 
for patients with signs of infection.
ii
Modified by amendment 4.


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13.3.2.14 Section 7.1.2.1 Screening period
Old text:
[…]

Bone marrow biopsy: mandatory at Screening and to confirm the first complete 
response, if positive at baseline. Biopsy will be performed as per local standard of care 
(clarified by amendment 1).
New text:
[…]

Blood test for CMV infection. Patients who are CMV testpositive at baseline will not 
be eligible.
[…]

Bone marrow biopsy: mandatory at Screening and to confirm the first complete 
response in patients with previous bone marrow infiltration at baseline. A bone 
marrow biopsy may also be performed at the investigator discretion if there is clinical 
suspicion of bone marrow infiltration. All specimens must be sent to central pathology 
review (clarified by amendment 1).
13.3.2.15 Section 7.1.2.2 Treatment period
Old text:
[…]
For Day 1 of subsequent open-label cycles, dosing criteria outlined in Table 6–2 will apply 
for patients who switch to open-label treatment (clarified by amendment 1 and 3).
New text:
[…]
For Day 1 of subsequent open-label cycles, dosing criteria outlined in Table 6–2 will apply 
for patients who switch to open-label treatment (clarified by amendment 1 and 3).
The following assessments should be performed at each visit before receiving study 
treatment 

Monitoring for OI (see Section 6.4.2.6): 
In addition to the weekly clinical review and laboratory tests outlined in the schedule 
of assessments, the following should be performed in all patients prior to IV infusion 
of copanlisib:
o
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


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o
Laboratory tests: CD4 (for patients with signs of infection), blood cultures if 
low ANC of CTCAE Grade 4, PCR for CMV (monthly for first 6 months of 
treatment and every 3 months thereafter)
Note: If PCR test is positive for CMV, treatment should be delayed until 
recovery. Treatment of CMV should be initiated based on local SOC. Re-
treatment with copanlisib will be allowed without dose reduction once PCR 
test for CMV is negative.
13.3.2.16 Section 7.1.2.2.1 Treatment – Cycle 1
Old text:
Cycle 1 Day 1
[…]

Toxicity/AE assessment: any new findings or worsening of any ongoing medical 
history conditions after the patient signed the informed consent are to be listed as AEs 
(see Section 7.5.1.3).

Concomitant medication review. Please 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).
[…]
Cycle 1 Day 8
[…]

Brief physical examination including ECOG performance status, vital signs 
(temperature, pulse and blood pressure), examination of pertinent organ systems, and 
brief interim history (change of symptoms) (see Section 7.5.3.2).

Blood tests for CBC and chemistry panel (excluding total cholesterol, LDL and 
triglycerides) (see Section 6.4 and Section 7.5.3.1).
[…]
Cycle 1 Day 15
[…]

Brief physical examination, including ECOG performance status, vital signs 
(temperature, pulse and blood pressure), examination of pertinent organ systems, and 
brief interim history (change of symptoms) (see Section 7.5.3.2).

Blood tests for CBC, chemistry and coagulation panels (excluding total cholesterol, 
LDL and triglycerides) (see Section 6.4 and Section 7.5.3.1).
[…]


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Cycle 1 Day 22
[…]

Brief physical examination, including ECOG performance status, vital signs 
(temperature, pulse and blood pressure), examination of pertinent organ systems, and 
brief interim history (change of symptoms) (see Section 7.5.3.2).. 

Blood tests for CBC and chemistry panel (excluding total cholesterol, LDL and 
triglycerides) (see Section 7.5.3.1).
New text:
Cycle 1 Day 1
[…]

Toxicity/AE assessment: any new findings or worsening of any ongoing medical 
history conditions after the patient signed the informed consent are to be listed as AEs 
(see Section 7.5.1.3).

Monitoring for OI (see Section 6.4.2.6).

Concomitant medication review. Please 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).
[…]
Cycle 1 Day 8
[…]

Brief physical examination including ECOG performance status, vital signs 
(temperature, pulse and blood pressure), examination of pertinent organ systems, and 
brief interim history (change of symptoms) (see Section 7.5.3.2).

Monitoring for OI (see Section 6.4.2.6).

Blood tests for CBC and chemistry panel (excluding total cholesterol, LDL and 
triglycerides) (see Section 6.4 and Section 7.5.3.1).
[…]
Cycle 1 Day 15
[…]

Brief physical examination, including ECOG performance status, vital signs 
(temperature, pulse and blood pressure), examination of pertinent organ systems, and 
brief interim history (change of symptoms) (see Section 7.5.3.2).

Monitoring for OI (see Section 6.4.2.6).


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
Blood tests for CBC, chemistry and coagulation panels (excluding total cholesterol, 
LDL and triglycerides) (see Section 6.4 and Section 7.5.3.1).
[…]
Cycle 1 Day 22
[…]

Brief physical examination, including ECOG performance status, vital signs 
(temperature, pulse and blood pressure), examination of pertinent organ systems, and 
brief interim history (change of symptoms) (see Section 7.5.3.2).

Monitoring for OI (see Section 6.4.2.6). 

Blood tests for CBC and chemistry panel (excluding total cholesterol, LDL and 
triglycerides) (see Section 7.5.3.1).
13.3.2.17 Section 7.1.2.2.2 Treatment – Cycle 2 and higher
Old text:
Cycle 2 and higher, Day 1
[…]

Toxicity/AE assessment (see Section 7.5.1.3).

Concomitant medication review. Please 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).
[…]
Cycle 2 and higher, Day 8
[…]

Brief physical examination, including ECOG performance status, vital signs 
(temperature, pulse and blood pressure), examination of pertinent organ systems, and 
brief interim history (change of symptoms) (see Section 7.5.3.2).

On Cycle 2, blood tests for CBC and chemistry panel (excluding total cholesterol, 
LDL and triglycerides) will be performed. From Cycle 3 onwards, only hemoglobin, 
platelet and ANC counts will be performed prior to each infusion (see Section 6.4 and 
Section 7.5.3.1).
[…]


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Cycle 2 and higher, Day 15
[…]

Brief physical examination, including ECOG performance status, vital signs 
(temperature, pulse and blood pressure), examination of pertinent organ systems, and 
brief interim history (change of symptoms) (see Section 7.5.3.2).

12-lead ECG removed by amendment 1.
New text:
Cycle 2 and higher, Day 1
[…]

Toxicity/AE assessment (see Section 7.5.1.3).

Monitoring for OI (see Section 6.4.2.6).

Concomitant medication review. Please 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).
[…]
Cycle 2 and higher, Day 8
[…]

Brief physical examination, including ECOG performance status, vital signs 
(temperature, pulse and blood pressure), examination of pertinent organ systems, and 
brief interim history (change of symptoms) (see Section 7.5.3.2).

Monitoring for OI (see Section 6.4.2.6). 

On Cycle 2, blood tests for CBC and chemistry panel (excluding total cholesterol, 
LDL and triglycerides) will be performed. From Cycle 3 onwards, only hemoglobin, 
platelet and ANC counts will be performed prior to each infusion (see Section 6.4 and 
Section 7.5.3.1).
[…]


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Cycle 2 and higher, Day 15
[…]

Brief physical examination, including ECOG performance status, vital signs 
(temperature, pulse and blood pressure), examination of pertinent organ systems, and 
brief interim history (change of symptoms) (see Section 7.5.3.2).

Monitoring for OI (see Section 6.4.2.6).

12-lead ECG removed by amendment 1.
13.3.2.18 Section 7.1.2.3 Tumor assessments
Old text:
Bone marrow biopsy will be mandatory at baseline and if positive at Screening, will be 
repeated for confirmation of the first CR. Biopsy will be performed as per local standard of 
care.
New text:
Bone marrow biopsy is mandatory at baseline and to confirm the first CR if there is bone 
marrow infiltration at baseline. It may also be performed at the investigator discretion if there 
is clinical suspicion of bone marrow infiltration. All specimens must be sent to central 
pathology review. Biopsy will be performed as per local standard of care.
13.3.2.19 Section 7.1.2.5.1 Safety follow-up
Old text:
If a patient discontinues study treatment at any time during the study for any reason (except 
death or lost to follow-up) SFU visit will take place 30-35 days after the last administration of 
study drug.
New text:
If a patient discontinues study treatment at any time during the study for any reason (except 
death or lost to follow-up) SFU visit will take place 30 days (window of +5 days allowed) 
after the last administration of study drug.
13.3.2.20 Section 7.5.1.3 Assessments and documentation of adverse events
Old text:
The observation phase for AEs will start with signing the ICF and will end in general with the 
SFU visit 30-35 days after the last dose of study drug. AEs still present at the end of the 
observation phase should be followed until resolution or stabilization unless, in the 


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investigator’s opinion, the condition is unlikely to resolve due to the patient’s underlying 
disease.
New text:
The observation phase for AEs will start with signing the ICF and shall end 30 days after the 
last dose of study drug. The safety follow-up visit shall occur 30 days (window of +5 days 
allowed) after the last dose of study medication. AEs still present at the end of the observation 
phase should be followed until resolution or stabilization unless the condition is unlikely to 
resolve due to the patient’s underlying disease.
13.3.2.21 Section 7.5.3.1 Laboratory
Old text:
All laboratory analyses will be performed locally according to the schedule summarized in the 
flow chart of Section 7.1.1. Dipsticks should be available for urinalysis (modified by 
amendment 1 and 3).

Complete blood count (CBC): hemoglobin, hematocrit, red blood cell count (RBC), 
and white blood cell count (WBC) with differential to include absolute neutrophil, 
lymphocyte, monocyte, basophil and eosinophil counts, and platelet count.
[…]

Hemoglobin A1c (bullet point added by amendment 3).
New text:
All laboratory analyses will be performed locally according to the schedule summarized in the 
flow chart of Section 7.1.1. Dipsticks should be available for urinalysis (modified by 
amendment 1 and 3).

Complete blood count (CBC): hemoglobin, hematocrit, red blood cell count (RBC), 
and white blood cell count (WBC) with differential to include absolute neutrophil, 
lymphocyte, monocyte, basophil and eosinophil counts, and platelet count. Differential 
blood count in percentage can be provided when absolute count is not available per 
SOC of the local lab.
[…]

Hemoglobin A1c (bullet point added by amendment 3).

CD4 (for patients with signs of infection), blood cultures when low ANC of CTCAE
Grade 4, PCR for CMV. 
For patients with identified risk factors and those who developed opportunistic 
infections, additional laboratory assessments will include: 
o
CD4, CD8 count and ratio, CRP, blood cultures.


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13.3.2.22 Section 7.5.3.2.1 Complete physical examination
Old text:
[…]

Lungs
New text:
[…]

Lungs: Evaluation of new onset or worsening of pulmonary symptoms, and lung 
examination.
13.3.2.23 Section 7.5.3.2.2 Brief physical examination
Old text:
[…]

Lungs
New text:
[…]

Lungs: Evaluation of new onset or worsening of pulmonary symptoms, and lung 
examination
13.3.2.24 Section 7.6.3 Electronic patient-reported outcomes evaluation 
Old text:
ePRO devices will be implemented in this study. They will be used to complete the FLymSI-
18 questionnaire (modified by amendment 1). A Site Manual will be provided to sites and 
each patient to help them understand how the ePRO devices work and how to use them 
correctly. If, for any reason, a device is not available at the site, or technical problems prevent 
it from working properly, the FLymSI-18 questionnaire will not be completed at that visit 
(changed by amendment 3). 
New text:
ePRO devices will be implemented in this study. It will be used to complete the FLymSI-18 
questionnaire (modified by amendment 1). A Site Manual will be provided to sites and each 
patient will be trained how the ePRO device works and how to use it correctly. If, for any 
reason, a device is not available at the site, or technical problems prevent it from working 
properly, the FLymSI-18 questionnaire will not be completed at that visit (changed by 
amendment 3). 


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13.3.2.25 Section 8.3.2 Safety variables 
Old text:
[…]
TEAE is defined as any event arising or worsening after start of study drug administration 
until 30-35 days after the last study drug intake (end of Safety follow-up).
New text:
[…]
TEAE is defined as any event arising or worsening after start of study drug administration 
until 30 days after the last study drug intake (end of Safety follow-up).
13.3.2.26 Section 14.1 Evaluation of tumor response
Old text:
[…]
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
No
Normal by 
morphology
If not 
assessable:
IHC negative
[…]
New text:
[…]
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
No
Normal by 
morphology
If not 
assessable:
IHC and/or PCR
negative
[…]


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13.4
Amendment 5
Amendment 5 is a global amendment dated 31 MAR 2017.
13.4.1
Overview of changes
13.4.1.1
Modification 1 - study design revised
Following sponsor’s decision to stop enrollment due to lack of feasibility to complete this 
study in reasonable time frame, the study design is modified from randomized, double-blind, 
placebo controlled study design to open label, single arm study. After unblinding all patients 
will be given an opportunity to continue treatment with copanlisib. 
Sections affected by this modification: Synopsis; Section 1.2 Rationale of the study; Section 
1.3 Benefit-risk assessment; Section 4. Study design; Section 5.2.1 Withdrawal; Section 6.1 
Treatments to be administered; Section 6.2 Identity of study treatment; Section 6.3 Treatment 
assignment; Section 6.4 Dosage and administration; Section 6.5 Blinding; Section 6.7 
Treatment compliance; Section 7.1.2.2 Treatment period; Section 7.1.2.4 End-of-treatment 
visit; Section 7.1.2.5 Follow-up periods; Section 7.1.2.5.1 Safety follow-up; Section 7.3.1 
Primary efficacy variable; Section 7.4 Pharmacokinetics / pharmacodynamics; Section 7.5.3 
Further safety; Section 10. Premature termination of the study; Section 11.2 Patient 
information and consent; Appendix 14.6 Quality of life questionnaire: NCCN-FACT 
FLymSI-18
13.4.1.2
Modification 2 – statistical methods and efficacy variables revised
Following sponsor’s decision to stop enrollment, limited number of patients will be included 
in the analyses, as a consequence the statistical analyses in this study will be focused on 
descriptive statistics without any hypothesis testing. 
The primary efficacy variable is changed from PFS to ORR. The following secondary 
efficacy variables are removed: Time to progression, Time to deterioration in disease-related 
symptoms – physical (DRS-P) of at least 3 points and Time to improvement in DRS-P of at 
least 3 points.
Sections affected by this modification: Synopsis; Section 2. Study objectives; Section 4. Study 
design; Section 7.1.1 Tabulated overview; Section 7.6.2 Quality of life questionnaire; Section 
7.6.3 Electronic patient-reported outcomes evaluation; Section 8.1 General considerations; 
Section 8.2 Analysis sets; Section 8.3.1 Efficacy variables; Section 8.3.1.1 Primary efficacy 
variable; Section 8.3.1.2 Secondary efficacy variables; Section 8.3.1.3 Other efficacy 
variables; Section 8.4.1 Population characteristics; Section 8.4.2 Efficacy; Section 8.4.2.1 
Primary efficacy analysis; Section 8.4.2.2 Secondary efficacy analysis; Section 8.4.2.3 
Confirmatory statistical testing strategy; Section 8.4.2.4 Subgroup analyses; Section 8.4.3 
Safety; Section 8.6 Determination of sample size; Section 9.3 Data processing


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13.4.1.3
Modification 3 - Central image evaluation revised
Following sponsor’s decision to stop enrollment, limited number of patients will be included 
in the efficacy analyses and the primary efficacy endpoint is changed from PFS to ORR.  The 
efficacy analyses will be done based on investigator’s assessment of tumor response. 
Therefore, language on central image evaluation is modified by removing central image 
review.
Sections affected by this modification: Synopsis; Section 3. Investigator and other study 
personnel; Section 4. Study design; Section 5.2.1.1 Withdrawal from study treatment; Section 
6.4 Dosage and administration; Section 7.1.2.5.2 Active follow-up; Section 7.3.2 Radiological 
tumor assessments; Section 7.3.3 Tumor assessments in patients with WM
13.4.1.4
Modification 4 - Change in frequency of tumor assessment
Text is modified to allow sites to determine the frequency of radiological tumor assessment 
and serum tests (for LPL/WM patients only) based on local standard of care, but no less than 
every 16 weeks. This change is made for easier site compliance, and the requirement for 
determination of no less than every 16 weeks is implemented with the consideration of 
biological characteristics of indolent lymphoma.
Section affected by this modification: Synopsis; Section 4. Study design; Section 7.1.1 
Tabulated overview; Section 7.1.2.3 Tumor assessments; Section 7.3.2 Radiological tumor 
assessments
13.4.1.5
Modification 5 – Survival follow-up revised 
The frequency of survival follow up is changed from every 3 months to every 6 month. This 
change is implemented with the consideration of biological characteristics of indolent 
lymphoma.
Sections affected by this modification: Synopsis; Section 4. Study design; Section 5.2.1.2 
Withdrawal from follow-up period; Section 7.1.1 Tabulated overview; Section 7.1.2.5.3  
Survival follow-up
13.4.1.6
Modification 6 – Bone marrow biopsy revised
Due to the change of study design language on bone marrow biopsy is modified. Bone 
marrow biopsy will be performed as per local standard of care. This was done to reduce the 
burden on patients and sites. In addition, as a result the overall number of samples to be 
shipped and processed will be reduced.
Sections affected by this modification: Synopsis; Section 4. Study design; Section 7.1.1 
Tabulated overview; Section 7.1.2.1 Screening period; Section 7.1.2.3 Tumor assessments
13.4.1.7
Modification 7 – laboratory evaluations revised
Frequency of HbA1C and total cholesterol, LDL and triglycerides are changed to be tested at
Screening and EOT.


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Sections affected by this modification: Section 7.1.1 Tabulated overview; Section 7.1.2.2.2 
Treatment – Cycle 2 and higher
13.4.1.8
Modification 8 – ECG and MUGA scan or echocardiogram evaluations 
revised
Frequency of 12-lead ECG and MUGA scan or echocardiogram are changed to Screening, 
EOT and clinically indicated, to avoid overtesting. The patient will have the ECG and/or 
MUGA or echocardiogram if clinically indicated to ensure patients’ safety. 
Sections affected by this modification: Section 7.1.1 Tabulated overview; Section 7.1.2.2.1 
Treatment – Cycle 1; Section 7.1.2.2.2 Treatment – Cycle 2 and higher
13.4.1.9
Modification 9 – change in the visits during treatment period
Visit on Cycle 1 Day 4 and Cycle 1 Day 22 are no longer required. The safety assessment will
be done in the following visit. The visits without study drug infusions are removed for easier 
patients’ compliance.  
Sections affected by this modification: Section 7.1.1 Tabulated overview; Section 7.1.2.2.1 
Treatment – Cycle 1; Section 7.1.2.2.2 Treatment – Cycle 2 and higher
13.4.1.10 Modification 10 – administrative information updated and other 
clarification

The study 
 changed. Therefore the contact details are updated.

The sponsor’s medically responsible person changed. Therefore the signature page 
was updated.

Whole blood collection for biomarker is removed, because it was already collected 
when the patient was screened.

Revision of list of references

Revision of list of abbreviations
Sections affected by this modification: Title Page; Signature of the sponsor’s medically 
responsible person; List of abbreviations; Section 3. Investigator and other study personnel; 
Section 7.1.1 Tabulated overview; Section 7.1.2.2.1 Treatment – Cycle 1; Section 7.6.1 
Biomarker investigations; Section 12. Reference list
13.4.2
Changes to the protocol text
In this section, all affected protocol sections are detailed; the sequence of the sections follows 
the structure of the original protocol. In the display of modifications, the “old text” refers to 
the protocol version preceding this amendment. Deletions are crossed out in the “old text”. 
Additions are underlined in the “new text”. Corrections of typing errors or omissions are not 
highlighted in this amendment.
PPD


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13.4.2.1
Title Page
Old text:
[..]
Clinical study phase:
III
Date:
21 JUL 2016
EudraCT no.:
2014-000925-19
Version no.: 4.0
[…]
Sponsor’s 
:
 MD, PhD
Bayer S.A.
Rua Domingos Jorge, 1100, Predio 9301, 2º andar
CEP 04779-900, Sao Paulo-SP, Brazil
Telephone no.: 
[…]
New text:
[..]
Clinical study phase:
III
Date:
31 MAR 2017
EudraCT no.:
2014-000925-19
Version no.: 5.0
[…]
Sponsor’s 
:
 MD
, Bayer Center,
No.27 Dong San Huan North Road,
Chaoyang District, Beijing, China, 100020
Telephone no.: 
[…]
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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13.4.2.2
Signature of the sponsor’s medically responsible person
Old text:
Name:
 MD
Role:  
 (
Date:
Signature:
New text:
Name:
 MD
Role:  
 (
Date:
Signature:
PPD
PPD
PPD
PPD
PPD
PPD


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13.4.2.3
Synopsis
Old text:
[…]
Study objectives
The primary objective of this study is:

To investigate whether copanlisib as monotherapy is superior to 
placebo in prolonging progression-free survival (PFS) in patients 
with rituximab-refractory iNHL who have received two or more 
prior lines of treatment, have been exposed to rituximab and 
alkylating agent(s), and have progressed within six months of the 
end of the last previous rituximab-containing regimen.
The secondary objectives of this study are to evaluate:

Efficacy including tumor response, time to progression and overall 
survival.

The following characteristics of disease-related symptoms: time to 
deterioration and time to improvement.

Safety.
The other objectives of this study are to evaluate:

PFS2 in placebo-treated patients who switched to open-label 
copanlisib treatment.

Pharmacokinetics.

Biomarkers.

Quality of life.
[…]
Duration of treatment
Treatment will be continued until disease progression (PD) (per central 
independent blinded radiology review) as defined in the Recommendations 
for Initial Evaluation, Staging, and Response Assessment of Hodgkin and 
Non-Hodgkin Lymphoma: The Lugano Classification. unacceptable 
toxicity, or until another criterion is met for withdrawal from the study 
treatment. For patients with Waldenström macroglobulinemia (WM), 
response assessment will be done according to the Response Assessment 
in Waldenström macroglobulinemia: update from the VIth International 
Workshop.
Reference drug
Not applicable. This is a placebo-controlled study.
[…]
Study design
A randomized, double-blind, two-arm Phase III study to evaluate the 
efficacy and safety of copanlisib as monotherapy in comparison to placebo 
in patients with rituximab-refractory iNHL.
Approximately 189 patients (144 FL and 45 other iNHL) who meet the 


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eligibility criteria will be randomly assigned in a 2:1 ratio to one of the 
double-blinded treatment arms: copanlisib monotherapy or placebo, 
respectively (changed by amendment 1).
Patients will be stratified at randomization based on NHL histology 
(FL histology vs. other iNHL histology), the time between last course of 
systemic anticancer therapy and most recent progression (≤ 6 months vs. 
> 6 months) and prior treatment with PI3K inhibitors (yes vs. no) 
(changed by amendment 1).
Patients who experience PD on placebo treatment (per central independent 
blinded radiology review) can be offered open-label copanlisib upon 
discretion of the investigator and patient’s consent. After individual patient 
unblinding, patients receiving placebo who switch to open-label copanlisib 
will have all study assessments and timing reset to the initial schedule of 
study evaluations (i.e. as if the patient was restarting the study at Cycle 1 
Day 1). 
Methodology
The primary efficacy variable is PFS, defined as the time (in days) from 
randomization to PD as assessed by central review or death from any 
cause (if no progression is documented).
Secondary efficacy variables are objective tumor response rate (ORR), 
duration of response (DOR), complete response rate (CRR), time to 
progression (TTP), overall survival (OS), time to deterioration and time to 
improvement in disease-related symptoms - physical (DRS-P) of at least 
3 points of lymphoma as measured by the FLymSI-18 questionnaire 
(changed by amendment 1).
Other efficacy variables are PFS2, FLymSI-18 subscale, total score 
analyses and time to onset of physical symptoms of lymphoma based on 
DRS-P, and ECOG performance status (changed by amendment 1).
The study is composed of the following periods: Screening, Treatment, 
Safety-follow-up, Active follow-up (if applicable) and Survival follow-up.
Patients randomized to the copanlisib treatment arm will receive 60 mg 
copanlisib IV infusion on Days 1, 8 and 15 of each 28-day treatment cycle.
Patients randomized to the placebo arm will receive placebo IV infusion 
on Days 1, 8 and 15 of each 28-day treatment cycle.
Treatment will be continued until PD (per central independent blinded 
radiology review) unacceptable toxicity, or until another criterion is met 
for withdrawal from the study treatment. 
[…]
Patients who discontinue study treatment due to PD will enter the Safety-
follow up period and patients who discontinue study treatment for reasons 
other than PD will enter the Active follow-up period (which also serves as 
a Safety follow-up), except for patients who object to follow-up data 
collection. The patients in the Active follow-up will have radiological 
assessments by central independent blinded review as outlined in this 
protocol from the day of randomization until the end of the Active follow-
up period, defined as when either PD is documented or a new anti-tumor 
treatment is administered, whichever occurs first.
[…] During the treatment period as well as during the Active follow-up 


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period tumor assessments with the same modality will be performed every 
12 weeks during Year 1, every 16 weeks during Year 2, and every 
24 weeks during Year 3. CT/MRI scans are not required at the EOT visit if 
the patient discontinues due to PD which has been radiologically 
confirmed within the 4 weeks preceding EOT. As long as the patient has 
not experienced PD, investigator’s assessment is sufficient for case 
management. In the event of progression, radiological real-time 
confirmation by central independent blinded evaluation is required before 
a final decision to stop the treatment is made. The final evaluation of 
treatment response (best response: ORR and CRR) will be done by central 
blinded review and for those not undergoing PD-confirmation in 
retrospective setting 
WM patients who do not have radiologically measurable lesion at 
Screening will not have further radiological assessments as per protocol. 
Their tumor response will be measured only by laboratory/clinical tests. 
However, in cases when WM patients will develop disease progression 
confirmed radiologically by presenting with measurable lesion(s) without 
simultaneous increase in IgM, the imaging scans should be submitted for 
central review and PD confirmation. WM patients who have radiologically 
measurable lesion at Screening will continue having radiological 
assessments and, in addition, will have laboratory tests performed on the 
same days.
Bone marrow biopsy will be mandatory at Screening. Bone marrow tissue 
biopsy will be done within 28 days before first study drug infusion and 
must be provided at screening. Bone marrow biopsy must be performed 
again to confirm the first complete response (CR) on patients with 
previous bone marrow infiltration at baseline, and may also be performed 
at the investigator discretion if there is clinical suspicion of bone marrow 
infiltration. All specimens must be sent to central pathology review .
Type of control
Inactive control: placebo.
Number of patients
Approximately 237 patients will be screened for enrollment to this study. 
Approximately 189 patients who meet the eligibility criteria will be 
randomized – the copanlisib monotherapy arm will consist of 
approximately 126 patients and placebo arm of approximately 63 patients.
Primary variable
The primary variable is PFS, defined as the time (in days) from 
randomization to PD as assessed by central review or death from any 
cause (if no progression is documented).
Plan for statistical analysis
Primary efficacy analysis:
The primary efficacy variable is PFS as assessed by central review. It will 
be evaluated whether PFS in the copanlisib group is higher compared to 
PFS in the placebo group for the total study population and separately for 
the FL subgroup. All efficacy analyses will be performed when 
approximately 82 centrally evaluated PFS events are observed in the FL 
subgroup.
The study-wise alpha of 1% will initially be split, according to the test 
strategy for this study: with 80% * 1% = 0.8% assigned to the one-sided 
PFS test in the FL subgroup, and 20% * 1% = 0.2% to the one-sided PFS 


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test in the total study population.
The following null hypothesis will be tested:
H0, PFS:  SCopanlisib(t) = SPlacebo(t) for all time points t ≥ 0
The alternative hypothesis will be:
H1,PFS:  SCopanlisib(t) > SPlacebo(t) for at least one time point t ≥ 0, and
            SCopanlisib(t) ≥ SPlacebo(t) for all time points t ≥ 0,
where SCopanlisib denotes the survival function of the copanlisib group and 
SPlacebo denotes the survival function of the placebo group in the total study 
population or the FL subgroup, respectively.
The following decision rule to test the null hypothesis will be applied:
According to the size of this study it is justified to assume that under H0, 
PFS the one-sided log-rank test is a sufficiently close approximation to the 
normal distribution. If the z-value from the one-sided log-rank test (for the 
difference SCopanlisib - SPlacebo, stratified by the same factors as used for 
randomization) is larger than the respective critical quantile from the 
normal distribution (for FL subgroup: z0.992 = 2.409, for the total study 
population: z0.998 = 2.878), the null hypothesis will be rejected in favor of 
the alternative hypothesis.
Additional analyses of the primary efficacy variable:
Kaplan-Meier estimates of median times to PFS (including 98% 
confidence interval) and Kaplan-Meier curves for the total study 
population and the FL subgroup will be presented for each treatment 
group.
The hazard ratio (including 98% confidence interval) will be derived for 
the total study population and separately for the FL subgroup from a Cox 
proportional hazards models that are stratified by the same factors as used 
for the primary efficacy analysis.
The censoring mechanism of patients without PFS event at the time of 
analysis is assumed to be non-informative for the primary efficacy 
analysis. Sensitivity analyses will be performed, assessing the impact of a 
potential informative censoring of such subjects. These will include the 
use of different rules for considering subjects without PFS events as 
having an event or being censored, and will be further outlined in the 
statistical analysis plan (SAP).


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New text:
[…]
Study objectives
The primary objective of this study is:

To investigate objective tumor response rate (ORR) assessed in all
patients with rituximab-refractory iNHL who have received two or 
more prior lines of treatment, have been exposed to rituximab and 
alkylating agent(s), and have progressed within six month of the 
end of the last previous rituximab-containing regimen. 
The secondary objectives of this study are to evaluate:

Efficacy including complete response rate and overall survival.

Safety.
The other objectives of this study are to evaluate:

Pharmacokinetics.

Biomarkers.
[…]
Duration of treatment
Treatment will be continued until disease progression (PD) (per 
investigator’s assessment) as defined in the Recommendations for Initial 
Evaluation, Staging, and Response Assessment of Hodgkin and Non-
Hodgkin Lymphoma: The Lugano Classification. unacceptable toxicity, or 
until another criterion is met for withdrawal from the study treatment. For 
patients with Waldenström macroglobulinemia (WM), response 
assessment will be done according to the Response Assessment in 
Waldenström macroglobulinemia: update from the VIth International 
Workshop.
Reference drug
Not applicable. 
[…]


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Study design
A randomized, double-blind, two-arm Phase III study to evaluate the 
efficacy and safety of copanlisib as monotherapy in comparison to placebo 
in patients with rituximab-refractory iNHL.
Following sponsor’s decision to stop enrollment due to lack of feasibility 
to complete this study in reasonable time frame, the study design is 
modified to reflect an open label study. After unblinding all patients will 
be given an opportunity to continue treatment with copanlisib. Patients 
who are on copanlisib treatment at the time of unblinding will continue 
copanlisib treatment. Patients who are on placebo at the time of unblinding 
will be offered to switch to copanlisib treatment after unblinding 
procedures are completed.
After individual patient unblinding, patients receiving placebo, who switch 
to copanlisib will have all study assessments reset to the initial schedule of 
study evaluations (i.e. as if the patient was restarted the study at Cycle 1 
Day 1). 
Methodology
[…] The patients in the Active follow-up will have radiological 
assessments as outlined in this protocol from the day of start of study 
treatment until the end of the Active follow-up period, defined as when 
either PD is documented or a new anti-tumor treatment is administered, 
whichever occurs first.
All patients will be followed off-study for overall survival at least at 6-
month intervals during the Survival follow-up period (up to 3 years after 
the last patient started study treatment), except for patients who object to 
follow-up data collection.
[…] During the treatment period as well as during the Active follow-up 
period tumor assessments with the same modality will be performed per 
local SOC but not less than every 16 weeks. CT/MRI scans are not 
required at the EOT visit if the patient discontinues due to PD which has 
been radiologically confirmed within the 4 weeks preceding EOT. The 
evaluation of treatment response (best response: ORR and CRR) will be 
done by the investigator.
[…]
Bone marrow biopsy will be mandatory at Screening. Bone marrow tissue 
biopsy will be done within 28 days before first study drug infusion and 
must be provided at screening. Bone marrow biopsy must be performed 
again to confirm the first complete response (CR) on patients with 
previous bone marrow infiltration at baseline, and may also be performed 
at the investigator discretion if there is clinical suspicion of bone marrow 
infiltration. Bone marrow biopsy will be performed per local standard of 
care.
Type of control
Not applicable.
Number of patients
Following sponsor’s decision to stop the study no further patients will be 
enrolled. All patients enrolled in the study by the time the protocol 
amendment 5 is approved will be unblinded.


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Primary variable
The primary efficacy analysis is ORR, which is defined as the proportion 
of patients who have a best response rating over the whole duration of the 
study of complete response (CR) or partial response (PR) according to the 
Lugano Classification (21), and for patients with WM, a response rating of 
CR, very good partial response (VGPR), PR, or minor response (MR) 
according to the Owen criteria (22).
Plan for statistical analysis
Due to the decision of stopping enrollment as protocol amendment 5 
becomes effective, limited number of patients will be included in the 
analyses. Therefore, the statistical analyses included in this study will be 
focused on descriptive statistics without any hypothesis testing.
Two sets of analyses will be performed at the timing when all treated 
patients completed at least 6 cycles of study treatment: 
1)
unblinding cutoff: analyze all data available before the unblinding  
(details in section 6.5); 
2)
final analysis: analyze all data available until all treated patients 
complete at least 6 cycles of study treatment. 
13.4.2.4
List of abbreviations
Old text:
[…]
ePRO
Electronic patient-reported outcome
[…]
FWB
Functional and well-being (subscale)
[…]
H0
Null hypothesis
H1
Alternative hypothesis
Hb
Hemoglobin
[…]
ImpDRSP
Improvement in disease-related symptoms – physical
[…]
ITF
Investigator’s trial file
[…]
NaOH
Sodium hydroxide
[…]
SAC
Statistical Analysis Center
[…]
SUV
Standardized uptake value
[…]
TMF
Trial master file
TSE
Treatment side effects (subscale)
TTP
Time to progression
[…]


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New text: no new abbreviations were added.
13.4.2.5
Section 1.2 Rationale of the study
Old text:
[…]
In order to provide a scientifically rigorous answer about copanlisib single agent activity, the 
randomized study is the most appropriate approach. Because no standard of care is available 
for the selected patient population, placebo is an appropriate choice of control in this 
randomized study. To minimize risk, following parameters are included in this study design 
(added by amendment 1):

2:1 randomization.

Exclusion of patients with bulky disease.

Opportunity for patients in the control arm to switch to active treatment after 
progression will ensure that all patients with radiologically confirmed PD will be 
treated with copanlisib.
Considering the pre-clinical profile of copanlisib and the evidence of clinical activity 
emerging from Phase I study 12871 and the ongoing Phase II study 16349, it is expected that 
copanlisib will improve progression-free survival (PFS) in patients with rituximab-refractory 
iNHL who have received two or more prior lines of treatment (changed by amendment 1).
New text:
[…]
Following sponsor’s decision to stop enrollment due to lack of feasibility to complete this 
study in reasonable time frame, the study design is modified to reflect an open label study. All 
patients on study treatment will be offered to continue treatment with copanlisib after 
unblinding procedures are completed.
13.4.2.6
Section 1.3 Benefit-risk assessment
Old text:
[…]
Hyperglycemia and hypertension, the most frequently observed and expected toxicities with 
copanlisib, have been manageable. Toxicities will be carefully monitored during the course of 
the study with a detailed and tailored program of management. A Data Monitoring Committee 
(DMC) will be instituted to maximize the safety of the patients participating in the study.
Because of the slowly progressing nature of the disease, the low symptom burden, and the 
opportunity to receive open-label copanlisib following PD on placebo, the patients assigned to 
the placebo arm will not be exposed to undue risk.


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[…]
New text: no new text was added.
13.4.2.7
Section 2. Study objectives
Old text:
The primary objective of this study is:

To investigate whether copanlisib as monotherapy is superior to placebo in prolonging 
progression-free survival (PFS) in patients with rituximab-refractory iNHL who have 
received two or more prior lines of treatment, have been exposed to rituximab and 
alkylating agent(s), and have progressed within six months of the end of the last 
previous rituximab-containing regimen (changed by amendment 1).
The secondary objectives of this study are to evaluate:

Efficacy including tumor response, time to progression and overall survival (modified 
by amendment 1).

The following characteristics of disease-related symptoms: time to deterioration and 
time to improvement (changed by amendment 1).

Safety.
The other objectives of this study are to evaluate:

PFS2 in placebo-treated patients who switched to open-label copanlisib treatment 
(added by amendment 1).

Pharmacokinetics.

Biomarkers.

Quality of life.
New text:
The primary objective of this study is:

To investigate objective tumor response rate (ORR) assessed in all patients with 
rituximab-refractory iNHL who have received two or more prior lines of treatment, 
have been exposed to rituximab and alkylating agent(s), and have progressed within 
six month of the end of the last previous rituximab-containing regimen. 
The secondary objectives of this study are to evaluate:

Efficacy including complete response rate and overall survival.

Safety.
The other objectives of this study are to evaluate:


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
Pharmacokinetics.

Biomarkers.
13.4.2.8
Section 3. Investigator and other study personnel
Old text:
Sponsor’s 
Name: 
 MD, PhD
Title: 
 Oncology
Address: Rua Domingos Jorge, 1100, Predio 9301, 2º andar
CEP 04779-900, Sao Paulo-SP, Brazil
Telephone no.:
[…]
Data Monitoring Committee
[…]
The DMC will include at least three members, including an independent Statistician and 
Oncologist. Safety review meetings will be held periodically as per separate DMC charter. 
Enrollment to the study will continue throughout the scheduled meetings of the DMC.
[…]
Central radiological evaluation
Radiological evaluation of computed tomography/magnetic resonance imaging (CT/MRI) 
scans will be performed centrally.
[…]
New text:
Sponsor’s 
Name: 
 MD
 Bayer Center,
No.27 Dong San Huan North Road,
Chaoyang District, Beijing, China, 100020
Telephone no.:
[…]
Central radiological evaluation
PPD
PPD
PPD
PPD
PPD
PPD
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PPD


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After study stopped for enrollment and all patients will be unblinded and offered an open 
label study treatment, there will be no central radiological evaluation.
13.4.2.9
Section 4. Study design
Old text: 
Design overview
[…]
The start of the study period is defined by signing of the informed consent form (ICF). 
Assuming a 20% screen failure rate, approximately 237 patients will be screened for 
enrollment to this study. Approximately 189 patients who meet the eligibility criteria (see 
Section 5.1) will be randomly assigned in a 2:1 ratio to one of the double-blinded treatment 
arms: copanlisib monotherapy or placebo. The copanlisib monotherapy arm will consist of 
approximately 126 patients and placebo arm of approximately 63 patients. Patients will be 
stratified at randomization based on NHL histology (FL histology vs. other iNHL histology), 
the time between last course of systemic anticancer therapy and most recent progression 
(≤6 months vs. > 6 months) and prior treatment with PI3K inhibitors (yes vs. no) (see 
Section 6.3). The study is planned to include approximately 144 patients with FL histology 
and 45 patients with other iNHL histologies (paragraph changed by amendment 1).
A graphical presentation of the overall study design is shown in Figure 4–2.
Figure 4–2
Overall study design 
NHL = Non-Hodgkin’s lymphoma, PI3K = Phosphatidylinositol 3-kinase.
Figure modified by amendment 1
The start of the treatment period is defined by first administration of study drug (copanlisib or 
placebo). Copanlisib will be administered IV over approximately 1 h at starting dose of 60 mg 
on Days 1, 8 and 15 of each 28-day treatment cycle. Patients in the placebo arm will receive a 
placebo IV infusion at the same schedule. Treatment will be continued until PD (per central 
Stratification
NHL histology 
Time between most recent 
progression and last course of 
systemic anticancer therapy
Prior treatment with PI3K 
inhibitors
Randomization
2:1
(N=189)
Copanlisib 60 mg
Days 1,8 and 15      
of each 28-day Cycle
Placebo
Days 1,8 and 15      
of each 28-day Cycle
Change from placebo 
to copanlisib 
(discretion of the 
investigator/patient)
Follow-up until further 
disease progression
Unblinding
Disease 
progression
Blinded central 
radiology review
O
F
F
T
R
E
A
T
M
E
N
T


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independent blinded radiology review) as defined in the Lugano Classification (21), 
unacceptable toxicity, or until another criterion is met for withdrawal from the study treatment 
(see Section 5.2). For patients with WM, response assessment will be done according to the 
Owen criteria (22).
Patients who experience PD on placebo treatment (per central independent blinded radiology 
review) can be offered open-label copanlisib upon discretion of the investigator and patient’s 
consent. After individual patient unblinding, patients receiving placebo who switch to open-
label copanlisib will have all study assessments and timing reset to the initial schedule of 
study evaluations (i.e. as if the patient was restarting the study at Cycle 1 Day 1).These 
patients will be treated until further disease progression (per central review) unacceptable 
toxicity, or until another criterion is met for withdrawal from the study treatment (see 
Section 5.2).
[…]
Patients who discontinue study treatment due to PD will enter the Safety-follow up period and 
patients who discontinue study treatment for reasons other than PD will enter the Active 
follow-up period (which also serves as a Safety follow-up), except for patients who object to 
follow-up data collection. The patients in the Active follow-up will have radiological 
assessments by central independent blinded review as outlined in this protocol from the day of 
randomization until the end of the Active follow-up period, defined as when either PD is 
documented or a new anti-tumor treatment is administered, whichever occurs first. 
[…] The method chosen at the baseline must be the same throughout the study. During the 
treatment period as well as during the Active follow-up period tumor assessments with the 
same modality will be performed every 12 weeks during Year 1, every 16 weeks during Year 
2, and every 24 weeks during Year 3 (modified by amendment 1). CT/MRI scans are not 
required at the EOT visit if the patient discontinues due to PD which has been radiologically 
confirmed within the 4 weeks preceding EOT. The response assessment will be done 
according to the Lugano Classification (21), and for patients with WM, according to the 
Owen criteria (22). Detailed instructions on tumor assessment are provided in Appendix 14.1. 
As long as the patient has not experienced PD, investigator’s assessment is sufficient for case 
management. In the event of progression, radiological real-time confirmation by central 
independent blinded evaluation is required before a final decision to stop the treatment is 
made. The final evaluation of treatment response (best response: objective tumor response 
rate [ORR] and complete response rate [CRR]) will be done by central blinded review and for 
those not undergoing PD-confirmation in retrospective setting (modified by amendment 3).
WM patients who do not have radiologically measurable lesion at Screening will not have 
further radiological assessments as per protocol. Their tumor response will be measured only 
by laboratory/clinical tests. However, in cases when WM patients will develop disease 
progression confirmed radiologically by presenting with measurable lesion(s) without 
simultaneous increase in IgM, the imaging scans should be submitted for central review and 
PD confirmation. WM patients who have radiologically measurable lesion at Screening will 
continue having radiological assessments and, in addition, will have laboratory tests 
performed on the same days.


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Bone marrow biopsy will be mandatory at Screening. Bone marrow tissue biopsy will be 
performed within 28 days before first study drug infusion and must be provided at screening. 
Bone marrow biopsy must be performed again to confirm the first complete response (CR) on 
patients with bone marrow infiltration at baseline, and may also be performed at the 
investigator discretion if there is clinical suspicion of bone marrow infiltration. All specimens 
must be sent to central pathology review (paragraph modified by amendment 4).
Tumor tissue collection will be mandatory at Screening for central pathology review. In 
addition, additional pre-treatment tumor tissue samples will be collected when available to 
investigate or identify biomarkers that may be predictive of copanlisib effects/efficacy in 
NHL and to contribute to better understanding the disease (see Section 7.6.1).
[…]
Health-related quality of life (QoL) will be assessed using the FLymSI-18 questionnaire. This 
questionnaire is to be completed according to schedule specified in Section 7.6.2. 
Primary variable
The primary efficacy variable of this study is progression-free survival (PFS), defined as the 
time (in days) from randomization to PD as assessed by central review or death from any 
cause (if no progression is documented). All efficacy analyses will be performed when 
approximately 82 centrally evaluated PFS events are observed in the FL subgroup (changed 
by amendment 1).
Justification of the design
The pre-clinical profile of copanlisib and preliminary efficacy data from Phase I study 12871 
and Phase II study 16349 suggest that copanlisib may improve PFS in patients with 
rituximab-refractory iNHL who have received two or more prior lines of treatment and have 
been exposed to rituximab and alkylating agent(s). The purpose of this study is to demonstrate 
efficacy and safety of treatment with copanlisib in patients where treatment is indicated, with 
a controlled randomized study with PFS as the primary endpoint.
The use of placebo as a comparator in this study is justified for the following reasons:

No standard of care is available for the defined patient population.

Published data indicates multiple options of chemotherapy combinations or single 
agent therapy used in these patients based on data from, often small, single arm 
studies.

No randomized study has confirmed efficacy or safety of these therapeutic options, 
including for those agents where regulatory approval was granted (bendamustine, 
idelalisib). Potential control agents have limited data on PFS.

The natural course of disease in patients with rituximab-refractory iNHL is not known. 

Use of placebo can minimize investigator bias in assessing treatment effects beyond 
tumor shrinkage. This is particularly important when assessing duration endpoints.


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
This study is designed to show significant improvement in PFS for study drug vs. 
control (132% improvement in median PFS).

2:1 randomization will assure that the majority of patients will be treated with 
copanlisib from onset.

Exclusion of patients with bulky disease.

Available opportunity for patients in the control arm to switch to active treatment after 
progression will ensure that all patients with radiologically confirmed PD will be 
treated with copanlisib. Additional exploratory efficacy endpoint is PFS2, which will 
assess PFS for patients on placebo arm who switched to receive therapy with 
copanlisib.
Although treatment with copanlisib is associated with two specific AEs, 
hyperglycemia and hypertension, the risk of inadvertent unblinding is low. In the 
majority of the cases, the intensity of both symptoms is low; both symptoms are 
relatively frequently found in the age group to which the majority of iNHL patients 
belong; and most investigators will treat 1-2 patients only due to the expected rarity 
of patients eligible for enrollment.
End of study
[…]
However, as the primary endpoint of this study is event-based, the end of the study as a whole 
will only be reached when this endpoint has been achieved in patients in all participating 
centers (EU and non-EU).
[…]
New text:
Design overview
[…]
The start of the study period is defined by signing of the informed consent form (ICF).
Approximately 189 patients (of  approx. 237 screened) will meet the eligibility criteria (see 
Section 5.1) and will be randomly assigned in a 2:1 ratio to one of the double-blinded 
treatment arms: copanlisib monotherapy (approx. 126 patients) or placebo (approx. 63 
patients). Patients will be stratified at randomization based on NHL histology (FL histology: 
approx. 144 patients; iNHL histology: approx. 45 patients) , the time between last course of 
systemic anticancer therapy and most recent progression and prior treatment with PI3K 
inhibitors (see Section 6.3).
Following sponsor’s decision to stop enrollment due to lack of feasibility to complete this 
study in reasonable time frame, the study design is modified to reflect an open label study. All 


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patients on study treatment will be offered to continue treatment with copanlisib after 
unblinding procedures are completed (see Section 6.5).
A graphical presentation of the study design valid as of amendment 5 is shown in Figure 4–2.
Figure 4–2
Overall study design as of amendment 5
Figure modified by amendment 1 and replaced by amendment 5.
The start of the treatment period is defined by first administration of study drug (copanlisib). 
Copanlisib will be administered IV over approximately 1 h at starting dose of 60 mg on Days 
1, 8 and 15 of each 28-day treatment cycle. Treatment will be continued until PD (per 
investigator’s assessment) as defined in the Lugano Classification (21), unacceptable toxicity, 
or until another criterion is met for withdrawal from the study treatment (see Section 5.2). For 
patients with WM, response assessment will be done according to the Owen criteria (22).
All patients after unblinding procedures are completed will be offered an opportunity to 
continue this clinical study and receive active treatment with copanlisib. Patients who are on 
copanlisib treatment at the time of unblinding will continue copanlisib treatment. Patients 
who are on placebo at the time of unblinding will switch to copanlisib treatment after 
unblinding procedures are completed. After individual patient unblinding, patients receiving 
placebo, who switch to copanlisib will have all study assessments reset to the initial schedule 
of study evaluations (i.e. as if the patient was restarted the study at Cycle 1 Day 1). Patients
will be treated until disease progression (per investigator’s assessment), unacceptable toxicity, 
or until another criterion is met for withdrawal from the study treatment (see Section 5.2).
[…]
Patients who discontinue study treatment due to PD will enter the Safety-follow up period and 
patients who discontinue study treatment for reasons other than PD will enter the Active 
follow-up period (which also serves as a Safety follow-up), except for patients who object to 
follow-up data collection. The patients in the Active follow-up will have radiological 
assessments by investigator as outlined in this protocol from the day of start of study 
treatment until the end of the Active follow-up period, defined as when either PD is 
documented or a new anti-tumor treatment is administered, whichever occurs first. During the 
Active follow-up period, serious adverse events (SAEs) and AEs assessed as related to study 
procedures by the investigator will be reported. AE pages of the electronic case report form 


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(eCRF) and the SAE form should be completed in the usual manner and forwarded to the 
sponsor’s GPV department. 
All patients will be followed off-study for overall survival at least at 6-month intervals during 
the Survival follow-up period (up to 3 years after the last patient started study treatment), 
except for patients who object to follow-up data collection. During this period, patients are 
not considered to be “on-study”.
[…] The method chosen at the baseline must be the same throughout the study. During the 
treatment period as well as during the Active follow-up period tumor assessments with the 
same modality will be performed, and the schedule of tumor assessment will be performed per 
local standard of care of the institution but not less than every 16 weeks. CT/MRI scans are 
not required at the EOT visit if the patient discontinues due to PD which has been 
radiologically confirmed within the 4 weeks preceding EOT. The response assessment will be 
done according to the Lugano Classification (21), and for patients with WM, according to the 
Owen criteria (22). Detailed instructions on tumor assessment are provided in Appendix 14.1. 
All the efficacy analyses will be done based on investigator’s assessment of tumor response.
WM patients who do not have radiologically measurable lesion at Screening will not have 
further radiological assessments as per protocol. Their tumor response will be measured only 
by laboratory/clinical tests. However, in cases when WM patients who develop 
extramedullary disease without simultaneous increase in IgM will have radiological 
assessment to confirm disease progression (per investigator’s assessment). WM patients who 
have radiologically measurable lesion at Screening will continue having radiological 
assessments and, in addition, will have laboratory tests performed on the same days.
Bone marrow biopsy will be mandatory at Screening. Bone marrow tissue biopsy will be 
performed within 28 days before first study drug infusion and must be provided at screening. 
Bone marrow biopsy must be performed again to confirm the first complete response (CR) on 
patients with bone marrow infiltration at baseline, and may also be performed at the 
investigator discretion if there is clinical suspicion of bone marrow infiltration. Bone marrow 
biopsy will be performed as per local standard of care. 
All collected tumor tissue samples will be utilized to investigate or identify biomarkers that 
may be predictive of copanlisib effects/efficacy in NHL and to contribute to better 
understanding the disease (see Section 7.6.1).
[…]
Primary variable
Due to the decision of stopping enrollment, limited number of patients will be included in the 
analyses. Therefore, the statistical analyses included in this study will be focused on 
descriptive statistics.
The primary efficacy variable of this study will be objective tumor response rate (ORR), 
which is defined as the proportion of patients who have a best response rating up to the dates 
of data cutoffs (for dates of data cutoffs, see details in section 8.1) of complete response (CR) 
or partial response (PR) according to the Lugano Classification (21), and for patients with 


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WM, a response rating of CR, very good partial response (VGPR), PR, or minor response 
(MR) according to the Owen criteria (22).
Justification of the design
The pre-clinical profile of copanlisib and preliminary efficacy data from Phase I study 12871 
and Phase II study 16349 suggest that copanlisib may improve PFS in patients with 
rituximab-refractory iNHL who have received two or more prior lines of treatment and have 
been exposed to rituximab and alkylating agent(s). The purpose of this study is to demonstrate 
efficacy and safety of treatment with copanlisib in patients where treatment is indicated, with 
ORR as the primary endpoint.
[…]
13.4.2.10 Section 5.2.1 Withdrawal
Old text:
A patient who, for any reason (e.g. failure to satisfy the selection criteria), terminates the 
study before randomization is regarded a “screening failure”. 
A patient who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the patient has already been randomized.
Re-screening of patients who have failed screening may only be allowed once after discussion 
with the sponsor’s designated medical representative and after approval by the sponsor. 
Sponsor approval of re-screening for the patient who has failed screening must be 
documented. The screening failure will be registered in IVRS/IWRS 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.
All initial screening laboratory tests will need to be taken within 7 days prior to planned 
Cycle 1 Day 1. 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 need to be repeated. Re-testing must be performed within 14 days of the 
initial test and with approval from the sponsor. However if this re-testing cannot be completed 
within 7 days of the Cycle 1 Day 1, all blood and urinary tests that are required to be within 
7 days of Cycle 1 Day 1 will need to be repeated. Patients may not begin study drug treatment 
until the results of re-testing are available and documented to be within protocol-required 
range. Diagnostic testing performed as part of the original screening or standard of practice 
(e.g. including fresh tumor tissue, CT/MRI scans, bone marrow sample, 
MUGA/echocardiogram and hepatitis testing) will not need to be repeated during the 14 day 
re-testing period. CT/MRI scans need to be re-submitted with the new PID (sentence added by 
amendment 3). 
If re-test laboratory results are still out of eligibility range, this will be considered a full 
screening failure, and only one re-screening will be allowed following the rules as outlined 
above.


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For patients with newly diagnosed diabetes mellitus that cannot meet protocol requirements, a 
single re-screening (which includes all screening procedures) should be performed when the 
patient’s diabetes is controlled and can meet protocol requirements for HbA1c (modified by 
amendment 4).
New text:
A patient who, for any reason (e.g. failure to satisfy the selection criteria), terminates the 
study before randomization is regarded a “screening failure”. 
A patient who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the patient has already entered treatment.
13.4.2.11 Section 5.2.1.1 Withdrawal from study treatment
Old text:
Patients must be withdrawn from the study treatment for the following reasons:

[…]

Disease progression (PD) as defined in the Lugano Classification (21), and for patients 
with WM, according to the Owen criteria (22) (changed by amendment 1). Detailed 
instructions on tumor assessment are provided in Appendix 14.1. Radiological PD 
must be assessed by central independent blinded review before unblinding of study 
treatment (copanlisib or placebo). The result of PD per central review instead of 
investigational site image assessment will be used to unblind the patient. Patients who 
have received placebo can be offered open-label copanlisib upon discretion of the 
investigator and patient’s consent.
[…]
New text: no new text was added.
13.4.2.12 Section 5.2.1.2 Withdrawal from follow-up period 
Old text:
[…]
All patients will be contacted at least every 3 months to determine survival status during the 
Survival follow-up period (up to 3 years after the last patient started study treatment).
[…]
New text:


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[…]
All patients will be contacted at least every 6 months to determine survival status during the 
Survival follow-up period (up to 3 years after the last patient started study treatment).
[…]
13.4.2.13 Section 6.1 Treatments to be administered
Old text:
The following treatments will be administered in this study:

Copanlisib (BAY 80-6946) solution for IV infusion (study drug/investigational 
medicinal product)

Placebo solution for IV infusion
Patients randomized to the copanlisib treatment arm will receive copanlisib IV infusion at a 
starting dose of 60 mg as single agent on Days 1, 8 and 15 of each 28-day treatment cycle.
Patients randomized to the placebo arm will receive placebo IV infusion on Days 1, 8 and 15 
of each 28-day treatment cycle.
In the event of toxicities, dose reductions to 45 mg and further to 30 mg are allowed. The dose 
modifications will follow the pre-defined dose levels outlined in Section 6.4.1. Dummy dose 
modifications are used if toxicities occur in the placebo arm.
[…]
New text:
The following treatments will be administered in this study:

Copanlisib (BAY 80-6946) solution for IV infusion (study drug/investigational 
medicinal product)

Placebo solution for IV infusion removed by amendment 5
Eligible patients will receive copanlisib IV infusion at a starting dose of 60 mg as single agent 
on Days 1, 8 and 15 of each 28-day treatment cycle.
[…]
13.4.2.14 Section 6.2 Identity of study treatment
Old text:
All study drugs will be labeled according to the requirements of local law and legislation. 
Label text will be approved according to the sponsor’s agreed procedures, and a copy of the 
labels will be made available to the study site upon request.


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For all study drugs, a system of numbering in accordance with all requirements of Good 
Manufacturing Practice (GMP) will be used, ensuring that each dose of study drug can be 
traced back to the respective bulk ware of the ingredients. Lists linking all numbering levels 
will be maintained by the sponsor’s clinical supplies QA group. 
A complete record of batch numbers and expiry dates of all study treatment as well as the 
labels will be maintained in the sponsor study file.
[…]
Placebo
Placebo is supplied as lyophilized preparation in a 6 mL injection vial. Placebo treatment will 
follow a dosing scheme to match the active drug product. Accordingly, the developed placebo 
lyophilisate is equivalent to the 60 mg copanlisib formulation, with regard to the composition 
of excipients and the instructions for reconstitution and dose preparation.
Reconstitution, dilution and storage of placebo preparation should be performed according to 
same instructions as for copanlisib.
For the guidance on preserving the blinding during handling of the study drugs, please refer to 
Section 6.5.
New text:
The 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 ware of the ingredients. Lists linking all numbering levels 
will be maintained by the sponsor’s clinical supplies QA group. 
A complete record of batch numbers and expiry dates of study treatment as well as the label 
will be maintained in the sponsor study file.
[…]
13.4.2.15 Section 6.3 Treatment assignment
Old text:
At the end of the Screening period, eligible patients will be randomly assigned in a 2:1 ratio to 
one of the double-blinded treatment arms: copanlisib monotherapy or placebo, respectively 
(modified by amendment 1). The randomization must be performed within 48 h before the first 
dose of study drug.
Treatment will be assigned based on information obtained from IVRS/IWRS. 


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IVRS/IWRS will stratify patients according to three factors based on baseline characteristics 
(modified by amendment 1): 

NHL histology, with categories: 
o
FL histology 
o
Other NHL histology, and

Time between last course of systemic anticancer therapy and most recent progression, 
with categories:
o
≤ 6 months
o
> 6 months, and

Prior treatment with PI3K inhibitors (added by amendment 1):
o
Yes
o
No
Resulting from the combination of these three stratification factors, patients will be 
randomized into 8 different strata (modified by amendment 1).
The IVRS/IWRS procedure is described in detail in a separate IVRS/IWRS instruction 
manual that will be maintained in the trial master file (TMF), and in each center’s 
investigator’s trial file (ITF).
Due to the potential of bias or unblinding, the size of randomization blocks within the 
randomization list must not be disclosed to blinded study individuals.
During the course of the study, the randomization list will be provided to the Statistical 
Analysis Center (SAC) for the DMC and its meetings, the Bioanalytics group and the 
Pharmacokinetic Evaluator in order to perform the PK analysis.
Unblinding of the treatment assignment of a patient may be carried out by the investigator for 
emergency purposes only. Investigators should note that the occurrence of an SAE should not 
routinely precipitate the immediate unblinding of the study drug (see Section 6.5).
New text:
With protocol amendment 5 there will be no randomization. All patients who are on study 
will be offered the opportunity to continue treatment with copanlisib.
The IXRS/IWRS will remain open in order to manage study drug.


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13.4.2.16 Section 6.4 Dosage and administration
Old text:
Study drug (copanlisib or placebo) 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.
[…]
Recommendations on meal timing on infusion days 
[…]
Patients will continue study treatment until PD (per central independent blinded radiology 
review) or they meet the criteria described in Section 5.2. Patients who experience PD on 
placebo treatment can be offered open-label copanlisib upon discretion of the investigator and 
patient’s consent. After individual patient unblinding, patients receiving placebo who switch 
to open-label copanlisib will have all study assessments and timing reset to the initial 
schedule of study evaluations (i.e. as if the patient was restarting the study at Cycle 1 Day 1). 
If not previously done within 7 days, patients switching to open-label copanlisib must 
complete the following within 7 days prior to the first dose of open-label copanlisib: 
UPCR/24 h total urine protein quantification, GFR measurement, urinalysis, HbA1c, CBC, 
chemistry and coagulation panels. For Day 1 of the first open-label cycle, laboratory 
parameters as outlined in inclusion criterion 13 and exclusion criteria 15 and 24 will apply. 
For Day 1 of subsequent open-label cycles, dosing criteria outlined in Table 6–2 will apply 
for patients who switch to open-label treatment (modified by amendment 3). These patients 
will be treated until further disease progression (per central review) unacceptable toxicity, or 
until another criterion is met for withdrawal from the study treatment (see Section 5.2) 
(changed by amendment 1).
[…]
New text: no new text was added.
13.4.2.17 Section 6.5 Blinding
Old text:
Patients will be randomized to receive copanlisib or placebo in a double-blind fashion such 
that neither the investigator, nor the sponsor, nor the patient will know which agent is being 
administered. The randomization number will be assigned through the IVRS/IWRS based on 
information supplied by the investigator when the patient qualifies for study treatment. 
The appearance of the packaging for copanlisib and placebo will be identical in order to 
preserve blinding. Both will be packaged in a drug pack labeled with a unique drug pack 


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number which will be pre-printed. The study drug pack number will be assigned to the patient 
through the IVRS/IWRS.
Because copanlisib solution may have a yellowish color while the placebo solution is 
colorless, measures will be taken to preserve the blind. This includes an unblinded, study-
independent pharmacist (or qualified person) who will handle the preparation of the study 
drug, and unblinded monitors, separate from the blinded monitoring team, to conduct the 
monitoring of the pharmacy and drug supplies. Additional details will be described in the 
Pharmacy Manual (paragraph changed by amendment 1.)
In compliance with applicable regulations, in the event of a SUSARs (see Section 7.5.1.5), the 
patient’s treatment code will usually be unblinded before reporting to the health authorities, 
ethic committees and investigators (see Section 7.5.1.4) if the SUSAR was related to the 
blinded treatment.
Emergency unblinding by the investigator
Unblinding of the treatment assignment of a patient may be carried out by the investigator for 
emergency purposes only. Investigators should note that the occurrence of an SAE should not 
routinely precipitate the immediate unblinding of the study drug. If unblinding is necessary 
for the treatment of a patient who has experienced an SAE, the treatment assignment of a 
patient will be unblinded via instructions provided through the IVRS/IWRS. This system 
allows the investigator, or other responsible person, to identify the study drug in case of an 
emergency, without jeopardizing the double-blind integrity of the remainder of the study.
The code can be broken by the investigator, or other responsible person, when knowledge of 
the patient’s treatment is required for the clinical management of the patient. If it becomes 
necessary to know the individual’s treatment during the study and, thus, break the code for 
that patient, the date and reason are to be entered in the relevant eCRF page. The investigator 
is required to promptly document and explain to the sponsor’s designee any premature 
unblinding (e.g. unblinding due to an SAE) of the study drug.
New text:
Not applicable. 
After individual patient unblinding, patients receiving active study drug will continue 
copanlisib treatment as scheduled. Patients receiving placebo will be offered to switch to 
copanlisib upon discretion of the investigator and patient’s consent.  


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13.4.2.18 Section 6.6 Drug logistics and accountability
Old text:
[…]
Study drug supply and predictive re-supply will be managed through the IVRS/IWRS. After a 
patient is randomized to a treatment group, the amount of study drug supply needed at the 
study site for each randomized patient will be calculated. Re-supply of study drug will be 
performed automatically at regular intervals through the IVRS/IWRS based on the expected 
dosing of the study drug. When a patient is permanently withdrawn from treatment, the study 
site must notify the Sponsor or the CRO through the IVRS/IWRS. 
Written instructions on medication destruction will be made available to affected parties as 
applicable.
New text:
Study drug supply and predictive re-supply will be managed through the IVRS/IWRS. After a 
patient is assigned to treatment, the amount of study drug supply needed at the study site for 
each patient will be calculated. Re-supply of study drug will be performed automatically at 
regular intervals through the IVRS/IWRS based on the expected dosing of the study drug. 
After closure of the study enrollment, the IxRS will continue to supply copanlisib treatment 
for all patients who remain in the study. When a patient is permanently withdrawn from 
treatment, the study site must notify the Sponsor  through the IVRS/IWRS. 
Written instructions on medication destruction will be made available to affected parties as 
applicable.
13.4.2.19 Section 6.7 Treatment compliance
Old text: 
The administration of IV copanlisib and placebo will be performed in the clinic on a weekly 
basis and must be recorded in the eCRF.
New text: no new text was added.
13.4.2.20 Section 7.1.1 Tabulated overview
Old text: see next page


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Table 7-1
Study flow chart
Screening 
maximum days 
before C1D1
Treatment *
EOT
SFU
Active 
follow-
up aa
Survival
follow-
up bb
Cycle 1
Cycle 2 and higher
Within (days) after
Days
-28 -14
-7
D1
D4
D8
D15
D22
D1
D8
D15
D22 y
7
30 + 5
days 
windowz
every 3
months
Acceptable deviation (in days)
-1 to +2 days
-1 to +2 days
Decision
to stop
Last 
dose
14 days
Screening and enrollment
Patient informed consent (including genetic)
Xcc,dd
Check in- and exclusion criteria
X
X
X
Medical history a
X
IVRS/IWRS transaction b, dd
X
Xb
X
X
HBsAg, HBcAb, HCV IgG
X
CMV PCR test ff,ii
X
Xff
Xff
Serum pregnancy test (if applicable) c
X
Xc
Xc, ee
UPCR / 24 h total urine protein 
quantification ee
X
GFR dd
X
X
Safety
Toxicity / AE assessment d
X
X
X
X
X
X
X
X
X
X
(X)d
Concomitant medication d
X
X
X
X
X
X
X
X
X
X
Complete physical examination e
X
X
X
X
Brief physical examination f, dd
X
X
X
X
X
(X)
12-lead ECG g, dd
X
X
Xg
Xg
MUGA scan or echocardiogram h, dd
Xh
Xh
Xh
HbA1c i
X
Xi
X
Complete blood count j
X
Xx
Xx
X
Xx
C2 onlyxC2 onlyx
X
(X)
Hemoglobin, ANC and platelet counts (C3->)
Xx
Xx
Chemistry panel k
Xk
Xx
Xx
X
Xk,x
C2 onlyxC2 onlyx
Xk
(X)
Coagulation panel: PT, INR and PTT
X
Xx
Xx
X
(X)
CD4 (for patients with signs of infection) and 
blood cultures when low ANC of CTCAE 
Grade 4 gg, hh,ii


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Table 7-1
Study flow chart
Screening 
maximum days 
before C1D1
Treatment *
EOT
SFU
Active 
follow-
up aa
Survival
follow-
up bb
Cycle 1
Cycle 2 and higher
Within (days) after
Days
-28 -14
-7
D1
D4
D8
D15
D22
D1
D8
D15
D22 y
7
30 + 5
days 
windowz
every 3
months
Acceptable deviation (in days)
-1 to +2 days
-1 to +2 days
Decision
to stop
Last 
dose
14 days
Urinalysis (dipstick)
X
X
X
Glucose l
X
X
X
X
X
X
Home glucose monitoring m, dd
X
X
X
X
X
X
X
X
X
X
Blood pressure n
X
X
X
X
X
X
Efficacy
Bone marrow biopsy o
X
Xo
CT/MRI and tumor evaluations p
Xp
Xp
Xp
Xp
Quality of life questionnaire (FLymSI-18) and 
PRO information sheet q, ee
X
X
X
X
Pharmacokinetic sampling r, dd
X
Biomarkers
Tumor tissue for central pathology and 
biomarkers s, dd
X
(X)
Plasma for tumor genetics t, dd
X
X
Plasma for non-genetic biomarker 
analysis u dd
X
X
X
C2
only
C2 
only
C2
only
X
Whole blood for biomarkers v
X
Study drug administration
Copanlisib or placebo IV infusion
X
X
X
X
X
X
Survival status, new anticancer therapy
X
For LPL/WM patients only
Serum protein electrophoresis w
Xw
Xw
(X)w
Immunofixation w
Xw
Xw
(X)w
Serum quantitative IgM test w
Xw
Xw
(X)w
Serum beta-2-microglobulin dd
Xw
Serum or plasma viscosity w
Xw
(X)w
(X)w


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AE = Adverse event; ALP = Alkaline phosphatase; ALT = Alanine aminotransferase; ANC = Absolute neutrophil count; AST = Aspartate 
aminotransferase; BUN = Blood urea nitrogen; CBC = Complete blood count; CD4 = Cluster of differentiation 4; CMV = cytomegalovirus; CT 
= Computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; D = Day; ECG = Electrocardiogram; ECOG = Eastern 
Cooperative Oncology Group; EOT = End of treatment; eCRF= Electronic case report form; ePRO = Electronic patient-reported outcome; FL = 
Follicular lymphoma; FLIPI = Follicular Lymphoma International Prognostic Index; FLymSI-18 = NCCN-FACT Lymphoma Symptom Index-18; 
GFR = Glomerular filtration rate; h = Hour(s); HbA1c = Glycated hemoglobin; HBcAb = Hepatitis B core antibody; HBsAg = Hepatitis B 
surface antigen; HCV = Hepatitis C virus; IgG = Immunoglobulin G; IgM = Immunoglobulin M; iNHL = Indolent non-Hodgkin’s lymphoma; 
INR = International normalized ratio; IV = Intravenous; IVRS = Interactive voice response system; IWRS = Interactive web response system; 
LDH = Lactate dehydrogenase; LDL = Low-density lipoprotein; LPL/WM = Lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia; 
LVEF = Left ventricular ejection fraction; min = Minute(s); MRI = Magnetic resonance imaging; MUGA = Multiple gated acquisition; NYHA = 
New York Heart Association; OI = Opportunistic infection; PCR = polymerase chain reaction; PD = Disease progression; PK = 
Pharmacokinetic(s); PRO = Patient-reported outcome; PT = Prothrombin time; PTT = Partial thromboplastin time; RBC = Red blood cell count; 
SAE = Serious adverse event; SCR = Serum creatinine; SFU = Safety follow-up; UPCR = Urine protein to creatinine ratio; WBC = White 
blood cell count.
*
NOTE: Patients who experience PD on placebo treatment (per central independent blinded radiology review) can be offered open-label copanlisib upon 
discretion of the investigator and patient’s consent. After individual patient unblinding, patients receiving placebo who switch to open-label
copanlisib will have all study assessments and timing reset to the initial schedule of study evaluations (i.e. as if the patient was restarting the 
study at Cycle 1 Day 1). For further information on laboratory requirements for patients who switch to open-label treatment, please see 
Section 7.1.2.2.
[…]
b
IVRS/IWRS transaction to register the patient in the system will be at Screening (modified by amendment 1). IVRS/IWRS randomization
transaction will take place within 48 h before the first dose of study drug. IVRS/IWRS transactions for medication dispensing will be on Day 1 
of each cycle. IVRS/IWRS transaction to register end of treatment will be at the EOT visit.
[…]
g
12-lead ECG (including QTcB and QTcF evaluation) will be performed at Screening (within 28 days before Cycle 1 Day 1), on Cycle 1 Day 1,
and on Day 1 of every 3rd cycle starting from Cycle 3 (3, 6, 9, etc.) prior to infusion and at the end of infusion (window of up to 2 h prior to and post-infusion is 
allowed) At the EOT visit, a 12-lead ECG is necessary only if not recorded within the previous 4 weeks.
h
MUGA scan or echocardiogram to measure LVEF at Screening (within 28 days before Cycle 1 Day 1), within 7 days prior to dosing on Day 1 of 
every 3rd cycle (3, 6, 9, etc.), and at the EOT visit (if not previously done within 4 weeks). The method chosen at Screening must be the same 
throughout the whole study.
i
HbA1c at Screening, on Day 1 of every odd cycle (3, 5, 7, etc.) starting from Cycle 3 and at the EOT visit. The testing is not required if the previous 
test was performed within 4 weeks preceding EOT visit.


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j
CBC: Hemoglobin, hematocrit, RBC, WBC (with differential to include absolute neutrophil, lymphocyte, monocyte, basophil and eosinophil 
counts and platelet count). From Cycle 3 onwards, only hemoglobin, platelet and ANC counts will be performed on Day 8 and Day 15 prior to 
each infusion. Differential blood count in percentage can be provided when absolute count is not available per standard of care of the local 
lab.
k
Chemistry panel: calcium, sodium, potassium, chloride, phosphorous, magnesium, bicarbonate (or carbon dioxide, if bicarbonate is not 
routinely measured at the site), total protein, albumin, glucose, BUN (or urea if BUN is not routinely measured at the site), SCR, uric acid, 
total bilirubin, creatine phosphokinase, ALT, AST, LDH, ALP, lipase, amylase (or pancreatic amylase, if total amylase is not routinely 
measured at the site), cholesterol (total and LDL) and triglycerides. 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.
[…]
o
Bone marrow biopsy must be performed within 28 days before first study drug infusion, and to confirm the first complete response if there is 
bone marrow infiltration at baseline, and also at the investigator discretion if there is clinical suspicion of bone marrow infiltration. All specimens 
must be sent to central pathology review.
p
The first IV (and oral, if indicated, per Imaging Manual) contrast enhanced CT/MRI scans of neck, chest, abdomen and pelvis must be 
performed at Screening (including WM patients). Corticosteroids must be stopped or reduced to the allowed dose (less than 15 mg of 
prednisone or equivalent) at least 7 days before performing the screening CT/MRI (if a patient is on chronic corticosteroid therapy, 
corticosteroids should be de-escalated to the maximum allowed dose before the Screening). The method chosen at the baseline must be the 
same throughout the study. During treatment, tumor scans will be done with the same modality every 12 weeks during Year 1, every 16 weeks 
during Year 2, and every 24 weeksduring Year 3. Time points for assessments are calculated from Cycle 1 Day 1. Tumor assessments must be 
performed within 14 days after the last dose (Day 15) and before the next dose (Day 1 of the subsequent cycle) starting from Cycle 3. 
CT/MRI scans are not required at the EOT visit if the patient discontinued due to PD which has been radiologically evaluated within the 4 
weeks preceding EOT. During Active follow-up period patients will have radiological assessments at same intervals as during treatment (time 
window of ±14 days is allowed) until PD is documented or new anti-tumor treatment is administered (see Section 7.1.2.3 and Section 7.3.2). For 
tumor assessments in patients with WM, see Section 7.3.3.
q
FLymSI-18 questionnaire is to be completed on Cycle 1 Day 1 and every cycle thereafter (i.e. on Day 1 of Cycles 2, 3, 4 etc.), at the EOT visit and at the 
SFU visit in both treatment arms. Questionnaire should be self-administered by the patient via an ePRO at the start of the visit before the patient sees the 
physician. A PRO information sheet will be provided and completed by the study personnel at each visit at which the FLymSI-18 questionnaire is to be 
administered, regardless of whether or not the FLymSI-18 questionnaire is completed by the patient (clarified by amendment 1).
[…]
v
Whole blood for biomarkers will be collected on Cycle 1 Day 1 prior to drug administration (only from patients who provide a separate consent for genetic 
research) (modified by amendment 1).
[…]


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y
After Cycle 1, there are no mandatory procedures on Day 22 of subsequent cycles. Tumor assessments and related procedures marked for Day 22 will be 
done according to schedule specified in Section 7.1.2.3 (changed by amendment 1).
z
The post-treatment follow-up 30 days (window of +5 days allowed) after the last administration of study drug can be conducted via telephone 
if the patient is no longer being actively seen at the clinic or has started another therapy. In this case, FLymSI-18 questionnaire does not need to be 
completed at the SFU evaluation (modified by amendments 1and 4). Procedures marked with “(X)” are only to be performed, if clinically indicated.
[…]
bb Patients or their health care providers will be contacted either in person or by telephone (except for patients who object to FU data collection). 
The contacts will be made at least every 3 months (± 14 days), until death or until the end of the trial (up to 3 years after the last patient 
started study treatment), whichever comes first. Information to be recorded: date of contact, survival status, the first new anticancer regimen 
including response (if applicable), and date and cause of death (if applicable).
[…]


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New text:
Table 7-1
Study flow chart
Screening 
maximum days before 
C1D1
Treatment *
EOT
SFU
Active 
follow-
up aa
Survival
follow-up
bb
Cycle 1
Cycle 2 and higher
Within (days) after
Days
-28 
-14
-7
D1
D8
D15
D1
D8
D15
7
30 + 5
days 
windowz
every 6
months
Acceptable deviation (in days)
-1 to +2 days
-1 to +2 days
Decision
to stop
Last 
dose
14 days
Screening and enrollment
Patient informed consent (including 
genetic) jj
Xcc,dd
[…]
[…]
g
12-lead ECG (including QTcB and QTcF evaluation) will be performed at Screening (within 28 days before Cycle 1 Day 1), EOT and as 
clinically indicated. At the EOT visit, a 12-lead ECG is necessary only if not recorded within the previous 4 weeks.
h
MUGA scan or echocardiogram to measure LVEF at Screening (within 28 days before Cycle 1 Day 1), EOT and as clinically indicated (if not 
previously done within 4 weeks). The method chosen at Screening must be the same throughout the whole study.
[…]
j
CBC: Hemoglobin, hematocrit, RBC, WBC (with differential to include absolute neutrophil, lymphocyte, monocyte, basophil and eosinophil 
counts and platelet count). From Cycle 2 onwards, only hemoglobin, platelet and ANC counts will be performed on Day 8 and Day 15 prior to 
each infusion. Differential blood count in percentage can be provided when absolute count is not available per standard of care of the local 
lab.
[…]
o
Bone marrow biopsy must be performed within 28 days before first study drug infusion, and to confirm the first complete response if there is 
bone marrow infiltration at baseline, and also at the investigator discretion if there is clinical suspicion of bone marrow infiltration. Bone 
marrow biopsy will be performed as per local standard of care.
p
The first IV (and oral, if indicated, per Imaging Manual) contrast enhanced CT/MRI scans of neck, chest, abdomen and pelvis must be 
performed at Screening (including WM patients). Corticosteroids must be stopped or reduced to the allowed dose (less than 15 mg of 
prednisone or equivalent) at least 7 days before performing the screening CT/MRI (if a patient is on chronic corticosteroid therapy, 


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corticosteroids should be de-escalated to the maximum allowed dose before the Screening). The method chosen at the baseline must be the 
same throughout the study. During treatment, tumor scans will be done with the same modality, and the schedule of tumor assessment will 
be done per local standard of care of the institution but no less than 16 weeks). Time points for assessments are calculated from Cycle 1 Day 
1. Tumor assessments must be performed within 14 days after the last dose (Day 15) and before the next dose (Day 1 of the subsequent 
cycle) starting from Cycle 3. CT/MRI scans are not required at the EOT visit if the patient discontinued due to PD which has been 
radiologically evaluated within the 4 weeks preceding EOT. During Active follow-up period patients will have radiological assessments at 
same intervals as during treatment until PD is documented or new anti-tumor treatment is administered (see Section 7.1.2.3 and Section 
7.3.2). For tumor assessments in patients with WM, see Section 7.3.3.
q     Footnote removed by amendment 5. 
[…]
V    Footnote removed by amendment 5
[…]
Y    Footnote removed by amendment 5
[…]
bb Patients or their health care providers will be contacted either in person or by telephone (except for patients who object to FU data collection). 
The contacts will be made at least every 6 months (± 14 days), until death or until the end of the trial (up to 3 years after the last patient 
started study treatment), whichever comes first. Information to be recorded: date of contact, survival status, the first new anticancer regimen 
including response (if applicable), and date and cause of death (if applicable).
[…]
jj     As of amendment 5, all patients will be reconsented and need to voluntarily agree to sign the ICF and have to do so, to continue in the study 
(added by amendment 5).


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13.4.2.21 Section 7.1.2.1 Screening period
Old text:
[…]
Within 28 days before the first administration of study drug (clarified by amendment 3):

[…]

Bone marrow biopsy: mandatory at Screening and to confirm the first complete 
response in patients with previous bone marrow infiltration at baseline. A bone 
marrow biopsy may also be performed at the investigator discretion if there is clinical 
suspicion of bone marrow infiltration. All specimens must be sent to central pathology 
review.
[…]
New text:
[…]
Within 28 days before the first administration of study drug (clarified by amendment 3):

[…]

Blood test for CMV infection per local SOC. Patients who are CMV testpositive at 
baseline will not be eligible.

[…]

Bone marrow biopsy: mandatory at Screening and to confirm the first complete 
response in patients with previous bone marrow infiltration at baseline. A bone 
marrow biopsy may also be performed at the investigator discretion if there is clinical 
suspicion of bone marrow infiltration. Bone marrow biopsy will be performed as per 
local standard of care.
[…]
13.4.2.22 Section 7.1.2.2 Treatment period
Old text:
After all screening assessments have been completed and the patient’s eligibility has been 
confirmed and documented, the patient will be randomized via IVRS/IWRS. The 
randomization will take place within 48 h before the first dose of study drug.
The following assessments should be performed both in patients on double-blinded study 
treatment (copanlisib or placebo) as well as those who are randomized to placebo and change 
to copanlisib. After individual patient unblinding, patients receiving placebo who switch to 


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open-label copanlisib will have all study assessments and timing reset to the initial schedule 
of study evaluations (i.e. as if the patient was restarting the study at Cycle 1 Day 1). If not 
previously done within 7 days, patients switching to open-label copanlisib must complete the 
following within 7 days prior to the first dose of open-label copanlisib: UPCR/24 h total urine 
protein quantification, GFR measurement, urinalysis, HbA1c, CBC, chemistry and 
coagulation panels. For Day 1 of the first open-label cycle, laboratory parameters as outlined 
in inclusion criterion 13 and exclusion criteria 15 and 24 will apply. For Day 1 of subsequent 
open-label cycles, dosing criteria outlined in Table 6–2 will apply for patients who switch to
open-label treatment.
[…]
New text:
After all screening assessments have been completed and the patient’s eligibility has been 
confirmed and documented, the patient will be assigned to treatment via IVRS/IWRS. The 
randomization will take place within 48 h before the first dose of study drug.
After individual patient unblinding, patients receiving placebo, who switch to copanlisib will 
have all study assessments reset to the initial schedule of study evaluations (i.e. as if the 
patient was restarted the study at Cycle 1 Day 1). 1315For Day 1 of subsequent cycles, dosing 
criteria outlined in Table 6–2 will apply for patients receiving open-label treatment.
[…]
13.4.2.23 Section 7.1.2.2.1 Treatment – Cycle 1
Old text:
[…]
Patients can stay overnight at the site, if needed, based on the investigator’s decision.

Quality of life (QoL) questionnaire (FLymSI-18): Patient completes the questionnaire 
at the start of a visit, before the patient sees the physician. To be completed by 
electronic patient-reported outcome (ePRO) device. A PRO information sheet will be 
provided and completed by the study personnel at each visit at which the FLymSI-18 
questionnaire is to be administered, regardless of whether or not the FLymSI-18 
questionnaire is completed by the patient (clarified by amendment 1) (see 
Section 7.6.2).

Check inclusion and exclusion criteria. No patient may receive treatment unless 
adherence to all selection criteria as given in Section 5.1 is established.

IVRS/IWRS randomization transaction will take place within 48 h before the first 
dose of study drug.

[…]


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
12-lead ECG including QTcB and QTcF evaluation prior to infusion and at the end of 
infusion (window of up to 2 h prior to and post-infusion is allowed) (modified by 
amendment 1) (see Section 7.5.3.4).

[…]

Collection of blood for biomarker analyses prior to infusion (see Section 7.6.1):
o
Plasma for tumor genetics (modified by amendment 1).
o
Plasma for non-genetic biomarker analysis.
o
Whole blood for genetic biomarker analysis (only from patients who provide a 
separate consent for genetic research).

[…]
Cycle 1 Day 4
Review of blood glucose measurements, meal timing, oral glucose lowering medication 
and/or insulin administration, if applicable. Patients, who might need treatment with glucose 
lowering medications not only on the day of infusion, may be referred to the local diabetes 
center/endocrinologist for glucose management if appropriate e.g. to be trained to self-
administer insulin or oral glucose lowering medication, and to be provided with glucose 
lowering medication prescription and an insulin sliding scale regimen, if applicable. 
Investigators will be free to manage patients in the same way as described in Section 6.4.2.1. 
If indicated, domiciliary support will be arranged (modified by amendment 3).
[…]
Cycle 1 Day 22

Toxicity/AE assessment (see Section 7.5.1.3).

Concomitant medication review. Please 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).

Brief physical examination, including ECOG performance status, vital signs 
(temperature, pulse and blood pressure), examination of pertinent organ systems, and 
brief interim history (change of symptoms) (see Section 7.5.3.2).
Monitoring for OI (see Section 6.4.2.6) (added by amendment 4). 

Blood tests for CBC and chemistry panel (excluding total cholesterol, LDL and 
triglycerides) (see Section 7.5.3.1).

Review of the home blood glucose measurements/meal timing/oral glucose lowering 
medication/insulin administration, if applicable. Provide glucose monitoring supplies 
if necessary (changed by amendment 1 and 3) (see Section 6.4.2.1).


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New text:
[…]
Patients can stay overnight at the site, if needed, based on the investigator’s decision.

QoL questionnaire removed by amendment 5. 

Check inclusion and exclusion criteria. No patient may receive treatment unless 
adherence to all selection criteria as given in Section 5.1 is established.

IVRS/IWRS transaction will take place within 48 h before the first dose of study drug.

[…]

12-lead ECG removed by amendment 5.

[…]

Collection of blood for biomarker analyses prior to infusion (see Section 7.6.1):
o
Plasma for tumor genetics (modified by amendment 1).
o
Plasma for non-genetic biomarker analysis.
o
Whole blood for genetic biomarker analysis removed by amendment 5.

[…]
Cycle 1 Day 4 removed by amendment 5
[…]
Cycle 1 Day 22 removed by amendment 5


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13.4.2.24 Section 7.1.2.2.2 Treatment – Cycle 2 and higher
Old text:
Cycle 2 and higher, Day 1
On Day 1 of each subsequent cycle, patients should be fasting for at least 8 h prior to the pre-
dose glucose measurement. For details on fasting requirements and pre-dose glucose levels, 
see Section 6.4 (added by amendment 1 and modified by amendment 3). 

QoL questionnaire (FLymSI-18) on Day 1 of each cycle (i.e. on Day 1 of Cycles 2, 3, 
4 etc.): Patient completes the questionnaire at the start of a visit, before the patient sees 
the physician (clarified by amendment 1). To be completed by ePRO device (see 
Section 7.6.2).

[…]

12-lead ECG including QTcB and QTcF evaluation on Day 1 of every 3rd cycle 
starting from Cycle 3 (3, 6, 9 etc.) prior to infusion and at the end of infusion (window 
of up to 2 h prior to and post-infusion is allowed) (modified by amendment 1) (see 
Section 7.5.3.4).

MUGA scan or echocardiogram to measure LVEF within 7 days prior to dosing on 
Day 1 of every 3rd cycle (3, 6, 9 etc.). The method chosen at Screening must be the 
same throughout the whole study (see Section 7.5.3.5).

Blood test for HbA1c will be done on Day 1 of every odd cycle (3, 5, 7 etc.) starting 
from Cycle 3.

Blood tests for CBC, chemistry and coagulation panels (see Section 6.4 and 
Section 7.5.3.1). Total cholesterol, LDL and triglycerides will be determined on Day 1 
of every 2nd cycle starting from Cycle 2. On these days patients must be fasting prior 
to sampling according to local standards (changed by amendment 3). If a patient can’t 
adhere to fasting requirements, the evaluation of lipid-panels including triglycerides is 
considered not feasible.

[…]
Cycle 2 and higher, Day 8

[…]

On Cycle 2, blood tests for CBC and chemistry panel (excluding total cholesterol, 
LDL and triglycerides) will be performed. From Cycle 3 onwards, only hemoglobin, 
platelet and ANC counts will be performed prior to each infusion (see Section 6.4 and 
Section 7.5.3.1).

[…]


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Cycle 2 and higher, Day 15

[…]

On Cycle 2, blood tests for CBC and chemistry panel (excluding total cholesterol, 
LDL and triglycerides) will be performed. From Cycle 3 onwards, only hemoglobin, 
platelet and ANC counts will be performed prior to each infusion (see Section 6.4 and 
Section 7.5.3.1).

[…]
Cycle 2 and higher, Day 22
After Cycle 1, there are no mandatory procedures on Day 22 of subsequent cycles. Tumor 
assessments and related procedures marked for Day 22 will be done according to schedule 
specified in Section 7.1.2.3 (paragraph added by amendment 1).
New text:
Cycle 2 and higher, Day 1
On Day 1 of each subsequent cycle, patients should be fasting for at least 8 h prior to the pre-
dose glucose measurement. For details on fasting requirements and pre-dose glucose levels, 
see Section 6.4 (added by amendment 1 and modified by amendment 3). 

QoL questionnaire removed by amendment 5.

[…]

12-lead ECG removed by amendment 5.

MUGA scan or echocardiogram removed by amendment 5.

Blood test for HbA1c removed by amendment 5.

Blood tests for CBC, chemistry and coagulation panels (see Section 6.4 and 
Section 7.5.3.1).

[…]
Cycle 2 and higher, Day 8

[…]

On Cycle 2, blood tests for CBC and chemistry panel (excluding total cholesterol, 
LDL and triglycerides) will be performed. From Cycle 2 onwards, only hemoglobin, 
platelet and ANC counts will be performed prior to each infusion (see Section 6.4 and 
Section 7.5.3.1).

[…]


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Cycle 2 and higher, Day 15

[…]

On Cycle 2, blood tests for CBC and chemistry panel (excluding total cholesterol, 
LDL and triglycerides) will be performed. From Cycle 2 onwards, only hemoglobin, 
platelet and ANC counts will be performed prior to each infusion (see Section 6.4 and 
Section 7.5.3.1).

[…]
Cycle 2 and higher, Day 22 removed by amendment 5


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13.4.2.25 Section 7.1.2.3 Tumor assessments
Old text:
Radiological tumor evaluations (IV [and oral, if indicated, per Imaging Manual] contrast-
enhanced CT/MRI scans of neck, chest, abdomen and pelvis) will be performed during the 
treatment period as well as during the Active follow-up period at the following intervals.
Time points for assessments are calculated from Cycle 1 Day 1.The method chosen at the 
baseline must be the same throughout the study (see also Section 7.3.2):

Year 1: every 12 weeks 

Year 2: every 16 weeks

Year 3: every 24 weeks
During treatment, tumor assessments must be performed within 14 days after the last dose 
(Day 15) and before the next dose (Day 1 of the subsequent cycle) starting from Cycle 3.
During Active follow-up, tumor assessments will be done until PD is documented or new 
anti-tumor treatment is administered. Time window of ±14 days is allowed for scheduling the 
visit for response assessment. 
Bone marrow biopsy is mandatory at baseline and to confirm the first CR if there is bone 
marrow infiltration at baseline. It may also be performed at the investigator discretion if there 
is clinical suspicion of bone marrow infiltration. All specimens must be sent to central
pathology review. Biopsy will be performed as per local standard of care.
[...]
New text:
Radiological tumor evaluations (IV [and oral, if indicated, per Imaging Manual] contrast-
enhanced CT/MRI scans of neck, chest, abdomen and pelvis) will be performed during the 
treatment period as well as during the Active follow-up period, the frequency of tumor 
assessment will be determined by investigator per local standard of care of the institution but 
not less than every 16 weeks. Time points for assessments are calculated from Cycle 1 
Day 1.The method chosen at the baseline must be the same throughout the study (see also 
Section 7.3.2):
[…]


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13.4.2.26 Section 7.1.2.4 End-of-treatment visit
Old text:
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:

QoL questionnaire (FLymSI-18): Patient completes the questionnaire at the start of a 
visit, before the patient sees the physician (clarified by amendment 1). To be 
completed by ePRO device (see Section 7.6.2).

[…]
New text:
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:

QoL questionnaire removed by amendment 5.

[…]
13.4.2.27 Section 7.1.2.5 Follow-up periods
Old text:
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 
Safety follow-up, Active follow-up or Survival follow-up (e.g. for a DMC meeting or data 
analysis). 
New text: no new text was added.
13.4.2.28 Section 7.1.2.5.1 Safety follow-up
Old text:
If a patient discontinues study treatment at any time during the study for any reason (except 
death or lost to follow-up) SFU visit will take place 30 days (window of +5 days allowed) 
after the last administration of study drug. This visit includes:


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
QoL questionnaire (FLymSI-18): Patient completes the questionnaire at the start of a 
visit, before the patient sees the physician (clarified by amendment 1). To be 
completed by ePRO device (see Section 7.6.2).

[…]
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. In this case, 
FLymSI-18 questionnaire does not need to be completed at the SFU evaluation.
New text:
If a patient discontinues study treatment at any time during the study for any reason (except 
death or lost to follow-up) SFU visit will take place 30 days (window of +5 days allowed) 
after the last administration of study drug. This visit includes:

QoL questionnaire removed by amendment 5.
[…]
13.4.2.29 Section 7.1.2.5.2 Active follow-up
Old text:
Patients who discontinue study treatment for reasons other than PD will enter the Active 
follow-up period (which also serves as a Safety follow-up), except for patients who object to 
follow-up data collection. The patients in the Active follow-up will have radiological 
assessments (also by central independent blinded review) as outlined in this CSP from the day 
of randomization until PD is documented or new anti-tumor treatment is administered (see 
Section 7.1.2.3). 
[…]
New text:
Patients who discontinue study treatment for reasons other than PD will enter the Active 
follow-up period (which also serves as a Safety follow-up), except for patients 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 day of start of treatment until PD is documented 
or new anti-tumor treatment is administered (see Section 7.1.2.3). 
[…]


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13.4.2.30 Section 7.1.2.5.3  Survival follow-up
Old text:
All patients will be followed off study for overall survival at least at 3-month intervals during 
the Survival follow-up period (up to 3 years after the last patient started study treatment), 
independent of the reason for study termination, except for patients who object to follow-up 
data collection. Patients or their healthcare providers will be contacted either in person or by 
telephone.
[…]
New text:
All patients will be followed off study for overall survival at least at 6-month intervals during 
the Survival follow-up period (up to 3 years after the last patient started study treatment), 
independent of the reason for study termination, except for patients who object to follow-up 
data collection. Patients or their healthcare providers will be contacted either in person or by 
telephone.
[…]
13.4.2.31 Section 7.3.1 Primary efficacy variable
Old text:
The primary efficacy variable of this study is progression-free survival (PFS), defined as the 
time (in days) from randomization to PD as assessed by central review or death from any 
cause (if no progression is documented).
For the other efficacy variables to be analyzed for this study please refer to Section 8.3.1.
New text:
The primary efficacy variable of this study is objective tumor response rate (ORR), which is 
defined as the proportion of patients who have a best response rating over the whole duration 
of the study up to the dates of data cutoffs (for dates of data cutoffs, see details in section 8.1) 
of complete response (CR) or partial response (PR) according to the Lugano Classification 
(21), and for patients with WM, a response rating of CR, very good partial response (VGPR), 
PR, or minor response (MR) according to the Owen criteria (22).
For the other efficacy variables to be analyzed for this study please refer to Section 8.3.1.


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13.4.2.32 Section 7.3.2 Radiological tumor assessments
Old text:
Radiological tumor assessments with IV (and oral, if indicated, per Imaging Manual) contrast-
enhanced CT/MRI will include neck, chest, abdomen and pelvis, and will be evaluated locally 
at the study site and by the central independent blinded review.
[…]
During the treatment phase as well as during the Active follow-up period, radiological (IV 
[and oral, if indicated, per Imaging Manual] contrast-enhanced CT/MRI) tumor assessment 
will be performed every 12 weeks during Year 1, every 16 weeks during Year 2, and every 
24 weeks during Year 3 (see Section 7.1.2.3). CT/MRI scans are not required at the EOT visit 
if the patient discontinues due to PD which has been radiologically confirmed within the 4 
weeks preceding EOT.
[…]
As long as the patient has not experienced PD, investigator’s assessment is sufficient for case 
management. In the event of progression, radiological real-time confirmation by central 
independent blinded evaluation is required before a final decision to stop the treatment is 
made. In case of uncertain radiological disease progression the patient may stay on treatment 
at the investigator’s discretion until progression is definitely confirmed on the subsequent 
tumor assessment. The final evaluation of treatment response (best response: ORR and CRR) 
will be done by central blinded review and for those not undergoing PD-confirmation in 
retrospective setting (modified by amendment 3).
[…]
Patients who experience PD on placebo treatment (per central independent blinded radiology 
review) can be offered open-label copanlisib upon discretion of the investigator and patient’s 
consent. After individual patient unblinding, patients receiving placebo who switch to open-
label copanlisib will have tumor assessments reset to the initial schedule as if the patient was 
restarting the study at Cycle 1 Day 1. For further instructions please refer to the Imaging 
Manual.
[…]
A prospective planned central image evaluation by independent radiology experts will be 
performed independent from the conduct of the clinical part of the study in order to facilitate 
an independent evaluation of efficacy in this study. All scans obtained for Screening, 
treatment period and Active follow-up including unscheduled scans should be forwarded to 
the designated Imaging Core Laboratory for central review. 
The independent reviewers will be experienced radiologists, who will not have been involved 
in the clinical part of the study and are considered independent from the study. They will be 
blinded to patient data (excluding those which are specified in the Independent Review 
Charter, e.g. for bone marrow biopsy). The primary efficacy variable will be analyzed based 


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on the assessment of the central image evaluation, as outlined in the Imaging Manual (or 
charter).
New text:
[…]
During the treatment phase as well as during the Active follow-up period, radiological (IV 
[and oral, if indicated, per Imaging Manual] contrast-enhanced CT/MRI) tumor assessment 
will be performed, per local standard of care of the institution but no less than every 16 weeks 
(see Section 7.1.2.3). CT/MRI scans are not required at the EOT visit if the patient 
discontinues due to PD which has been radiologically confirmed within the 4 weeks 
preceding EOT.
For patients switching from placebo to copanlisib therapy after unblinding procedures 
completed  CT/MRI scans are not required if the patient had radiological tumor evaluation 
performed and documented in eCRF within 4 weeks preceeding the start date of copanlisib 
treatment.
If the patients on placebo treatment had symptoms/signs of clinical progressive disease prior 
to switching to copanlisib treatment, it is recommended to have radiological tumor 
assessments before starting copanlisib therapy unless CT/MRI scans performed within 4 
weeks prior to a scheduled date of the first copanlisib infusion. For patients who previously 
received placebo and will be treated with copanlisib the tumor assessments should be 
continued as the initial schedule. For further instructions please refer to the Imaging Manual.
[…]
The primary efficacy variable will be analyzed based on the assessment by the investigator.
13.4.2.33 Section 7.3.3 Tumor assessments in patients with WM
Old text:
WM patients who do not have radiologically measurable lesion at Screening will not have 
further radiological assessments as per protocol. Their tumor response will be measured only 
by laboratory/clinical tests, and response assessment will be done according to the Owen 
Criteria. If PD was assessed by an investigator based on laboratory parameters alone, no 
independent confirmation of PD by independent blinded review is necessary. However, in 
cases when WM patients will develop disease progression confirmed radiologically by 
presenting with measurable lesion(s) without simultaneous increase in IgM, the imaging scans
should be submitted for central review and PD confirmation.


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WM patients who have radiologically measurable lesion at Screening will continue having 
radiological assessments and, in addition, will have laboratory tests performed on the same 
days. CT/MRI scans will be done and collected according to the schedule specified in the 
protocol (see Section 7.1.2.3). For patients who have PD assessed based on CT/MRI, scans 
must be submitted for review to confirm disease progression by an independent blinded 
radiology review.
Sites must notify the sponsor about disease progression and follow procedures outlined in the 
protocol.
[…]
New text:
WM patients who do not have radiologically measurable lesion at Screening will not have 
further radiological assessments as per protocol. Their tumor response will be measured only 
by laboratory/clinical tests, and response assessment will be done according to the Owen 
Criteria. However, in cases when WM patients will develop extramedullary disease without 
simultaneous increase in IgM the radiological assessment should be performed to confirm 
disease progression (per investigator’s assessment).
[…]
13.4.2.34 Section 7.4 Pharmacokinetics / pharmacodynamics
Old text:
[…]
Patients who experience PD on placebo treatment (per blinded central independent blinded 
radiology review) can be offered open-label copanlisib upon discretion of the investigator and 
patient’s consent. After individual patient unblinding, patients receiving placebo who switch 
to open-label copanlisib will have PK assessments reset to the initial schedule as if the patient 
was restarting the study at Cycle 1 Day 1.
[…]
New text: no new text was added.
13.4.2.35 Section 7.5.3 Further safety
Old text:
The following assessments should be performed both in patients on double-blinded study 
treatment (copanlisib or placebo) as well as those who are randomized to placebo and change 
to copanlisib. After individual patient unblinding, patients receiving placebo who switch to 


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open-label copanlisib will have all study assessments and timing reset to the initial schedule 
of study evaluations (i.e. as if the patient was restarting the study at Cycle 1 Day 1). If not 
previously done within 7 days, patients switching to open-label copanlisib must complete the 
following within 7 days prior to the first dose of open-label copanlisib: UPCR/24 h total urine 
protein quantification, GFR measurement, urinalysis, HbA1c, CBC, chemistry and 
coagulation panels. For further information on laboratory requirements for patients who 
switch to open-label treatment, please see Section 7.1.2.2 (clarified by amendment 1 and 
modified by amendment 3). 
New text: no new text was added.
13.4.2.36 Section 7.6.1 Biomarker investigations
Old text:
[…] 
Whole blood (only applicable for patients who provided ‘genetic’ research consent) 
(modified by amendment 1): On Cycle 1 Day 1, a whole blood sample will be obtained. The 
blood sample will be used as a source of DNA and gene products for the evaluation factors 
that are associated with the drug or the pathomechanisms of the disease. Results will be 
reported under separate cover, if the evaluations are performed.
Patients who experience PD on placebo treatment (per blinded central independent blinded 
radiology review) can be offered open-label copanlisib upon discretion of the investigator and 
patient’s consent. 
After individual patient unblinding, patients receiving placebo who switch to open-label
copanlisib will have biomarker plasma sampling analogous to the initial schedule as if the 
patient was restarting the study at Cycle 1 Day 1.
[…] 
New text:.
Whole blood removed by amenmdnet 5
After individual patient unblinding, patients receiving placebo who switch to copanlisib upon 
discretion of the investigator and patient’s consent will have biomarker plasma sampling 
analogous to the initial schedule as if the patient was restarting the study at Cycle 1 Day 1.


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13.4.2.37 Section 7.6.2 Quality of life questionnaire
Old text (section removed):
The effect of treatment on the physical symptoms of lymphoma is an important issue for 
patients; therefore the collection of this information is a routine component in many protocols.
The main purpose of the symptom assessment in this study is to describe any differences 
between the treatment groups in the time to deterioration and in time to improvement in 
disease-related symptoms – physical (DRS-P) at least 3 points (changed by amendment 1).
In this study physical symptoms of lymphoma will be assessed using the NCCN-FACT 
Lymphoma Symptom Index-18 (FLymSI-18), version 4 (see Appendix 14.6) (NCCN-FACT: 
National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy).
The FLymSI-18 is a validated instrument that was developed to assess symptoms of 
lymphoma, symptoms of treatment of lymphoma, and health related QoL of patients with 
lymphoma. The instrument was developed in accordance with recent Food and Drug 
administration (FDA) guidance for the development of instruments for PROs. 
The instrument contains 18 items, each of which utilizes a Likert scale with 5 possible 
responses ranging from 0 “Not at all” to 4 “Very much”. Nine items reflect DRS-P, and the 
responses to the items are summed to calculate a DRS-P subscale score. Four items represent 
disease-related symptoms – emotional (DRS-E), and the responses to those items may be used 
to calculate a DRS-E subscale score. Three items represent treatment side effects, and the 
responses to these items may be summed to calculate a treatment side-effect (TSE) subscale 
score. Finally, two items represent function and well-being (FWB), and responses to those 
items may be summed to calculate a FWB subscale score. The questionnaire allows for 
calculation of total score and four subscales: DRS-P, DRS-E, TSE and FWB (26, 27). 
The FLymSI-18 questionnaire is to be completed on Cycle 1 Day 1 and every cycle thereafter 
(i.e. on Day 1 of Cycles 2, 3, 4 etc.), at the EOT visit and at the SFU visit (see flowchart 
in Table 7–1). 
Patients who experience PD on placebo treatment (per central independent blinded radiology 
review) can be offered open-label copanlisib upon discretion of the investigator and patient’s 
consent. After individual patient unblinding, patients receiving placebo who switch to open-
label copanlisib will have symptom assessments reset to the initial schedule as if the patient 
was restarting the study at Cycle 1 Day 1.
The FLymSI-18 questionnaire should be completed at the start of the visit before the patient 
sees the physician and before any study-related procedure is conducted, so that any interaction 
between the patient and physicians or other health care providers does not influence the 
response to the FLymSI-18 questionnaire.
A patient-reported outcome (PRO) information sheet will be provided and completed by the 
study personnel at each visit at which the FLymSI-18 questionnaire is to be administered 
(modified by amendment 1), regardless of whether or not the FLymSI-18 questionnaire is 
completed by the patient. This is to document information such as questionnaire completion, 
date of completion, and reasons for non-completed questionnaires.


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New text: no new text was added.
13.4.2.38 Section 7.6.3 Electronic patient-reported outcomes evaluation 
Old text (section removed):
ePRO devices will be implemented in this study. It will be used to complete the FLymSI-18 
questionnaire (modified by amendment 1). A Site Manual will be provided to sites and each 
patient will be trained how the ePRO device works and how to use it correctly. If, for any 
reason, a device is not available at the site, or technical problems prevent it from working 
properly, the FLymSI-18 questionnaire will not be completed at that visit (changed by 
amendment 3 and modified by amendment 4). 
New text: no new text was added.
13.4.2.39 Section 8.1 General considerations
Old text: no text was removed.
New text:
[…]
Due to the decision of stopping enrollment as protocol amendment 5 becomes effective, 
limited number of patients will be included in the analyses. Therefore, the statistical analyses 
included in this study will be focused on descriptive statistics without any hypothesis testing.
Two sets of analyses will be performed at the timing when all treated patients completed at 
least 6 cycles of study treatment. 
3) unblinding cutoff: analyze all data available before the unblinding (details in section 
6.5); 
4) final analysis: analyze all data available until all treated patients complete at least 6 
cycles of study treatment.
The data cutoffs and treatment groups included for each analysis are summarized in the 
following table. 


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Table 8-1
Analysis data cutoffs and treatment group overview
Analysis cutoff on the 
date of unblinding
Final analysis cutoff4
Patients randomized to Copanlisib1


Placebo Patients: Period 1  
(before their PD) 2

Not shown
Placebo Patients: Period 2 
(after PD period 2) 2
Not shown

Placebo Patients: switching to 
Copanlisib per protocol amend 53
NA

1 All patients randomized/assgined into Copanlisib arm
2 Patients randomized into Placebo arm, with at least one tumor response assessment until date of 
unblinding
3 Includes patients switched from Placebo to Copanlisib before their first tumor response assessment
4 When all treated patients complete at least 6 cycles of study treatment 
13.4.2.40 Section 8.2 Analysis sets
Old text: 
The statistical analysis sets are defined as follows:

Full analysis set (FAS): all patients randomized. Following the intent to treat (ITT) 
principle, the treatment the patient is randomized to will be used in the analysis (as 
randomized rather than as treated).

Safety analysis set (SAF): all FAS patients with at least one intake of study drug.
[…]
New text: 
The statistical analysis sets are defined as follows:

Full analysis set (FAS): all patients assigned to treatment. Following the intent to treat 
(ITT) principle, the treatment the patient is assigned to will be used in the analysis (as 
assgined rather than as treated).

Safety analysis set (SAF): all patients with at least one intake of study drug. The SAF 
will be analyzed as treated.
[…]


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13.4.2.41 Section 8.3.1 Efficacy variables 
Old text: 
Disease progression (PD) in the context of statistical efficacy evaluation is considered to be 
radiological progression, as assessed by central review. Death related to PD is considered to 
be any death except for:

Death due to an AE unrelated to progression.

Death with a specification of “other” as reason (which excludes PD).
If PD is reported after a switch to open-label copanlisib treatment in placebo patients (see 
Section 6.4), this information is not used for calculation of primary or secondary efficacy 
variables.
New text: 
[…]
If PD was reported after a switch to copanlisib treatment in placebo patients (see Section 6.4), 
this information is not used for calculation of primary or secondary efficacy variables.
13.4.2.42 Section 8.3.1.1 Primary efficacy variable 
Old text: 
Progression-free survival (PFS), defined as the time (in days) from randomization to PD as 
assessed by central review or death from any cause (if no progression is documented). The 
actual date of tumor assessments will be used for this calculation. PFS for patients without PD 
or death at the time of analysis will be censored at the date of their last tumor evaluation. PFS 
for patients who have neither tumor assessments nor death after baseline will be censored at 
Day 1.
New text:
Objective tumor response rate (ORR) assessed in all patients, which is defined as the 
proportion of patients who have a best response rating up to the dates of data cutoffs (for dates 
of data cutoffs, see details in section 8.1) of complete response (CR) or partial response (PR) 
according to the Lugano Classification (21), and for patients with WM, a response rating of 
CR, very good partial response (VGPR), PR, or minor response (MR) according to the Owen 
criteria (22). Detailed instructions on tumor assessment are provided in Appendix 14.1. In 
addition to the ORR by treatment group, and period, a listing will be provided for all patients 
with their best response, histology type along with other important demographic and disease 
characteristics information.


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13.4.2.43 Section 8.3.1.2 Secondary efficacy variables
Old text: 
Objective tumor response rate (ORR) assessed in all patients up to the time of analysis of 
PFS. ORR is defined as the proportion of patients who have a best response rating over the 
whole duration of the study (i.e. until the time of analysis of PFS) of complete response (CR) 
or partial response (PR) according to the Lugano Classification (21), and for patients with 
WM, a response rating of CR, very good partial response (VGPR), PR, or minor response 
(MR) according to the Owen criteria (22) (changed by amendment 1). Detailed instructions on 
tumor assessment are provided in Appendix 14.1.
Duration of response (DOR), defined as the time (in days) from first observed tumor 
response (CR, VGPR, PR or MR) until PD or death from any cause, whichever is earlier. 
DOR will only be defined for patients with at least one CR, VGPR, PR or MR (modified by 
amendment 1). Patients without PD or death at the time of analysis will be censored at the 
date of their last tumor evaluation.
Complete response rate (CRR), assessed in all patients up to the time of analysis of PFS.
Time to progression (TTP), defined as the time (in days) from randomization to PD or death 
related to PD, whichever is earlier. The actual dates of tumor assessments will be used for this 
calculation. TTP for patients without PD at the time of analysis or death not related to 
progression will be censored at the date of their last tumor evaluation. TTP for patients who 
have neither tumor assessments nor death related to PD after baseline will be censored at 
Day 1.
Overall survival (OS), defined as the time (in days) from randomization until death from any 
cause. OS of patients alive at the time of analysis will be censored at the last date they were 
known to be alive. 
Time to deterioration in disease-related symptoms – physical (DRS-P) of at least 
3 points, as measured by the FLymSI-18 questionnaire. Patients will be considered as 
“censored” at the date of their last tumor evaluation, if the reason for stopping treatment is not 
related to PD. Patients dropping out due to progression-related reason or experiencing a PD 
event or death due to any reason will be considered as having had their decline in DRS-P at 
the date of their last tumor evaluation. Due to the symptom-related inclusion criteria (i.e. 
ECOG performance status ≤ 1), a worsening of symptoms can potentially occur in all patients. 
Therefore all patients will be included into this analysis (modified by amendment 1). 
Time to improvement in DRS-P of at least 3 points, as measured by the FLymSI-18 
questionnaire, will be evaluated for patients with a baseline DRS-P score of 30 points or less 
(i.e. patients who still have room for improvement in symptoms). Patients will be considered 
as "censored" at the date of their last tumor evaluation, if the reason for stopping treatment is 
not related to PD. Patients dropping out due to progression-related reason or experiencing a 
PD event or deaths due to any reason will be considered censored at the largest observation 


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time (of events and censoring in all subjects evaluated for improvement), plus 1 day 
(paragraph added by amendment 1).
Further sensitivity analyses for the DRS-P will be described in the SAP (e.g. might involve 
different handling of the last response status for that patient or considering PD and death as 
censored). Considering at least 3 points decline or increase, respectively, to be an important 
change with regard to DRS-P is the current assessment (two previous sentences modified by 
amendment 1). The important change for DRS-P is however under continuing research by the 
developer of the questionnaire. Therefore, the value of 3 points might be updated in the SAP, 
considering forthcoming research findings.
New text:
Duration of response (DOR), defined as the time (in days) from first observed tumor 
response (CR, VGPR, PR or MR) until PD or death from any cause, whichever is earlier. 
DOR will only be defined for patients with at least one CR, VGPR, PR or MR (modified by 
amendment 1). Patients without PD or death at the time of analysis will be considered as 
responders till at the date of their last tumor evaluation. DOR will be summarized by 
descriptive statistics. Further details will be included in the SAP.
Complete response rate (CRR), defined as the proportion of patients who have a best 
response up to the dates of data cutoffs (for dates of data cutoffs, see details in section 8.1) of 
complete response (CR) according to the Lugano Classification (3), and for patients with 
WM, a response rating of CR according to the Owen criteria (4).
Overall survival (OS), defined as the time (in days) from assignment to study drug until 
death from any cause. OS of patients alive at the time of analysis will be censored at the last 
date they were known to be alive.
13.4.2.44 Section 8.3.1.3 Other efficacy variables
Old text (section removed): 

PFS2 defined as the time (in days) from first PD after start of study treatment to 
second PD (both assessed by central review) or death from any cause (if no 
progression is documented). PFS2 will be evaluated only in placebo-treated patients 
who switched to open-label copanlisib treatment after first PD (added by 
amendment 1).

AUC across all data of FLymSI-18 DRS-P subscale score.

FLymSI-18 total and subscale scores (DRS-P, DRS-E, TSE, FWB), and time to onset 
of physical symptoms of lymphoma based on the DRS-P subscale.

ECOG performance status.
New text: no new text was added.


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13.4.2.45 Section 8.4.1 Population characteristics
Old text: 
Demographics and baseline characteristics will be summarized by treatment and total 
population, using descriptive statistics and frequency tables as appropriate. In addition, the 
same summaries will be provided separately by FL and other iNHL subgroups (modified by 
amendment 1).
New text: no new text was added.
13.4.2.46 Section 8.4.2 Efficacy
Old text: 
All efficacy analyses will be performed when approximately 82 centrally evaluated PFS 
events are observed in the FL subgroup (see Section 8.6) (changed by amendment 1). 
Evaluations from central blinded review. will be used for the primary efficacy analyses of 
primary and secondary variables containing radiological tumor assessments.
The study-wise alpha of 1% will initially be split, according to the test strategy for this study 
(see Figure 8–1): with 80% * 1% = 0.8% assigned to the one-sided PFS test in the FL 
subgroup, and 20% * 1% = 0.2% to the one-sided PFS test in the total study population 
(paragraph added by amendment 1).
New text: 
Evaluations by investigators will be used for the primary efficacy analyses of primary and 
secondary variables containing radiological tumor assessments.
For variables other than OS, the data collected after switching from placebo to copanlisib will 
be summarized separately using descriptive statistics and frequency tables. Further details will 
be included in the SAP.
13.4.2.47 Section 8.4.2.1 Primary efficacy analysis
Old text (section removed): 
The primary efficacy variable is PFS as assessed by central review (for definition see 
Section 8.3.1.1). It will be evaluated whether PFS in the copanlisib group is higher compared 
to PFS in the placebo group for the total study population and separately for the FL subgroup. 


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The following null hypothesis will be tested:
H0, PFS: SCopanlisib(t) = SPlacebo(t) for all time points t ≥ 0
The alternative hypothesis will be:
H1,PFS: SCopanlisib(t) > SPlacebo(t) for at least one time point t ≥ 0, and
SCopanlisib(t) ≥SPlacebo(t) for all time points t ≥ 0,
where SCopanlisib denotes the survival function of the copanlisib group and SPlacebo denotes the 
survival function of the placebo group in the total study population or the FL subgroup, 
respectively.
The following decision rule to test the null hypothesis will be applied:
According to the size of this study it is justified to assume that under H0, PFS the one-sided log-
rank test (28) is a sufficiently close approximation to the normal distribution. If the z-value 
from the one-sided log-rank test (for the difference SCopanlisib - SPlacebo, stratified by the same 
factors as used for randomization: FL vs. other iNHL histology [in the test for total study 
population only], the time between last course of systemic anticancer therapy and most recent 
progression [≤ 6 months vs. > 6 months] and previous treatment with PI3K inhibitors [yes vs. 
no]) is larger than the respective critical quantile from the normal distribution (for FL 
subgroup: z0.992 = 2.409, for the total study population: z0.998 = 2.878), the null hypothesis will 
be rejected in favor of the alternative hypothesis. 
Additional analyses of the primary efficacy variable
Kaplan-Meier estimates of median times to PFS (including 98% confidence interval) and 
Kaplan-Meier curves for the total study population and the FL subgroup will be presented for 
each treatment group (changed by amendment 1).
The hazard ratio (including 98% confidence interval) will be derived for the total study 
population and separately for the FL subgroup from Cox proportional hazards models that are 
stratified by the same factors as used for the primary efficacy analysis (changed by 
amendment 1). 
The censoring mechanism of patients without PFS event at the time of analysis is assumed to 
be non-informative for the primary efficacy analysis. Sensitivity analyses will be performed, 
assessing the impact of a potential informative censoring of such subjects. These will include 
the use of different rules for considering subjects without PFS events as having an event or 
being censored, and will be further outlined in the SAP.
New text: no new text was added.


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13.4.2.48 Section 8.4.2.2 Secondary efficacy analysis
Old text (section removed): 
Depending on study success in the primary efficacy variable in the FL subgroup the 
secondary efficacy variables ORR, time to deterioration and time to improvement in DRS-P 
subscale of FLymSI-18 of at least 3 points will be tested hierarchically in the FL subgroup 
according to the multiple testing strategy outlined in Figure 8–1.
If the study shows success in all secondary endpoints in the FL subgroup and in the primary 
efficacy endpoint for the total study population, then the secondary efficacy endpoints ORR, 
time to deterioration and time to improvement in DRS-P subscale of FLymSI-18 of at least 
3 points will also be tested hierarchically in the total study population.
Despite the initial split of study-wise alpha for the primary efficacy tests of PFS, the applied 
multiple test strategy includes the chance of so-called re-tests at full study-wise alpha-level of 
1% in certain cases. The details are described in Section 8.4.2.3 below.
The ORR will be analyzed using the Cochran-Mantel-Haenszel test (29), stratified for the 
same stratification factors as used for PFS. The null hypothesis is defined as:
H0, ORR: ORRCopanlisib ≤ ORRPlacebo
The alternative hypothesis will be:
H1, ORR: ORRCopanlisib > ORRPlacebo
The following decision rule to test the null hypothesis will be applied:
If the p-value for the two-sided Cochran-Mantel-Haenszel test is smaller than twice the 
available significance level for the respective test and the estimated difference ORRCopanlisib -
ORRPlacebo (comparing copanlisib vs. placebo) is greater than 0.0, the null hypothesis will be 
rejected in favor of the alternative hypothesis.
The time to deterioration and time to improvement in DRS-P subscale of FLymSI-18 will be 
analyzed analogously to the PFS, using similar hypotheses, decision rules, and significance 
level according to the testing strategy.
OS, CRR, TTP as well as DOR will not be included into the confirmatory testing strategy but 
analyzed supportively only.
OS will be analyzed using stratified log-rank tests similar to that for the primary variable, 
PFS. In addition, statistical methods to include the time after change to copanlisib by placebo 
patients in an analysis of OS will be investigated. Further details will be included in the SAP.
For variables other than OS, the data collected after the change from placebo to copanlisib 
will be summarized separately using descriptive statistics and frequency tables. Further details 
will be included in the SAP.
TTP, DOR, time to deterioration and time to improvement in DRS-P of at least 3 points will 
be analyzed using stratified log-rank tests similar to that for the primary variable, PFS.


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CRR will be analyzed using the Cochran-Mantel-Haenszel test analogous to the analysis of 
ORR. The test will be adjusted for the same stratification factors as used for PFS.
New text: no new text was added.
13.4.2.49 Section 8.4.2.3 Confirmatory statistical testing strategy
Old text (section removed):
A graphical summary of the testing strategy is displayed in Figure 8–1, using methodology as 
outlined in "A graphical approach to sequentially rejective multiple test procedures" (30). 
Package "gMCP"(Graph Based Multiple Test Procedures) for the statistical software R has 
been used for display (31, 32).
Figure 8–1
Confirmatory statistical testing strategy (figure added by amendment 1)
FL = follicular lymphoma; ImpDRSP = improvement in disease-related symptoms – physical; ORR = objective 
tumor response rate; PFS = progression-free survival; total = total study population; WorseDRSP = worsening of 
disease-related symptoms – physical.
Note: This design involving ε is a technical construct to potentially allow propagation of alpha to secondary 
endpoints in the total study population, in case all FL secondary endpoints can be rejected. The amount ε will be 
close to zero, and will be exactly defined in the SAP.
PFS is tested in parallel in the FL subgroup (tested at significance level of 0.8%), and in the 
total study population (tested at significance level of 0.2%).
The secondary endpoints in the FL subgroup and in the total study population, respectively, 
will only be tested if the test for the primary endpoint PFS is successful in the respective 
(sub-) population. A sequentially rejective multiple test procedure (30) will be used for the 
secondary efficacy endpoints in order to control the study-wise alpha level of 1%.
Tests on primary endpoint PFS in the FL subgroup and total study population
Section added by amendment 1.


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As the study is powered to show a success in the FL subgroup, the multiple testing strategy 
also reflects the priority of the FL subgroup by propagating alpha-level first to the FL 
subgroup. After a successful test in the FL subgroup, the alpha-level of 0.8% will be 
propagated to the secondary endpoints in the FL subgroup.
In case of a successful test of PFS in the total study population, the respective alpha-level of 
0.2% will be propagated to the test hierarchy in the FL subgroup except for an amount ε (with 
ε close to zero). The remaining proportion ε of available alpha of 0.2% will be propagated to 
the secondary endpoints in the total study population.
Test hierarchy in secondary endpoints
Section added by amendment 1.
The secondary endpoints are tested hierarchically both within the FL subgroup and the total 
study population.
Within each (sub-) group, ORR is tested first, followed by worsening in DRS-P, followed by 
improvement in DRS-P according to the pre-defined test sequence.
If both the primary and all secondary efficacy endpoints within the FL subgroup are tested 
successfully, the respective alpha-level is then finally propagated to the test sequence in the 
total study population. This means that for all practical purposes, the secondary endpoints for 
the total study population are only tested if all tests in the FL subgroup and the primary 
efficacy endpoint PFS in the total study population were successful.
Potential for re-tests
Section added by amendment 1.
Therefore, re-tests at (practically) the full study-wise alpha level of 1% could occur, if either:
1. PFS test in the total study population is successful: Then the FL-related test hierarchy, 
starting from PFS in FL subgroup, can be re-tested at full alpha-level (except for the 
small ε part), or
2. Primary as well as all secondary assessments in the FL subgroup are successful: In this 
case, PFS and secondary efficacy hierarchy in the total study population can be tested 
at full alpha.
Other efficacy evaluations
PFS2 will be descriptively evaluated using Kaplan-Meier estimates for quantiles, including 
98% two-sided confidence intervals (added by amendment 1).


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An additional analysis of the physical symptoms of lymphoma (as measured using the 
FLymSI-18 DRS-P subscale) will be performed to assess differences between treatment arms 
both in the total study population and the FL subgroup based on AUC. Total FLymSI-18 and 
subscales will be evaluated descriptively. Further details on PRO data analysis will be 
provided in the SAP. 
ECOG performance status will be summarized using descriptive statistics for the original 
score, as well as for the change from baseline score by treatment group in the total study 
population and in the FL subgroup.
New text: no new text was added.
13.4.2.50 Section 8.4.2.4 Subgroup analyses
Old text (section removed): 
Countries will be combined into regions as US vs. Europe vs. rest of world in order to defined 
regional subgroups.
Subgroup analyses will include forest plots as well as treatment-interaction analyses, both for 
the region subgroups as well as further subgroups (e.g. based on stratification factors and/or 
baseline characteristics) and will be provided both for the primary efficacy endpoint as well as 
other relevant efficacy and/or safety endpoints.
As an efficacious result in the confirmatory multiple testing strategy in the FL subgroup could 
dominate the result for the total population, a pre-defined consistency assessment across 
iNHL subtypes will be pre-specified in the SAP.
New text: no new text was added.
13.4.2.51 Section 8.4.3 Safety 
Old text: 
Safety variables will be summarized by means of descriptive statistics and/or frequency tables 
as appropriate. Summaries will be given by treatment group and total. Summaries will be 
provided for the total study population and separately for the FL subgroup (modified by 
amendment 1).
[…]


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New text: 
Safety variables will be summarized by means of descriptive statistics and/or frequency tables 
as appropriate. Summaries will be given by treatment group and total. As clarified in 
section 8.1, safety data analyses will be provided based on two sets of data, unblinding cutoff 
and final data cutoff.
[…]
13.4.2.52 Section 8.6 Determination of sample size
Old text: 
Sample size estimation is based on the evaluation of the primary efficacy variable, PFS, in the 
primary subgroup of follicular lymphoma (FL). Study recruitment will be closed as soon as 
the required number of evaluable FL patients is reached. 
Copanlisib versus placebo treatment groups will be compared. The stratification factor NHL 
histology (FL vs. other iNHL) will be used to derive two subgroups of patients. Superiority of 
the copanlisib arm over the placebo arm will be tested for the total study population and 
separately for the FL subgroup. A study-wise alpha level of 1% will be used to show 
superiority in the FL subgroup and/or the total study population.
For the placebo arm, a median PFS of 6 months is assumed, whereas the copanlisib arm will 
be considered to have a median PFS of 14 months.
The study is planned to detect a 132% increase in median PFS in copanlisib versus placebo 
comparison (i.e. to detect a hazard ratio of 0.43), using a stratified log-rank test. 
Study-wise alpha level of 1% will be split in terms of the test strategy planned (see 
Figure 8–1), performing the one-sided primary efficacy test (and successive test hierarchy) 
with an initial alpha level of 0.8% for FL subgroup, and an initial alpha of 0.2% for the one-
sided efficacy test in PFS for the total study population. Depending on the outcome of the 
primary efficacy tests, respective alpha will be propagated to further hypotheses in accordance 
with the planned test procedure.
Randomization ratio will be 2:1 between copanlisib group and placebo group, respectively.
Sample size justification for primary efficacy test on PFS in FL patients
Section modified by amendment 1.
Using the software PASS 11 and with the above assumptions (especially alpha level of 0.8%), 
it was determined that this study can be evaluated after approximately 82 PFS events are 
observed in the FL subgroup to achieve a statistical power of 90% of observing a significant 
result in the primary efficacy test in the FL subgroup.
In case a re-test in the test strategy is possible, because the test of PFS in the total study 
population was significant at the 0.2% level, the power of showing success in PFS for FL 
patients would increase to 91.4%, which is not considered as an excessive overpowering.


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To determine the number of FL patients required to reach this number of events, a drop-out 
rate of 20% (equally distributed among treatment arms and time), and an accrual time of 
12 months (including 6 month ramp-up phase for study site openings) with a maximum of 
10 month follow-up for last recruited patient was assumed.
PASS 11 calculations (assuming exponential distribution of events) resulted in a required 
number of patients per group: approximately 96 patients in the copanlisib monotherapy arm 
and approximately 48 patients in the placebo arm (total of 144 FL patients) for the study.
Sample size assumptions for other iNHL patients
Section added by amendment 1.
Recruitment will be open to several types of iNHL patients. The size of the other iNHL 
subgroup is expected to reach between 20% and 25% of overall patients. Inclusion of these 
patients in addition to FL subgroup was encouraged by advice from EMA Scientific Advice 
Working Party to seek significance in FL subgroup, but to not exclude other subtypes. 
Assuming 23% of patients in the total population have other iNHL histologies, we expect ~45 
other iNHL patients to also be included into the study.
The total study population will thus comprise approximately189 recruited patients.
Sample size justification for primary efficacy test on PFS in the total study population
Section added by amendment 1.
Under comparable assumptions as for the FL subjects (but using alpha level of 0.2%), the 
power to detect a difference in PFS for the total study population will be 91.3%. In case the 
tests on primary and all secondary efficacy variables are significant in the FL subgroup, the 
total study population can be re-tested with the full study alpha of 1.0% in accordance with 
the test strategy. Under this assumption a power of 96.8% in the primary efficacy test for PFS 
in the total study population is achieved.
As an efficacious result in the FL subgroup could dominate the result for the total population, 
a pre-defined consistency assessment across iNHL subtypes will be pre-specified in the SAP.
New text:
All patients assigned to treatment in this study will be included in the analyses.


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13.4.2.53 Section 9.3 Data processing
Old text: 
[…] This is applicable for data recorded on CRF as well as for data from other sources (e.g. 
IVRS, laboratory, ePRO).
[…]
After its initial release for biometrical analysis, the clinical database is planned to be re-
opened for the inclusion of the following additional data (e.g. pharmacokinetic data, 
biomarker data).
New text: 
[…]
Clinical data will be entered into Rave by clinical site staff and will be transferred from Rave 
into SAS datasets. Data review will be performed by sponsor on an ongoing basis to ensure 
data is accurate, consistent and complete. Data for, external supplier sources will be checked 
by sponsor. Data corrections will be made under the supervision of clinical site staff.
For data coding (e.g. AEs, medication), internationally recognized and accepted dictionaries 
will be used. Medical Dictionary for Regulatory Activities (MedDRA) will be used for AEs 
and medical history, and WHO-Drug Dictionary (WHO-DD) for concomitant medications. 
The SAS datasets to be used for descriptive statistical analysis to be included in the clinical 
study report will remain unmodified after the data is declared clean and ready for analysis.
[…]
13.4.2.54 Section 10. Premature termination of the study
Old text: no text was removed.
New text:
[…]
The sponsor’s decision was to stop enrollment due to lack of feasibility to complete this study 
in reasonable time frame. Therefore, the study design is modified to reflect an open label 
study. All patients on study treatment will be offered the possibility to continue treatment 
with copanlisib after unblinding procedures are completed.
Details for individual patient's withdrawal can be found in Section 5.2.1.


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13.4.2.55 Section 11.2 Patient information and consent
Old text: 
[…]
Only if the patient voluntarily agrees to sign the ICF and has done so, may he/she enter the 
study. Additionally, the investigator and other information provider (if any) will personally 
sign and date the form. The patient will receive a copy of the signed and dated form. 
Documentation of the informed consent process should be recorded in the patient’s medical 
record.
[…]
New text: 
[…]
As of amendment 5, all patients will be reconsented and need to voluntarily agree to sign the 
ICF and have to do so, to continue in the study. Additionally, the investigator and other 
information provider (if any) will personally sign and date the form. The patient will receive a 
copy of the signed and dated form. Documentation of the informed consent process should be 
recorded in the patient’s medical record.
[…]
13.4.2.56 Section 12. Reference list
Old text:
26. Hlubocky FJ, Webster K, Beaumont J, Cashy J, Paul D, Abernethy A, et al. A 
preliminary study of a health related quality of life assessment of priority symptoms in 
advanced lymphoma: the National Comprehensive Cancer Network-Functional 
Assessment of Cancer Therapy - Lymphoma Symptom Index. Leuk Lymphoma. 
2013;54:1942-6.
27. Cella D, Rosenbloom SK, Beaumont JL, Yount SE, Paul D, Hampton D, et al. 
Development and validation of 11 symptom indexes to evaluate response to 
chemotherapy for advanced cancer. J Natl Compr Canc Netw. 2011;9:268-78.
28. Collett D. Modelling Survival Data in Medical Research: Chapman and Hall; 2003.
29. Koch GG, Carr GJ, Amara IA, Stokes ME, Uryniak TJ. Categorical Data Analysis in 
Statistical methodology in the pharmaceutical sciences /edited by Berry DA, Marcel 
Dekker; 1990 (added by amendment 1).
30. Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to sequentially rejective 
multiple test procedures. Stat Med. 2009;28:586-604 (added by amendment 1).


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31. Bretz F, Posch M, Glimm E, Klinglmueller F, Maurer W, Rohmeyer K. Graphical 
approaches for multiple comparison procedures using weighted Bonferroni, Simes or 
parametric tests. Biometrical Journal. 2011;53:894-913 (added by amendment 1).
32. Rohmeyer K, Klinglmueller F, Bomkamp B. gMCP: Graph Based Multiple Test 
Procedures, R package version 0.8-5.2013. Available from: http://CRAN.R-
project.org/package=gMCP (added by amendment 1).
New text: no reference was added.
13.4.2.57 Appendix 14.6 Quality of life questionnaire: NCCN-FACT FLymSI-18
Old text (appendix removed):


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CCI


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13.5
Amendment 6
Amendment 6 is a global amendment dated 01 DEC 2017.
13.5.1
Overview of changes
13.5.1.1
Modification 1 – Study design revised
Following sponsor’s decision to stop enrollment due to lack of feasibility to complete this 
study in reasonable time frame, the study design was modified. Since only limited number of 
patients will be included in the analyses, the study design was changed to only assess the 
safety of copanlisib. As a consequence, Active and Survival follow-up periods were removed. 
Sections affected by this modification: Synopsis, Section 2. Study objectives, Section 4. Study 
design, Section 5.2.1.1 Withdrawal from study treatment, Section 5.2.1.2 Withdrawal from 
follow-up period, Section 7.1.1 Tabulated overview, Section 7.1.2.3 Tumor assessments, 
Section 7.1.2.5 Follow-up periods, Section 7.1.2.5.2 Active follow-up, Section 7.1.2.5.3 
Survival follow-up, Section 7.3.1 Primary efficacy variable, Section 7.3.2 Radiological tumor 
assessments, Section 7.5.1.3 Assessments and documentation of adverse events, Section 7.7 
Appropriateness of procedures / measurements, Section 8.1 General considerations, Section 
8.2 Analysis sets, Section 8.3.1 Efficacy variables, Section 8.3.1.1 Primary efficacy variable, 
Section 8.3.1.2 Secondary efficacy variables, Section 8.4.2 Efficacy, Section 8.4.3 Safety
13.5.1.2
Modification 2 – Change in primary endpoint
Following sponsor’s decision to stop enrollment due to lack of feasibility to complete this 
study in reasonable time frame, the study design was modified. Since only limited number of 
patients will be included in the analyses, the study design was changed to only assess the 
safety of copanlisib. As a consequence, the study primary endpoint was changed to safety and 
other study objectives were removed.
Sections affected by this modification: Synopsis, Section 2. Study objectives, Section 4. Study 
design, Section 7.3.1 Primary efficacy variable, Section 8.2 Analysis sets, Section 8.3.1 
Efficacy variables, Section 8.3.1.1 Primary efficacy variable, Section 8.3.1.2 Secondary 
efficacy variables, Section 8.4.2 Efficacy, Section 8.4.3 Safety
13.5.1.3
Modification 3 – Change in statistical analysis
Since the study design was changed to only assess the safety of copanlisib, the timing of the 
statistical analysis was changed to perform a final analysis of safety data available until all 
patients have completed the copanlisib study treatment and Safety follow-up period. 
In addition, it was clarified that for TEAE summaries based on placebo randomized patients 
switching to copanlisib, the baseline reference period will be defined in the SAP.
Sections affected by this modification: Synopsis, Section 8.1 General considerations, Section 
8.3.2 Safety variables


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13.5.1.4
Modification 4 – Clarification in determination of sample size
The section of determination of sample size has been revised to clarify that determination of 
sample size has not been applicable since amendment 5 became effective.
Sections affected by this modification: Section 8.6 Determination of sample size
13.5.1.5
Modification 5 – PK and biomarker analyses removed 
Following the study design modification to only assess the safety of copanlisib, the study 
objectives related to PK and biomarker analysis were removed. The sponsor reserves the right 
to perform biomarker and PK analysis on the blood/tissue samples already collected.
Sections affected by this modification: Synopsis, Section 2. Study objectives, Section 4. Study 
design, Section 7.1.1 Tabulated overview, Section 7.1.2.1 Screening period, Section 7.1.2.2.1 
Treatment – Cycle 1, Section 7.1.2.2.2 Treatment – Cycle 2 and higher, Section 7.1.2.4 End-
of-treatment visit, Section 7.4 Pharmacokinetics / pharmacodynamics, Section 7.6.1 
Biomarker investigations, Section 8.2 Analysis sets, Section 8.4.4 Pharmacokinetic data
13.5.1.6
Modification 6 – Bone marrow biopsy revised
Following the removal of all efficacy variables from the study, language on bone marrow 
biopsy was modified. Bone marrow biopsy after first CR is no longer required. 
Sections affected by this modification: Synopsis, Section 4. Study design, Section 7.1.1 
Tabulated overview, Section 7.1.2.1 Screening period, Section 7.1.2.3 Tumor assessments
13.5.1.7
Modification 7 – Meal timing on infusion days revised
Based on available safety data on copanlisib, fasting status has no significant clinical impact
on post-infusion blood glucose. On infusion days, the timing of meal intake and additional 
glucose testing (if applicable) is managed and monitored by the investigators.
Sections affected by this modification: Section 6.4 Dosage and administration, Section 7.1.1 
Tabulated overview, Section 7.1.2.2.1 Treatment – Cycle 1, Section 7.1.2.2.2 Treatment –
Cycle 2 and higher, Section 7.5.3.6 Glucose measurement on infusion days, Section 12. 
Reference list, Section 14.7 The average glycemic index of common foods derived from 
multiple studies by different laboratories
13.5.1.8
Modification 8 – Home glucose monitoring
Based on available data, post-infusion blood glucose increase related to copanlisib treatment 
is transient and manageable. Home glucose monitoring language was modified to allow 
investigator to determine based on post-infusion glucose profile and clinical status of the 
patient if home glucose monitoring is needed.
Sections affected by this modification: Section 6.4.2.1 Management of transient post-infusion 
glucose increases that can occur with study treatment, Section 7.1.1 Tabulated overview, 
Section 7.1.2.1 Screening period, Section 7.1.2.2.1 Treatment – Cycle 1, Section 7.1.2.2.2 
Treatment – Cycle 2 and higher, Section 7.1.2.4 End-of-treatment visit


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13.5.1.9
Modification 9 – Clarification and change in withdrawal criteria
It was clarified that patients who experienced clinical PD may be withdrawn from study 
treatment at investigator’s discretion.
Based on available safety data on copanlisib and to align with Aliqopa prescribing 
information, withdrawal criteria for persistent occurrence of post infusion blood glucose was 
modified from 400 to > 500 mg/dL.
Sections affected by this modification: Section 5.2.1.1 Withdrawal from study treatment
13.5.1.10 Modification 10 – Change in glucose increase dose modification rules
Based on available safety data on copanlisib and to align with withdrawal criteria and Aliqopa 
prescribing information, dose reduction and drug permanent discontinuation protocol 
requirements for blood glucose increases were modified from 400 to 500 mg/dL.
Sections affected by this modification: Section 6.4.1.2 Non-hematological toxicity
13.5.1.11 Modification 11 – Change in tumor assessments 
Following the revised study design and removal of all efficacy endpoints and variables, text 
was modified to allow sites to perform tumor assessments and to determine the frequency of 
radiological tumor assessments and serum tests (for LPL/WM patients only) based on local 
standards of care. For all patients who discontinue due to radiological PD or clinical PD, only 
date of PD will be collected and recorded in eCRF. 
Sections affected by this modification: Synopsis, Section 4. Study design, Section 5.2.1.1 
Withdrawal from study treatment, Section 7.1.1 Tabulated overview, Section 7.1.2.1 
Screening period, Section 7.1.2.2.2 Treatment – Cycle 2 and higher, Section 7.1.2.3 Tumor 
assessments, Section 7.1.2.4 End-of-treatment visit, Section 7.3.2 Radiological tumor 
assessments, Section 7.3.3 Tumor assessments in patients with WM, Section 11.2 Patient 
information and consent
13.5.1.12 Modification 12 – Addition of a clarification note related to hemoglobin 
test results on infusion Days 8 and 15
A clarification note related to hemoglobin test results was added to clarify the protocol 
requirement for the laboratory test results of hemoglobin < 8 g/dL on infusion Day 8 and 
Day 15. 
Sections affected by this modification: Section 6.4 Dosage and administration
13.5.1.13 Modification 13 – Administrative information updated and other 
clarification
In addition to the modifications specified above, there have been updates to administrative 
information as well as minor corrections for better clarity and consistency. 

The study 
 changed. Therefore the contact details were updated.
PPD


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
A note was added that the screening procedures are no longer applicable by the time 
the protocol amendment 6 becomes effective, as screening for the study ended on 
03 MAR 2017.

On infusion days the allowed time window for post-infusion glucose measurements 
was modified to 10 min for easier site compliance. 

References to the open label study were removed for consistency.

Introductory information on the number of patients treated with copanlisib was 
updated based on most recent data.

Refererences to Imaging Manual were removed since Imaging Manual will not be 
applicable after amendment 6 becomes effective.

Definition of end of study was modified by including the sites last contact with the 
patient along with the last study visit in the definition.

Relevant references to placebo were removed for consistency.

Since only year of birth is collected for screening failure patients, the language on data 
recording was corrected accordingly.
Sections affected by this modification: Title page, Synopsis, Section 1.1.2 Clinical experience, 
Section 1.2 Rationale of the study, Section 3. Investigator and other study personnel, Section 
4. Study design, Section 6.4.1 Dose modification, Section 7.1.1 Tabulated overview, Section 
7.1.2.1 Screening period, Section 7.1.2.2.1 Treatment – Cycle 1, Section 7.1.2.2.2 Treatment 
– Cycle 2 and higher, Section 7.1.2.3 Tumor assessments, Section 7.1.2.4 End-of-treatment 
visit, Section 7.3.2 Radiological tumor assessments, Section 7.5.3.6 Glucose measurement on 
infusion days, Section 8.1 General considerations, Section 9.1 Data recording, Section 10. 
Premature termination of the study, Section 11.2 Patient information and consent


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13.5.2
Changes to the protocol text
In this section, all affected protocol sections are detailed; the sequence of the sections follows 
the structure of the original protocol. In the display of modifications, the “old text” refers to 
the protocol version preceding this amendment. Deletions are crossed out in the “old text”. 
Additions are underlined in the “new text”. Corrections of typing errors or omissions are not 
highlighted in this amendment.
13.5.2.1
Title page
Old text:
Sponsor’s 
:
 MD
 Bayer Center,
No.27 Dong San Huan North Road,
Chaoyang District, Beijing, China, 100020
Telephone no.: 
 
New text:
Sponsor’s 
:
 MD, PhD
Rua Domingos Jorge, 1100 – Bloco 301 - 2º andar 
04779-900, São Paulo, SP Brasil
Telephone: 
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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13.5.2.2
Synopsis
Old text:
[…]
Study objectives
The primary objective of this study is:

To investigate objective tumor response rate (ORR) assessed in all 
patients with rituximab-refractory iNHL who have received two or 
more prior lines of treatment, have been exposed to rituximab and 
alkylating agent(s), and have progressed within six month of the 
end of the last previous rituximab-containing regimen. 
The secondary objectives of this study are to evaluate:

Efficacy including complete response rate and overall survival.

Safety.
The other objectives of this study are to evaluate:

Pharmacokinetics.

Biomarkers.
[…]
Duration of treatment
Treatment will be continued until disease progression (PD) (per 
investigator’s assessment) as defined in the Recommendations for Initial 
Evaluation, Staging, and Response Assessment of Hodgkin and Non-
Hodgkin Lymphoma: The Lugano Classification, unacceptable toxicity, or 
until another criterion is met for withdrawal from the study treatment. For 
patients with Waldenström macroglobulinemia (WM), response 
assessment will be done according to the Response Assessment in 
Waldenström macroglobulinemia: update from the VIth International 
Workshop.
[…]
Study design
A randomized, double-blind, two-arm Phase III study to evaluate the 
efficacy and safety of copanlisib as monotherapy in comparison to placebo 
in patients with rituximab-refractory iNHL.
Following sponsor’s decision to stop enrollment due to lack of feasibility 
to complete this study in reasonable time frame, the study design is 
modified to reflect an open label study. After unblinding all patients will 
be given an opportunity to continue treatment with copanlisib. Patients 
who are on copanlisib treatment at the time of unblinding will continue 
copanlisib treatment. Patients who are on placebo at the time of unblinding 
will be offered to switch to copanlisib treatment after unblinding 
procedures are completed.
[…]
Methodology
The study is composed of the following periods: Screening, Treatment, 
Safety-follow-up, Active follow-up (if applicable) and Survival follow-up.
Patients will receive 60 mg copanlisib IV infusion on Days 1, 8 and 15 of 


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each 28-day treatment cycle.
Treatment will be continued until PD, unacceptable toxicity, or until 
another criterion is met for withdrawal from the study treatment. 
An End-of-treatment (EOT) visit will be performed within 7 days after the 
decision is made to discontinue study treatment. Following completion of 
the EOT visit, patients will enter either the Safety follow-up or the Active 
follow-up period, if applicable. In both cases, the Safety follow-up (SFU) 
visit will take place 30 days (window of +5 days allowed) after the last 
administration of study drug.
Patients who discontinue study treatment due to PD will enter the Safety-
follow up period and patients who discontinue study treatment for reasons 
other than PD will enter the Active follow-up period (which also serves as 
a Safety follow-up), except for patients who object to follow-up data 
collection. The patients in the Active follow-up will have radiological 
assessments as outlined in this protocol from the day of start of study 
treatment until the end of the Active follow-up period, defined as when 
either PD is documented or a new anti-tumor treatment is administered, 
whichever occurs first.
All patients will be followed off-study for overall survival at least at 6-
month intervals during the Survival follow-up period (up to 3 years after 
the last patient started study treatment), except for patients who object to 
follow-up data collection.
[…]
The first radiological tumor assessments with IV (and oral, if indicated, 
per Imaging Manual) contrast enhanced computed tomography/magnetic 
resonance imaging (CT/MRI) scans of neck, chest, abdomen and pelvis 
will be performed at Screening (including WM patients). Corticosteroids 
must be stopped or reduced to the allowed dose (less than 15 mg of 
prednisone or equivalent) at least 7 days before performing the screening 
CT/MRI (if a patient is on chronic corticosteroid therapy, corticosteroids 
should be de-escalated to the maximum allowed dose before the 
Screening). The method chosen at the baseline must be the same 
throughout the study. During the treatment period as well as during the 
Active follow-up period tumor assessments with the same modality will be 
performed per local SOC but not less than every 16 weeks. CT/MRI scans 
are not required at the EOT visit if the patient discontinues due to PD 
which has been radiologically confirmed within the 4 weeks preceding 
EOT. The evaluation of treatment response (best response: ORR and 
CRR) will be done by the investigator.
WM patients who do not have radiologically measurable lesion at 
Screening will not have further radiological assessments as per protocol. 
Their tumor response will be measured only by laboratory/clinical tests. 
However, in cases when WM patients will develop disease progression 
confirmed radiologically by presenting with measurable lesion(s) without 
simultaneous increase in IgM. WM patients who have radiologically 
measurable lesion at Screening will continue having radiological 
assessments and, in addition, will have laboratory tests performed on the 
same days.
Bone marrow biopsy will be mandatory at Screening. Bone marrow tissue 


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biopsy will be done within 28 days before first study drug infusion and 
must be provided at screening. Bone marrow biopsy must be performed 
again to confirm the first complete response (CR) on patients with 
previous bone marrow infiltration at baseline, and may also be performed 
at the investigator discretion if there is clinical suspicion of bone marrow 
infiltration. Bone marrow biopsy will be performed per local standard of 
care.
[…]
Primary variable
The primary efficacy analysis is ORR, which is defined as the proportion 
of patients who have a best response rating over the whole duration of the 
study of complete response (CR) or partial response (PR) according to the 
Lugano Classification (21), and for patients with WM, a response rating of 
CR, very good partial response (VGPR), PR, or minor response (MR) 
according to the Owen criteria (22).
Plan for statistical analysis
Due to the decision of stopping enrollment as protocol amendment 5 
becomes effective, limited number of patients will be included in the 
analyses. Therefore, the statistical analyses included in this study will be 
focused on descriptive statistics without any hypothesis testing.
Two sets of analyses will be performed at the timing when all treated 
patients completed at least 6 cycles of study treatment:
1)
unblinding cutoff: analyze all data available before the unblinding
(details in section 6.5); 
2)
final analysis: analyze all data available until all treated patients 
complete at least 6 cycles of study treatment. 
New text:
[…]
Study objectives
The primary objective of this study is:

To assess the safety of copanlisib.
[…]
Duration of treatment
Treatment will be continued until disease progression (PD) by radiological 
assessments or clinical progression (tumor evaluations will be made at 
intervals that comply with the institution’s standard of care [per 
investigator’s assessment]), unacceptable toxicity, or until another 
criterion is met for withdrawal from the study treatment.
[…]
Study design
Initially this was a randomized, double-blind, two-arm Phase III study to 
evaluate the efficacy and safety of copanlisib as monotherapy in 
comparison to placebo in patients with rituximab-refractory iNHL.
Following sponsor’s decision to stop enrollment due to lack of feasibility 
to complete this study in reasonable time frame, the study design is 


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modified. All patients will be given an opportunity to continue treatment 
with copanlisib. Patients who are on copanlisib treatment at the time of 
unblinding will continue copanlisib treatment. Patients who are on placebo 
at the time of unblinding will be offered to switch to copanlisib treatment 
after unblinding procedures are completed.
[…]
Methodology
The study is composed of the following periods: Screening, Treatment, 
and Safety-follow-up.
By the time the protocol amendment 6 becomes effective, screening 
procedures are no longer applicable as screening for the study ended on 
03 MAR 2017. All screened eligible patients have started treatment.
Patients will receive 60 mg copanlisib IV infusion on Days 1, 8 and 15 of 
each 28-day treatment cycle.
Treatment will be continued until PD, unacceptable toxicity, or until 
another criterion is met for withdrawal from the study treatment. 
An End-of-treatment (EOT) visit will be performed within 7 days after the 
decision is made to discontinue study treatment. Following completion of 
the EOT visit, patients will enter the Safety follow-up. The Safety follow-
up (SFU) visit will take place 30 days (window of +5 days allowed) after 
the last administration of study drug.
[…]
Tumor assessments (and laboratory/clinical tests for WM patients) will be 
made according to the institution’s standard of care.
Bone marrow biopsy may be performed at the investigator discretion if 
there is clinical suspicion of bone marrow infiltration. Bone marrow 
biopsy will be performed per local standard of care.
[…]
Primary variable
The primary analysis is safety, which includes treatment-emergent AEs 
(TEAEs) and serious adverse events (SAEs), laboratory parameters, and 
vital signs.
Plan for statistical analysis
Due to the decision of stopping enrollment as protocol amendment 5 
becomes effective, limited number of patients will be included in the 
analyses. Therefore, the statistical analyses included in this study will be 
focused on descriptive statistics on safety variables only.
Two sets of analyses will be performed at the timing when all patients 
have completed the study treatment and Safety follow-up period  (if 
applicable):
1)
unblinding cutoff: analyze all data available before the unblinding 
(details in section 6.5); 
2)
final analysis: analyze all data available until all patients have 
completed the copanlisib study treatment and Safety follow-up 
period. 


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13.5.2.3
Section 1.1.2 Clinical experience
Old text:
Copanlisib is currently under investigation in various trials enrolling cancer patients. As of 
01 FEB 2016, approximately 627 patients with advanced cancer have been treated with 
copanlisib in Phase 1, Phase 2, and Phase 3 clinical trials (please refer to IB) as a single agent 
or in combination with other agents.
[…]
New text:
Copanlisib is currently under investigation in various trials enrolling cancer patients. As of 
21 JUN 2017, approximately 772 patients with advanced cancer have been treated with 
copanlisib in Phase 1, Phase 2, and Phase 3 clinical trials (please refer to IB) as a single agent 
or in combination with other agents.
[…]
13.5.2.4
Section 1.2 Rationale of the study
Old text:
[…]
Following sponsor’s decision to stop enrollment due to lack of feasibility to complete this 
study in reasonable time frame, the study design is modified to reflect an open label study. All 
patients on study treatment will be offered to continue treatment with copanlisib after 
unblinding procedures are completed.
New text:
[…]
Following sponsor’s decision to stop enrollment due to lack of feasibility to complete this 
study in reasonable time frame, the study design is modified. All patients on study treatment 
will be offered to continue treatment with copanlisib after unblinding procedures are 
completed.
13.5.2.5
Section 2. Study objectives
Old text:
The primary objective of this study is:

To investigate objective tumor response rate (ORR) assessed in all patients with 
rituximab-refractory iNHL who have received two or more prior lines of 
treatment, have been exposed to rituximab and alkylating agent(s), and have 
progressed within six month of the end of the last previous rituximab-containing 
regimen. 


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The secondary objectives of this study are to evaluate:

Efficacy including complete response rate and overall survival.

Safety.
The other objectives of this study are to evaluate:

Pharmacokinetics.

Biomarkers.
New text:
The primary objective of this study is:

To assess the safety of copanlisib.
13.5.2.6
Section 3. Investigator and other study personnel
Old text:
Sponsor’s 
Name: 
 MD
 Bayer Center,
No.27 Dong San Huan North Road,
Chaoyang District, Beijing, China, 100020
Telephone no.:
New text:
Sponsor’s 
Name: 
 MD, PhD
Rua Domingos Jorge, 1100 – Bloco 301 - 2º andar 
04779-900, São Paulo, SP Brasil
Telephone: 
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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13.5.2.7
Section 4. Study design
Old text:
Design overview
This is a randomized, double-blind, two-arm Phase III study to evaluate the efficacy and 
safety of copanlisib as monotherapy in comparison to placebo in patients with rituximab-
refractory iNHL.
[…]
The overview of study periods is presented in Figure 4-1.
Figure 4-1
Study periods
On study
Off study
Screening
Treatment
Safety follow-up / 
Active follow-upa
Survival 
follow-up
Cycle 1
(Day 1 to 28)
Cycle 2 etc.
(Day 1 to 28)
EOT
visit
SFU
visit
Informed
consent
First dose of 
study drug 
Last dose of 
study drug/
End of last cycle
Last protocol-
stipulated 
procedure
EOT = End of treatment; SFU = Safety follow-up.
a: If applicable.
[…]
Approximately 189 patients (of  approx. 237 screened) will meet the eligibility criteria (see 
Section 5.1) and will be randomly assigned in a 2:1 ratio to one of the double-blinded 
treatment arms: copanlisib monotherapy (approx. 126 patients) or placebo (approx. 63 
patients). Patients will be stratified at randomization based on NHL histology  (FL histology: 
approx. 144 patients; iNHL histology: approx. 45 patients) , the time between last course of 
systemic anticancer therapy and most recent progression and prior treatment with PI3K 
inhibitors (see Section 6.3).
Following sponsor’s decision to stop enrollment due to lack of feasibility to complete this 
study in reasonable time frame, the study design is modified to reflect an open label study. All 
patients on study treatment will be offered to continue treatment with copanlisib after 
unblinding procedures are completed (see Section 6.5).
[…]
The start of the treatment period is defined by first administration of study drug (copanlisib). 
Copanlisib will be administered IV over approximately 1 h at starting dose of 60 mg on Days 
1, 8 and 15 of each 28-day treatment cycle. Treatment will be continued until PD (per 
investigator’s assessment) as defined in the Lugano Classification (21), unacceptable toxicity, 


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or until another criterion is met for withdrawal from the study treatment (see Section 5.2). For 
patients with WM, response assessment will be done according to the Owen criteria (22).
[…]
An End-of-treatment (EOT) visit will be performed within 7 days after the decision is made to 
discontinue study treatment. Following completion of the EOT visit, patients will enter either 
the Safety follow-up or the Active follow-up period, if applicable. In both cases, the Safety 
follow-up (SFU) visit will take place 30 days (window of +5 days allowed) after the last 
administration of study drug.
Patients who discontinue study treatment due to PD will enter the Safety-follow up period and 
patients who discontinue study treatment for reasons other than PD will enter the Active 
follow-up period (which also serves as a Safety follow-up), except for patients who object to 
follow-up data collection. The patients in the Active follow-up will have radiological 
assessments by investigator as outlined in this protocol from the day of start of study 
treatment until the end of the Active follow-up period, defined as when either PD is 
documented or a new anti-tumor treatment is administered, whichever occurs first. During the 
Active follow-up period, serious adverse events (SAEs) and AEs assessed as related to 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. 
All patients will be followed off-study for overall survival at least at 6-month intervals during 
the Survival follow-up period (up to 3 years after the last patient started study treatment), 
except for patients who object to follow-up data collection. During this period, patients are 
not considered to be “on-study”.
[…]
The first radiological tumor assessment with IV (and oral, if indicated, per Imaging Manual) 
contrast enhanced computed tomography/magnetic resonance imaging (CT/MRI) scans of 
neck, chest, abdomen and pelvis will be performed at Screening (including WM patients) (see 
Table 7–1 and Section 7.3.2). Corticosteroids must be stopped or reduced to the allowed dose 
(less than 15 mg of prednisone or equivalent) at least 7 days before performing the screening 
CT/MRI (if a patient is on chronic corticosteroid therapy, corticosteroids should be de-
escalated to the maximum allowed dose before the Screening). The method chosen at the 
baseline must be the same throughout the study. During the treatment period as well as during 
the Active follow-up period tumor assessments with the same modality will be performed, 
and the schedule of tumor assessment will be performed per local standard of care of the 
institution but not less than every 16 weeks. CT/MRI scans are not required at the EOT visit if 
the patient discontinues due to PD which has been radiologically confirmed within the 4 
weeks preceding EOT. The response assessment will be done according to the Lugano 
Classification (21), and for patients with WM, according to the Owen criteria (22). Detailed 
instructions on tumor assessment are provided in Appendix 14.1. All the efficacy analyses 
will be done based on investigator’s assessment of tumor response.
WM patients who do not have radiologically measurable lesion at Screening will not have 
further radiological assessments as per protocol. Their tumor response will be measured only 


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by laboratory/clinical tests. However, in cases when WM patients who develop 
extramedullary disease without simultaneous increase in IgM will have radiological 
assessment to confirm disease progression (per investigator’s assessment). WM patients who 
have radiologically measurable lesion at Screening will continue having radiological 
assessments and, in addition, will have laboratory tests performed on the same days.
Bone marrow biopsy will be mandatory at Screening. Bone marrow tissue biopsy will be 
performed within 28 days before first study drug infusion and must be provided at screening. 
Bone marrow biopsy must be performed again to confirm the first complete response (CR) on 
patients with bone marrow infiltration at baseline, and may also be performed at the 
investigator discretion if there is clinical suspicion of bone marrow infiltration. Bone marrow 
biopsy will be performed as per local standard of care. 
All collected tumor tissue samples will be utilized to investigate or identify biomarkers that 
may be predictive of copanlisib effects/efficacy in NHL and to contribute to better 
understanding the disease (see Section 7.6.1).
Sparse blood samples for PK analysis will be collected from all patients to characterize the 
PK of copanlisib (see Section 7.4).
Plasma samples for biomarker analyses will be collected from all patients, according to the 
schedule specified in Section 7.6.1. Blood samples for exploratory genetic biomarker analysis 
will be collected on Cycle 1 Day 1 from patients who provide “genetic research” consent 
(voluntary).
Primary variable
Due to the decision of stopping enrollment, limited number of patients will be included in the 
analyses. Therefore, the statistical analyses included in this study will be focused on 
descriptive statistics.
The primary efficacy variable of this study will be objective tumor response rate (ORR), 
which is defined as the proportion of patients who have a best response rating up to the dates 
of data cutoffs (for dates of data cutoffs, see details in section 8.1) of complete response (CR) 
or partial response (PR) according to the Lugano Classification (21), and for patients with 
WM, a response rating of CR, very good partial response (VGPR), PR, or minor response 
(MR) according to the Owen criteria (22).
Justification of the design
The pre-clinical profile of copanlisib and preliminary efficacy data from Phase I study 12871 
and Phase II study 16349 suggest that copanlisib may improve PFS in patients with 
rituximab-refractory iNHL who have received two or more prior lines of treatment and have 
been exposed to rituximab and alkylating agent(s). The purpose of this study is to demonstrate
efficacy and safety of treatment with copanlisib in patients where treatment is indicated, with 
ORR as the primary endpoint.


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End of study
For each participating EU country, the end of the study according to the EU Clinical Trial 
Directive will be reached when the last visit of the last patient for all centers in the respective 
country has occurred.
[…]
New text:
Design overview
Following sponsor’s decision to stop enrollment due to lack of feasibility to complete this 
study in reasonable time frame, the study design is modified. All patients on study treatment 
will be offered to continue treatment with copanlisib after unblinding procedures are 
completed (see Section 6.5).
By the time the protocol amendment 6 becomes effective, screening procedures are no longer 
applicable as screening for the study ended on 03 MAR 2017. All screened eligible patients 
have started treatment.
Initially this was a randomized, double-blind, two-arm Phase III study to evaluate the efficacy 
and safety of copanlisib as monotherapy in comparison to placebo in patients with rituximab-
refractory iNHL.
[…]
The overview of study periods updated by amendment 6 is presented in Figure 4–1.
Figure 4-1
Study periods as of amendment 6
Screening
Treatment
Safety follow-up 
Cycle 1
(Day 1 to 28)
Cycle 2 etc.
(Day 1 to 28)
EOT
visit
SFU
visit
Informed
consent
First dose of 
study drug 
Last dose of 
study drug/
End of last cycle
Last protocol-
stipulated 
procedure
EOT = End of treatment; SFU = Safety follow-up.
[…]
The start of the treatment period is defined by first administration of study drug (copanlisib). 
Copanlisib will be administered IV over approximately 1 h at starting dose of 60 mg on Days 
1, 8 and 15 of each 28-day treatment cycle. Treatment will be continued until PD by 
radiological assessments or clinical progression (tumor evaluations will be made at intervals 
that comply with the institution’s standard of care [per investigator’s assessment]),


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unacceptable toxicity, or until another criterion is met for withdrawal from the study treatment 
(see Section 5.2). 
[…]
An End-of-treatment (EOT) visit will be performed within 7 days after the decision is made to 
discontinue study treatment. Following completion of the EOT visit, patients will enter the 
Safety follow-up. The Safety follow-up (SFU) visit will take place 30 days (window of +5 
days allowed) after the last administration of study drug.
[…]
Tumor assessments (and laboratory/clinical tests for WM patients) will be made according to 
the institution’s standard of care.
The response assessment will be done according to the Lugano Classification (21), and for 
patients with WM, according to the Owen criteria (22). Detailed instructions on tumor 
assessment are provided in Appendix 14.1. 
Bone marrow biopsy may be performed at the investigator discretion if there is clinical 
suspicion of bone marrow infiltration. Bone marrow biopsy will be performed as per local 
standard of care. 
All collected blood, plasma and tumor tissue samples may be utilized for biomarker analysis 
to contribute to better understanding the mechanism of action and the disease (see 
Section 7.6.1).
Primary variable
Due to the decision of stopping enrollment, limited number of patients will be included in the 
analyses. Therefore, the statistical analyses included in this study will be focused on 
descriptive statistics for safety only.
Justification of the design
The pre-clinical profile of copanlisib and preliminary efficacy data from Phase I study 12871 
and Phase II study 16349 suggest that copanlisib may improve PFS in patients with 
rituximab-refractory iNHL who have received two or more prior lines of treatment and have 
been exposed to rituximab and alkylating agent(s). The purpose of this study is to evaluate the 
safety of copanlisib treatment.
End of study
For each participating EU country, the end of the study according to the EU Clinical Trial 
Directive will be reached when the last visit or contact of the last patient for all centers in the 
respective country has occurred.
[…]


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13.5.2.8
Section 5.2.1.1 Withdrawal from study treatment
Old text:
Patients must be withdrawn from the study treatment for the following reasons:

At their own request or at the request of their legally acceptable representative.
At any time during the study and without giving reasons, a patient may decline to 
participate further. The patient will not suffer any disadvantage as a result. Patients 
who withdraw consent from treatment will still participate in the Active or Survival 
follow-up unless they object to follow-up data collection (see Section 11.2). 

[…]

Persistent occurrence of post-infusion blood glucose > 400 mg/dL based on laboratory 
analysis which occurred at the lowest study drug dose level despite optimal glucose 
lowering therapy (after at least one cycle of treatment) with consultation of a diabetes 
specialist (e.g. diabetologist or endocrinologist). 
Definition of persistent occurrence is based on repeated post-infusion blood glucose 
laboratory analysis taken at different time during the whole cycle of treatment.

[…]
Patients may be withdrawn from the study for the following reasons:

At the specific request of the sponsor and in liaison with the investigator (e.g. obvious 
non-compliance, safety concerns).
[…]
For patients who withdraw consent and object to 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. 
[…]
New text:
Patients must be withdrawn from the study treatment for the following reasons:

At their own request or at the request of their legally acceptable representative.
At any time during the study and without giving reasons, a patient may decline to 
participate further. The patient will not suffer any disadvantage as a result. (See 
Section 11.2). 

[…]

Persistent occurrence of post-infusion blood glucose > 500 mg/dL based on laboratory 
analysis which occurred at the lowest study drug dose level despite optimal glucose 
lowering therapy (after at least one cycle of treatment). 
Definition of persistent occurrence is based on repeated post-infusion blood glucose 
laboratory analysis taken at different time during the whole cycle of treatment.


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
[…]
Patients may be withdrawn from the study for the following reasons:

At the specific request of the sponsor and in liaison with the investigator (e.g. obvious 
non-compliance, safety concerns).

Clinical progression per investigator assessment.
[…]
For all patients who discontinue due to radiological PD or clinical PD, only date of PD will be 
collected and recorded in eCRF. 
For patients who withdraw consent and object to follow-up data collection, no further study-
related procedures will be allowed, and no further data will be collected. The patients will not 
suffer any disadvantage as a result. 
[…]
13.5.2.9
Section 5.2.1.2 Withdrawal from follow-up period
Old text:
Following completion of the EOT visit, patients who discontinue study treatment due to PD 
will enter the Safety-follow up period and patients who discontinue study treatment for 
reasons other than PD will enter the Active follow-up period (which also serves as a Safety 
follow-up).
All patients will be contacted at least every 6 months to determine survival status during the 
Survival follow-up period (up to 3 years after the last patient started study treatment).
Reasons for not performing the Safety follow-up or discontinuation of the Survival follow-up 
include the following: 

Death

Objection to follow-up data collection

Lost to follow-up
New text:
Following completion of the EOT visit, patients will enter the Safety-follow up period.
Reasons for not performing the Safety follow-up include the following: 

Death

Objection to follow-up data collection

Lost to follow-up


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13.5.2.10 Section 6.4 Dosage and administration
Old text:
[…]
Table 6-1
Fasting requirements and pre-dose glucose levels
Period
Fasting ≥ 8 h required 
before first glucose 
measurement
Pre-dose glucose levels
(first glucose measurement)
Fasting required before 
study drug infusion
Day 1 of
cycle 1
Yes
≤125 mg/dL (non-diabetic patients)
<160 mg/dL (diabetic patients)
Yes a
Day 1 of 
subsequent 
cycles
Yes
<160 mg/dL (fasting)
< 200 mg/dL (non-fasting) c
Conditional a, b, d
Days 8 and 15 
of each cycle
No
<160 mg/dL (fasting)
<200 mg/dL (non-fasting)
Conditional a, b, d
a: Diabetic patients who take insulin treatment at any cycle visit: Timing and content of caloric 
intake on infusion days will be managed and monitored by the investigator. Consultation with 
treating physician or diabetes specialist is advised.
b: The decision regarding meal timing and fasting can be made by the investigator based on 
glucose response patterns during prior treatment days (see text below “Recommendations on 
meal timing on infusion days” for further details).
c: In case of non-compliance with the fasting requirement.
d: A low glycemic index meal may be taken at least 4 h before the start of the study drug infusion 
for patients who have their infusions scheduled at a later hour, or due to their age or medical 
condition when fasting prior to infusion is not viable.
The investigator will accurately document fasting/non-fasting for each glucose measurement 
done at the site. 
[…]
Any capillary or plasma glucose levels > 250 mg/dL should be confirmed by repeated 
laboratory analysis. 
Recommendations on meal timing on infusion days 
[…]
It is recommended that timing and content of caloric intake on infusion days is managed and 
monitored by the investigators. Consultation with treating physician or diabetes specialist 
(e.g. diabetologist or endocrinologist) is advised.
The investigator will review the glucose profile during and post the study drug infusions. 
The investigator may manage the timing of post-infusion meals based on the glucose profile 
during prior infusion(s) to minimize glucose increases. This is in addition to glucose lowering 
medication. Low glycemic index meals (see Appendix 14.7) should be provided for patients 
who are kept in clinic for continued observation.


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A low glycemic index diet is recommended for the first 48 h after study drug infusion. 
However, caloric restriction is not intended for the population under study.
All glucose measurements, oral glucose lowering medication and/or insulin administration, if 
applicable, and meal timing will be collected as part of the clinical source documentation. 
Note: Caloric intake and timing recommendations for diabetic patients who require insulin 
treatment prior to the infusion at any cycle visit should be managed and monitored by the 
investigator based on consultation with treating physician or diabetes specialist.

On infusion days at any cycle:
The decision regarding meal timing and fasting can be made by the investigator based 
on glucose response patterns during prior treatment days.
Note: If patient needs to take a low glycemic meal, then glucose test should be taken 
prior to meal intake and at 1 h and 2 h after the meal (see Section 7.5.3.6).

Cycle 1 Day 1:  
Fasting is required before start of infusion. 
A low glycemic index meal (see Appendix 14.7) may be taken 3 h after start of 
infusion.

Day 1 of each subsequent cycle after Cycle 1 Day 1:
Fasting is required before the first glucose measurement.
After Cycle 1, a low glycemic index meal may be taken at least 4 h before the start of 
the study drug infusion for patients who have their infusions scheduled at a later hour, 
or due to their age or medical condition when fasting prior to infusion is not viable.

Day 8 and Day 15 of each cycle:
Fasting is not required before start of infusion.
A low glycemic index meal may be taken at least 4 h before the start of the study drug 
infusion for patients who have their infusions scheduled at a later hour, or due to their 
age or medical condition when fasting prior to infusion is not viable.
[…]
Dosing criteria
[…]


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A blood count will be performed and assessed prior to infusion on Days 8 and 15 of each 
cycle. The study drug will not be administered if, on the day of scheduled dosing, any of the 
following criteria is met:

CTCAE Grade ≥ 3 neutrophil count decreased (ANC < 1,000/mm3)

CTCAE Grade ≥ 3 platelet count decreased (platelets < 50,000/mm3)

CTCAE Grade ≥ 3 anemia (hemoglobin < 8 g/dL)
Doses scheduled for Days 1 (after Cycle 1 Day 1), 8 and 15 may be delayed by up to 2 days. 
A delay of more than 2 days will be considered a missed dose. Missed doses will not be 
replaced. The minimum interval needed between two infusions of study drugs is 5 days.
New text:
[…]
Table 6-1
Fasting requirements and pre-dose glucose levels
Period
Fasting ≥ 8 h required before 
first glucose measurement
Pre-dose glucose levels 
(first glucose measurement)
Day 1 of
cycle 1
Yes a
≤125 mg/dL (non-diabetic patients)
<160 mg/dL (diabetic patients)
Subsequent infusions after
Cycle 1 Day 1 
No b
<160 mg/dL (fasting)
< 200 mg/dL (non-fasting)
a: Diabetic patients who take insulin treatment at any cycle visit: Timing and content of meal intake will be 
managed by the investigator. Consultation with treating physician or endocrinologist is advised.
b: The decision regarding meal timing and fasting can be made by the investigator based on glucose 
response patterns during prior treatment days.
[…]
Recommendations on meal timing on infusion days 
[…]
It is recommended on infusion days that timing of meal intake and additional glucose testing 
(if applicable) are managed and monitored by the investigators. Consultation with treating 
physician or diabetes specialist (e.g. diabetologist or endocrinologist) is advised.
All glucose measurements done at the site, oral glucose lowering medication and/or insulin 
administration, if applicable, fasting/non-fasting status and meal intake timing on infusion 
days will be collected as part of the clinical source documentation. 

On infusion days at any cycle:
The decision regarding meal timing and fasting can be made by the investigator based 
on glucose response patterns during prior treatment days.


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
Cycle 1 Day 1:  
Fasting is required before start of infusion. 

Subsequent visits after C1D1 visit:
Fasting is not required before start of infusion.
[…]
Dosing criteria
[…]
A blood count will be performed and assessed prior to infusion on Days 8 and 15 of each 
cycle. The study drug will not be administered if, on the day of scheduled dosing, any of the 
following criteria is met:

CTCAE Grade ≥ 3 neutrophil count decreased (ANC < 1,000/mm3)

CTCAE Grade ≥ 3 platelet count decreased (platelets < 50,000/mm3)

CTCAE Grade ≥ 3 anemia (hemoglobin < 8 g/dL)
If hemoglobin is < 8 g/dL but ≥ 6 g/dL on the day of planned study drug administration it 
is permissible to give the study drug dose on schedule and transfuse within 48 h after the 
dose, if the patient is hemodynamically stable and in opinion of investigator benefits 
outweigh risks. Rationale and treatment should be recorded in the source documentation 
and in the eCRF.
Doses scheduled for Days 1 (after Cycle 1 Day 1), 8 and 15 may be delayed by up to 2 days. 
A delay of more than 2 days will be considered a missed dose. Missed doses will not be 
replaced. The minimum interval needed between two infusions of study drugs is 5 days.
13.5.2.11 Section 6.4.1 Dose modification
Old text:
[…]
The dose modification levels of study treatment (copanlisib or placebo) will follow the pre-
defined dose levels shown in Table 6-3. Dummy dose modifications are used for placebo.
[…]


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New text:
[…]
The dose modification levels of study treatment (copanlisib) will follow the pre-defined dose 
levels shown in Table 6–3. 
[…]
13.5.2.12 Section 6.4.1.2 Non-hematological toxicity
Old text:
[…]
a) Glucose increases
[…]

Continuing occurrence of post-infusion blood glucose > 400 mg/dL based on repeated 
laboratory analysis despite optimal glucose lowering therapy after 2 infusions of study 
drug will require dose reduction by one dose level.

Further dose reduction is allowed as long as discontinuation criteria was not met.

[…]

Persistent occurrence of post-infusion blood glucose > 400 mg/dL based on laboratory 
analysis which occurred at the lowest study drug dose level despite optimal glucose 
lowering therapy (after at least one cycle of treatment) with consultation of a diabetes 
specialist requires permanent discontinuation of the study treatment (see 
Section 5.2.1.1).
New text:
[…]
a) Glucose increases
[…]

Continuing occurrence of post-infusion blood glucose > 500 mg/dL based on repeated 
laboratory analysis despite optimal glucose lowering therapy after 2 infusions of study 
drug will require dose reduction by one dose level.

Further dose reduction is allowed as long as discontinuation criteria were not met.

[…]

Persistent occurrence of post-infusion blood glucose > 500 mg/dL based on laboratory 
analysis which occurred at the lowest study drug dose level despite optimal glucose 


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lowering therapy (after at least one cycle of treatment) with consultation of a diabetes 
specialist requires permanent discontinuation of the study treatment (see 
Section 5.2.1.1).
13.5.2.13 Section 6.4.2.1 Management of transient post-infusion glucose increases 
that can occur with study treatment
Old text:
[…]
Table 6-9
Management of transient post-infusion glucose increases
Criteria 
Recommendation
Suggested Treatment
[…]
[…]
Glucose monitoring at home
At least 3 times per full day including fasting glucose (morning before breakfast) and 
2 further measurements approximately 2 h after intake of food for at least 72 h after the start 
of infusion is required for: 

All diabetic patients regardless of glucose level on infusion day

Non-diabetic patients who experience persisting glucose > 250 mg/dL or who require 
insulin administration post-infusion. Consultation with diabetes specialist is 
recommended.
Patients will be trained how to measure their capillary blood glucose levels at home. If 
applicable, patients will be provided with glucose meter and supplies (lancets, test strips and 
diary) to register measured values and record meal timing, oral glucose lowering medication 
and/or insulin administration. The appropriate calibration of glucose meters will be 
documented.
Monitoring of diabetic patients
If the patient already monitors his/her blood glucose as part of routine antidiabetic care, the 
routine measurements should not be replaced by the study specific measurements. In this 
situation, patients should add the study specific measurements to their routine, if applicable. 
After the required 72 h, if blood glucose values are at goal (random non-fasting glucose < 
200 mg/dL) after each infusion, patients can then stop only the study specific measurements 
until the next day of infusion, but should keep their routine measurements unchanged and 
ongoing as usual.
Sites recruiting patients with diabetes should have the option to extend glucose monitoring 
overnight.


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New text:
[…]
Table 6-9
Management of transient post-infusion glucose increases
Criteria 
Recommendation
Suggested Treatment
[…]
[…]
The need for glucose monitoring at home should be determined by the investigator based on 
post-infusion glucose profile and clinical status of the patient.
Monitoring of diabetic patients
If the patient already monitors his/her blood glucose as part of routine antidiabetic care, the 
routine measurements should not be replaced by the study specific measurements. 


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13.5.2.14 Section 7.1.1 Tabulated overview
Old text:
Table 7-1
Study flow chart
Screening 
maximum days before 
C1D1
Treatment *
EOT
SFU
Active 
follow-
up aa
Survival
follow-up
bb
Cycle 1
Cycle 2 and higher
Within (days) after
Days
-28 
-14
-7
D1
D8
D15
D1
D8
D15
7
30 + 5
days 
windowz
every 6 
months
Acceptable deviation (in days)
-1 to +2 days
-1 to +2 days
Decision
to stop
Last 
dose
14 days
Screening and enrollment
Patient informed consent (including 
genetic) jj
Xcc,dd
Check in- and exclusion criteria
X
X
X
Medical history a
X
IVRS/IWRS transaction b, dd
X
Xb
X
X
HBsAg, HBcAb, HCV IgG
X
CMV PCR test ff,ii
X
Xff
Xff
Serum pregnancy test (if applicable) c
X
Xc
Xc, ee
UPCR / 24 h total urine protein 
quantification ee
X
GFR dd
X
X
Safety
Toxicity / AE assessment d
X
X
X
X
X
X
X
X
X
(X)d
Concomitant medication d
X
X
X
X
X
X
X
X
X
Complete physical examination e
X
X
X
X
Brief physical examination f, dd
X
X
X
X
(X)
12-lead ECG g, dd
X
Xg
MUGA scan or echocardiogram h, dd
Xh
Xh
HbA1c i
X
X
Complete blood count j
X
Xx
Xx
Xx
C2 onlyx
C2 onlyx
X
(X)


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Table 7-1
Study flow chart
Screening 
maximum days before 
C1D1
Treatment *
EOT
SFU
Active 
follow-
up aa
Survival
follow-up
bb
Cycle 1
Cycle 2 and higher
Within (days) after
Days
-28 
-14
-7
D1
D8
D15
D1
D8
D15
7
30 + 5
days 
windowz
every 6 
months
Acceptable deviation (in days)
-1 to +2 days
-1 to +2 days
Decision
to stop
Last 
dose
14 days
Hemoglobin, ANC and platelet counts 
(C3->)
Xx
Xx
Chemistry panel k
Xk
Xx
Xx
Xk,x
C2 onlyx
C2 onlyx
Xk
(X)
Coagulation panel: PT, INR and PTT
X
Xx
Xx
X
(X)
CD4 (for patients with signs of infection) 
and blood cultures when low ANC of 
CTCAE Grade 4 gg, hh,ii
Urinalysis (dipstick)
X
X
X
Glucose l
X
X
X
X
X
X
Home glucose monitoring m, dd
X
X
X
X
X
X
X
X
Blood pressure n
X
X
X
X
X
X
Efficacy
Bone marrow biopsy o
X
CT/MRI and tumor evaluations p
Xp
Xp
Xp
Pharmacokinetic sampling r, dd
X
Biomarkers
Tumor tissue for central pathology and 
biomarkers s, dd
X
(X)
Plasma for tumor genetics t, dd
X
X
Plasma for non-genetic biomarker 
analysis u dd
X
X
X
C2
only
C2 
only
C2
only
X
Study drug administration
Copanlisib IV infusion
X
X
X
X
X
X
Survival status, new anticancer 
therapy
X


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Table 7-1
Study flow chart
Screening 
maximum days before 
C1D1
Treatment *
EOT
SFU
Active 
follow-
up aa
Survival
follow-up
bb
Cycle 1
Cycle 2 and higher
Within (days) after
Days
-28 
-14
-7
D1
D8
D15
D1
D8
D15
7
30 + 5
days 
windowz
every 6 
months
Acceptable deviation (in days)
-1 to +2 days
-1 to +2 days
Decision
to stop
Last 
dose
14 days
For LPL/WM patients only
Serum protein electrophoresis w
Xw
(X)w
Immunofixation w
Xw
(X)w
Serum quantitative IgM test w
Xw
(X)w
Serum beta-2-microglobulin dd
Xw
Serum or plasma viscosity w
Xw
(X)w
(X)w
[…] IgM = Immunoglobulin M;
[…] PD = Disease progression; PK = Pharmacokinetic(s);
[…] SAE = Serious adverse event;
[…]
d
After Screening: AE assessment and concomitant medication review must be updated before each dose and all AEs starting within 30 days 
after the last dose of study drug should be collected and recorded in eCRF. After the patient signs the informed consent, any new finding 
discovered not present in the patient’s medical history or a worsening of a prior medical history finding must be recorded as an AE. Contrast 
media does not need to be recorded as concomitant medication unless there is an AE related to its administration (e.g. allergic reaction). 
During the Active follow-up period, AEs and SAEs assessed as related to study procedures by the investigator will be reported in the usual 
manner.
[…]
l
On Cycle 1 Day 1, glucose will be measured at pre-dose and post-dose after the end of study drug infusion (0), 1 h and 2 h. Additional 
measurements to be performed at the clinic as clinically indicated. On subsequent infusions, glucose will be measured prior to and 1 h after 
the end of infusion. Deviation of ± 5 min is allowed for glucose measurements, except for the pre-dose measurement. The pre-dose glucose 
sample on Day 1 of each cycle should be after an 8 h fasting. For details on fasting requirements and pre-dose glucose levels, see 
Section 6.4. Glucose is also measured as part of the chemistry panel.
m
Home glucose monitoring is required for all diabetic patients after each infusion. For non-diabetic patients home glucose measurement is 


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required if patients experience persisting glucose > 250 mg/dL or require insulin administration post-infusion. Measurements should be 
performed according to guidance provided in Section 6.4.2.1. Patients will be trained to measure their capillary blood glucose levels at home 
starting at Screening. On Cycle 1 Day 1, patients will be provided with glucose meter and supplies, (lancets, test strips and diary) to record 
glucose values, meal timing, oral glucose lowering medication and/or insulin administration, if applicable.
[…]
o
Bone marrow biopsy must be performed within 28 days before first study drug infusion, and to confirm the first complete response if there is 
bone marrow infiltration at baseline, and also at the investigator discretion if there is clinical suspicion of bone marrow infiltration Bone 
marrow biopsy will be performed as per local standard of care.
p
The first IV (and oral, if indicated, per Imaging Manual) contrast enhanced CT/MRI scans of neck, chest, abdomen and pelvis must be 
performed at Screening (including WM patients). Corticosteroids must be stopped or reduced to the allowed dose (less than 15 mg of 
prednisone or equivalent) at least 7 days before performing the screening CT/MRI (if a patient is on chronic corticosteroid therapy, 
corticosteroids should be de-escalated to the maximum allowed dose before the Screening). The method chosen at the baseline must be the 
same throughout the study. During treatment, tumor scans will be done with the same modality, and the schedule of tumor assessment will 
be done per local standard of care of the institution but no less than 16 weeks). Time points for assessments are calculated from Cycle 1 Day 
1. Tumor assessments must be performed within 14 days after the last dose (Day 15) and before the next dose (Day 1 of the subsequent 
cycle) starting from Cycle 3. CT/MRI scans are not required at the EOT visit if the patient discontinued due to PD which has been 
radiologically evaluated within the 4 weeks preceding EOT. During Active follow-up period patients will have radiological assessments at 
same intervals as during treatment until PD is documented or new anti-tumor treatment is administered (see Section 7.1.2.3 and Section 
7.3.2). For tumor assessments in patients with WM, see Section 7.3.3.
[…]
r
PK sampling will be performed for copanlisib, its metabolite M-1 and other metabolites, if needed, in all patients on Cycle 1 Day 8: pre-
infusion, 5 to 15 min, 55 min (or within 5 min prior to end of infusion) and 1.5 to 5 h after start of 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.
s
Tumor tissue collection will be mandatory at Screening for central pathology review. In addition, additional pre-treatment tumor tissue 
samples will be collected when available to investigate or identify biomarkers that may be predictive of copanlisib effects/efficacy in NHL and 
to contribute to better understanding the disease. A tumor biopsy is also encouraged at the time of progression (optional) to allow 
investigation of copanlisib resistance. In addition, if a tumor biopsy/excision occurs during the course of the study based on medical need, a 
sample should be submitted (though no biopsy is required during treatment) (see Section 7.6.1).
t
Plasma for tumor genetics: blood samples will be collected on Cycle 1 Day 1 and at the EOT visit. On Cycle 1 Day 1, blood for plasma 
preparation should be drawn prior to drug administration. 
u
Plasma for non-genetic biomarker analysis will be prepared from whole blood samples. On treatment days, blood for plasma preparation 
should be drawn prior to drug administration. Samples are to be collected on Cycle 1 (Days 1, 8 and 15), Cycle 2 (Days 1, 8 and 15), and at 
the EOT visit.
[…] 


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w
Only for patients affected by LPL/WM: Serum protein electrophoresis, immunofixation, serum quantitative IgM test and serum beta-2-
microglobulin measurement will be performed at Screening. Serum or plasma viscosity will be tested at Screening only if hyperviscosity 
syndrome is suspected. Only for patients affected by WM: Serum protein electrophoresis, immunofixation and serum quantitative IgM test will 
be performed on the days of tumor evaluation and at the EOT visit only if the last assessment is older than 4 weeks. If serum or plasma 
viscosity is abnormal at baseline, the measurement will be repeated every 3rd cycle starting from Day 1 of Cycle 3, and at the EOT visit.
[…]
aa Patients who discontinue study treatment for reasons other than PD will enter the Active follow-up period (which also serves as a Safety 
follow-up), except for patients who object to follow-up data collection. The patients in the Active follow-up will have radiological assessments 
as outlined in this protocol from the day of randomization until PD is documented or new anti-tumor treatment is administered, whichever 
occurs first. 
bb Patients or their health care providers will be contacted either in person or by telephone (except for patients who object to FU data collection). 
The contacts will be made at least every 6 months (± 14 days), until death or until the end of the trial (up to 3 years after the last patient 
started study treatment), whichever comes first. Information to be recorded: date of contact, survival status, the first new anticancer regimen 
including response (if applicable), and date and cause of death (if applicable).
cc
Written informed consent must be obtained prior to any study-specific procedures. Certain results from diagnostic testing performed as part of 
the standard of practice prior to the informed consent date and time may be used to fulfill screening criteria. This includes fresh tissue as 
noted in the protocol as well as results from CT/MRI scans, bone marrow sample, MUGA/echocardiogram and hepatitis testing which may 
also be used provided that they fall into the protocol-specified time window. Archival tissue obtained from the patients at any time during the 
course of their iNHL may also be used prior to the informed consent date and time if performed as part of the standard of practice. CT/MRI 
must also meet the quality standards of the Imaging Manual. The maximum interval allowed between signature of informed consent and start 
of treatment is 28 days unless written sponsor authorization has been obtained for laboratory re-testing (up to additional 14 days permitted).
[…]


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New text:
Table 7-1
Study flow chart
Screening 
maximum days before 
C1D1
Treatment *
EOT
SFU
Cycle 1
Cycle 2 and higher
Within (days) after
Days
-28 
-14
-7
D1
D8
D15
D1
D8
D15
7
30 + 5
days windowz
Acceptable deviation (in days)
-1 to +2 days
-1 to +2 days
Decision
to stop
Last dose
Screening and enrollment
Patient informed consent (including 
genetic) jj
Xcc,dd
Check in- and exclusion criteria
X
X
X
Medical history a
X
IVRS/IWRS transaction b, dd
X
Xb
X
X
HBsAg, HBcAb, HCV IgG
X
CMV PCR test ff,ii
X
Xff
Xff
Serum pregnancy test (if applicable) c
X
Xc
Xc, ee
UPCR / 24 h total urine protein 
quantification ee
X
GFR dd
X
X
Safety
Toxicity / AE assessment d
X
X
X
X
X
X
X
X
X
Concomitant medication d
X
X
X
X
X
X
X
X
X
Complete physical examination e
X
X
X
X
Brief physical examination f, dd
X
X
X
X
(X)
12-lead ECG g, dd
X
Xg
MUGA scan or echocardiogram h, dd
Xh
Xh
HbA1c i
X
X
Complete blood count j
X
Xx
Xx
Xx
C2 onlyx
C2 onlyx
X
(X)
Hemoglobin, ANC and platelet counts 
(C3)
Xx
Xx
Chemistry panel k
Xk
Xx
Xx
Xk,x
C2 onlyx
C2 onlyx
Xk
(X)
Coagulation panel: PT, INR and PTT
X
Xx
Xx
X
(X)


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Table 7-1
Study flow chart
Screening 
maximum days before 
C1D1
Treatment *
EOT
SFU
Cycle 1
Cycle 2 and higher
Within (days) after
Days
-28 
-14
-7
D1
D8
D15
D1
D8
D15
7
30 + 5
days windowz
Acceptable deviation (in days)
-1 to +2 days
-1 to +2 days
Decision
to stop
Last dose
CD4 (for patients with signs of infection) 
and blood cultures when low ANC of 
CTCAE Grade 4 gg, hh,ii
Urinalysis (dipstick)
X
X
X
Glucose l
X
X
X
X
X
X
Blood pressure n
X
X
X
X
X
X
Bone marrow biopsy o
X
CT/MRI and tumor evaluations and 
laboratory/clinical tests for LPL/WM 
patientsp
Xp
Xp
Study drug administration
Copanlisib IV infusion
X
X
X
X
X
X
[…]
d
After Screening: AE assessment and concomitant medication review must be updated before each dose and all AEs starting within 30 days 
after the last dose of study drug should be collected and recorded in eCRF. After the patient signs the informed consent, any new finding 
discovered not present in the patient’s medical history or a worsening of a prior medical history finding must be recorded as an AE. Contrast 
media does not need to be recorded as concomitant medication unless there is an AE related to its administration (e.g. allergic reaction).
[…]
l
On Cycle 1 Day 1, glucose will be measured at pre-dose and post-dose after the end of study drug infusion (0), 1 h and 2 h. Additional 
measurements to be performed at the clinic as clinically indicated. On subsequent infusions, glucose will be measured prior to and 1 h after 
the end of infusion. Deviation of ± 10 min is allowed for glucose measurements, except for the pre-dose measurement. For details on fasting 
requirements and pre-dose glucose levels, see Section 6.4. Glucose is also measured as part of the chemistry panel.
m
Footnote removed by amendment 6.
[…]


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o
Bone marrow biopsy may be performed at the investigator discretion if there is clinical suspicion of bone marrow infiltration. Bone marrow 
biopsy will be performed as per local standard of care.
p
Tumor assessments and their frequency as well as laboratory/clinical tests for WM patients will follow the institution’s standard of care.
[…]
r
Footnote removed by amendment 6.
s
Footnote removed by amendment 6.
t
Footnote removed by amendment 6.
u
Footnote removed by amendment 6.
[…]
w
Footnote removed by amendment 6.
[…]
aa Footnote removed by amendment 6.
bb Footnote removed by amendment 6.
cc
Written informed consent must be obtained prior to any study-specific procedures. Certain results from diagnostic testing performed as part of 
the standard of practice prior to the informed consent date and time may be used to fulfill screening criteria. This includes fresh tissue as 
noted in the protocol as well as results from CT/MRI scans, bone marrow sample, MUGA/echocardiogram and hepatitis testing which may 
also be used provided that they fall into the protocol-specified time window. Archival tissue obtained from the patients at any time during the 
course of their iNHL may also be used prior to the informed consent date and time if performed as part of the standard of practice. The 
maximum interval allowed between signature of informed consent and start of treatment is 28 days unless written sponsor authorization has 
been obtained for laboratory re-testing (up to additional 14 days permitted). 


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13.5.2.15 Section 7.1.2.1 Screening period
Old text:
Screening examinations will be performed after the patient has given written informed 
consent. Certain results from diagnostic testing performed as part of the standard of practice 
prior to the informed consent date and time may be used to fulfill screening criteria. This 
includes fresh tissue as noted in the protocol as well as results from CT/MRI scans, bone 
marrow sample, MUGA/echocardiogram and hepatitis testing which may also be used 
provided that they fall into the protocol-specified time window. Archival tissue obtained from 
the patients at any time during the course of their iNHL may also be used prior to the 
informed consent date and time if performed as part of the standard of practice. CT/MRI must 
also meet the quality standards of the Imaging Manual. The maximum interval allowed 
between signature of informed consent and start of treatment is 28 days unless written sponsor 
authorization has been obtained for laboratory re-testing (up to additional 14 days permitted).
Within 28 days before the first administration of study drug:

[…]

Bone marrow biopsy: mandatory at Screening and to confirm the first complete 
response in patients with previous bone marrow infiltration at baseline. A bone 
marrow biopsy may also be performed at the investigator discretion if there is clinical 
suspicion of bone marrow infiltration. Bone marrow biopsy will be performed as per 
local standard of care. 

IV (and oral, if indicated, per Imaging Manual) contrast-enhanced CT/MRI of neck, 
chest, abdomen and pelvis (including WM patients). Corticosteroids must be stopped 
or reduced to the allowed dose (less than 15 mg of prednisone or equivalent) at least 
7 days before performing the screening CT/MRI (if a patient is on chronic 
corticosteroid therapy, corticosteroids should be de-escalated to the maximum allowed 
dose before the Screening). The method chosen at the baseline must be the same 
throughout the study (see Section 7.3.2).

Tumor tissue collection will be mandatory at Screening for central pathology review. 
In addition, additional pre-treatment tumor tissue samples will be collected when 
available to investigate or identify biomarkers that may be predictive of copanlisib 
effects/efficacy in NHL and to contribute to better understanding the disease (see 
Section 7.6.1).
Within 14 days before the first administration of study drug:

[…]

Only in patients affected by Lymphoplasmacytoid lymphoma/Waldenström 
macroglobulinemia (LPL/WM):
o Serum protein electrophoresis.


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o Immunofixation.
o Serum quantitative IgM test.

Serum beta-2-microglobulin.
o Serum or plasma viscosity (if hyperviscosity syndrome is suspected).
Within 7 days before the first administration of study drug:

[…]

Training on glucose self-monitoring with a glucose meter.
New text:
By the time the protocol amendment 6 becomes effective, screening procedures are no longer 
applicable as screening for the study ended on 03 MAR 2017. All screened eligible patients 
have started treatment.
Screening examinations will be performed after the patient has given written informed 
consent. Certain results from diagnostic testing performed as part of the standard of practice 
prior to the informed consent date and time may be used to fulfill screening criteria. This 
includes fresh tissue as noted in the protocol as well as results from CT/MRI scans, bone 
marrow sample, MUGA/echocardiogram and hepatitis testing which may also be used 
provided that they fall into the protocol-specified time window. Archival tissue obtained from 
the patients at any time during the course of their iNHL may also be used prior to the 
informed consent date and time if performed as part of the standard of practice. The 
maximum interval allowed between signature of informed consent and start of treatment is 
28 days unless written sponsor authorization has been obtained for laboratory re-testing (up to 
additional 14 days permitted).
Within 28 days before the first administration of study drug:

[…]

Bone marrow biopsy: mandatory at Screening. A bone marrow biopsy may be 
performed at the investigator discretion if there is clinical suspicion of bone marrow 
infiltration. Bone marrow biopsy will be performed as per local standard of care.

IV (and oral, if indicated) contrast-enhanced CT/MRI of neck, chest, abdomen and 
pelvis (including WM patients). Corticosteroids must be stopped or reduced to the 
allowed dose (less than 15 mg of prednisone or equivalent) at least 7 days before 
performing the screening CT/MRI (if a patient is on chronic corticosteroid therapy, 
corticosteroids should be de-escalated to the maximum allowed dose before the 
Screening). The method chosen at the baseline must be the same throughout the study 
(see Section 7.3.2).


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
Tumor tissue collection removed by amendment 6.
Within 14 days before the first administration of study drug:

[…]

Laboratory/clinical tests for LPL/WM patients removed by amendment 6.
Within 7 days before the first administration of study drug:

[…]

Training on glucose self-monitoring removed by amendment 6.
13.5.2.16 Section 7.1.2.2.1 Treatment – Cycle 1
Old text:
Cycle 1 Day 1
[…]

Glucose will be measured at pre-dose and post-dose after the end of study drug 
infusion (0), 1 h and 2 h (deviation of 5 min is allowed, except for the pre-dose 
measurement). Additional measurements to be performed at the clinic as clinically 
indicated.
Note: If patient needs to take a low glycemic meal, then glucose test should be taken 
prior to meal intake and at 1 h and 2 h after the meal (see Section 6.4 and 
Section 7.5.3.6).

Home blood glucose monitoring: 
o
All diabetic patients regardless of glucose level on infusion day.
o
Non-diabetic patients who experience persisting glucose > 250 mg/dL or who 
require insulin administration post-infusion.

Training on glucose self-monitoring with a glucose meter, if needed. Patients will be 
provided with glucose meter and supplies (lancets, test strips and diary) to record 
glucose values, meal timing, oral glucose lowering medication and/or insulin 
administration, if applicable (see Section 6.4.2.1).

[…]

Collection of blood for biomarker analyses prior to infusion (see Section 7.6.1):
o
Plasma for tumor genetics.
o
Plasma for non-genetic biomarker analysis.
o
[…]


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Cycle 1 Day 8

[…]

Glucose test prior to study drug infusion and 1 h after the end of study drug infusion 
(deviation of 5 min is allowed, except for the pre-dose measurement). Patients are 
not required to be fasting prior to pre-dose glucose measurement.
Note: If patient needs to take a low glycemic meal, then glucose test should be taken 
prior to meal intake and at 1 h and 2 h after the meal (see Section 6.4 and 
Section 7.5.3.6).

Review of the home blood glucose measurements/meal timing/oral glucose lowering 
medication/insulin administration, if applicable. Provide glucose monitoring supplies 
if necessary (see Section 6.4.2.1).

Home blood glucose monitoring:
o
All diabetic patients regardless of glucose level on infusion day.
o
Non-diabetic patients who experience persisting glucose > 250 mg/dL or who 
require insulin administration post-infusion.

[…]

PK sampling for copanlisib, its metabolite M-1 and other metabolites, if needed: pre-
infusion, 5 to 15 min, 55 min (or within 5 min prior to end of infusion) and 1.5 to 5 h 
after start of 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 7.4).

Collection of plasma for non-genetic biomarker analyses prior to infusion (see 
Section 7.6.1).

[…]
Cycle 1 Day 15

[…]

Glucose test prior to study drug infusion and 1 h after the end of study drug infusion 
(deviation of 5 min is allowed, except for the pre-dose measurement). Patients are 
not required to be fasting prior to pre-dose glucose measurement
Note: If patient needs to take a low glycemic meal, then glucose test should be taken 
prior to meal intake and at 1 h and 2 h after the meal (see Section 6.4 and 
Section 7.5.3.6). 

Review of the home blood glucose measurements/meal timing/oral glucose lowering 
medication/insulin administration, if applicable. Provide glucose monitoring supplies 
if necessary (see Section 6.4.2.1).


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
Home blood glucose monitoring:
o
All diabetic patients regardless of glucose level on infusion day.
o
Non-diabetic patients who experience persisting glucose > 250 mg/dL or who 
require insulin administration post-infusion.

[…]

Collection of plasma for non-genetic biomarker analyses prior to infusion (see 
Section 7.6.1).

[…]
New text:
Cycle 1 Day 1
[…]

Glucose will be measured at pre-dose and post-dose after the end of study drug 
infusion (0), 1 h and 2 h (deviation of 10 min is allowed, except for the pre-dose 
measurement). Additional measurements to be performed at the clinic as clinically 
indicated (see Section 6.4 and Section 7.5.3.6).

Home blood glucose monitoring removed by amendment 6.

[…]

Biomarker sampling removed by amendment 6.

[…]
Cycle 1 Day 8

[…]

Glucose test prior to study drug infusion and 1 h after the end of study drug infusion 
(deviation of 10 min is allowed, except for the pre-dose measurement) (see 
Section 6.4 and Section 7.5.3.6).

Review of the blood glucose measurements/meal timing/oral glucose lowering 
medication/insulin administration, if applicable (see Section 6.4.2.1).

Home blood glucose monitoring removed by amendment 6.

[…]

PK sampling removed by amendment 6.

Biomarker sampling removed by amendment 6.

[…]


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Cycle 1 Day 15

[…]

Glucose test prior to study drug infusion and 1 h after the end of study drug infusion 
(deviation of 10 min is allowed, except for the pre-dose measurement) (see 
Section 6.4 and Section 7.5.3.6). 

Review of the blood glucose measurements/meal timing/oral glucose lowering 
medication/insulin administration, if applicable (see Section 6.4.2.1).

Home blood glucose monitoring removed by amendment 6.

[…]

Biomarker sampling removed by amendment 6.

[…]
13.5.2.17 Section 7.1.2.2.2 Treatment – Cycle 2 and higher
Old text:
Cycle 2 and higher, Day 1
On Day 1 of each subsequent cycle, patients should be fasting for at least 8 h prior to the pre-
dose glucose measurement. For details on fasting requirements and pre-dose glucose levels, 
see Section 6.4.

[…]

Glucose test prior to study drug infusion and 1 h after the end of study drug infusion 
(deviation of 5 min is allowed, except for the pre-dose measurement). The pre-dose 
glucose sample on Day 1 of each cycle should be after an 8 h fasting
Note: If patient needs to take a low glycemic meal, then glucose test should be taken 
prior to meal intake and at 1 h and 2 ho after the meal (see Section 6.4 and 
Section 7.5.3.6). 

Review of the home blood glucose measurements/meal timing/oral glucose lowering 
medication/insulin administration, if applicable. Provide glucose monitoring supplies 
if necessary (see Section 6.4.2.1).

Home blood glucose monitoring:
o
All diabetic patients regardless of glucose level on infusion day.
o
Non-diabetic patients who experience persisting glucose > 250 mg/dL or who 
require insulin administration post-infusion.

[…]


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
Only in Cycle 2: collection of plasma for non-genetic biomarker analyses prior to 
infusion (see Section 7.6.1).

[…]

Only in patients affected by WM:
o Serum or plasma viscosity: if abnormal at baseline then every 3rd cycle, starting 
from Day 1 of Cycle 3.
Cycle 2 and higher, Day 8

[…]

Glucose test prior to study drug infusion and 1 h after the end of study drug infusion 
(deviation of 5 min is allowed, except for the pre-dose measurement). Patients are 
not required to be fasting prior to pre-dose glucose measurement 
Note: If patient needs to take a low glycemic meal, then glucose test should be taken 
prior to meal intake and at 1 h and 2 h after the meal (see Section 6.4 and 
Section 7.5.3.6). 

Review of the home blood glucose measurements/meal timing/oral glucose lowering 
medication/insulin administration, if applicable. Provide glucose monitoring supplies 
if necessary (see Section 6.4.2.1).

Home blood glucose monitoring :
o
All diabetic patients regardless of glucose level on infusion day.
o
Non-diabetic patients who experience persisting glucose > 250 mg/dL or who 
require insulin administration post-infusion.

[…]

Only in Cycle 2: collection of plasma for non-genetic biomarker analyses prior to 
infusion (see Section 7.6.1).

[…]
Cycle 2 and higher, Day 15

[…]

Glucose test prior to study drug infusion and 1 h after the end of study drug infusion 
(deviation of 5 min is allowed, except for the pre-dose measurement). Patients are 
not required to be fasting prior to pre-dose glucose measurement
Note: If patient needs to take a low glycemic meal, then glucose test should be taken 
prior to meal intake and at 1 h and 2 h after the meal (see Section 6.4 and 
Section 7.5.3.6). 

Review of the home blood glucose measurements/meal timing/oral glucose lowering 
medication/insulin administration, if applicable. Provide glucose monitoring supplies 
if necessary (see Section 6.4.2.1).


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
Home blood glucose monitoring:
o
All diabetic patients regardless of glucose level on infusion day.
o
Non-diabetic patients who experience persisting glucose > 250 mg/dL or who 
require insulin administration post-infusion.

[…]

Only in Cycle 2: collection of plasma for non-genetic biomarker analyses prior to 
infusion (see Section 7.6.1).

[…]
New text:
Cycle 2 and higher, Day 1
Fasting requirement removed by amendment 6.

[…]

Glucose test prior to study drug infusion and 1 h after the end of study drug infusion 
(deviation of 10 min is allowed, except for the pre-dose measurement) (see Section 
6.4 and Section 7.5.3.6). 

Review of the blood glucose measurements/meal timing/oral glucose lowering 
medication/insulin administration, if applicable (see Section 6.4.2.1).

Home blood glucose monitoring removed by amendment 6.

[…]

Biomarker sampling removed by amendment 6.

[…]

Laboratory/clinical tests for LPL/WM patients removed by amendment 6.
Cycle 2 and higher, Day 8

[…]

Glucose test prior to study drug infusion and 1 h after the end of study drug infusion 
(deviation of 10 min is allowed, except for the pre-dose measurement) (see 
Section 6.4 and Section 7.5.3.6). 

Review of the blood glucose measurements/meal timing/oral glucose lowering 
medication/insulin administration, if applicable (see Section 6.4.2.1).

Home blood glucose monitoring removed by amendment 6.

[…]


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
Biomarker sampling removed by amendment 6.

[…]
Cycle 2 and higher, Day 15

[…]

Glucose test prior to study drug infusion and 1 h after the end of study drug infusion 
(deviation of 10 min is allowed, except for the pre-dose measurement) (see 
Section 6.4 and Section 7.5.3.6). 

Review of the blood glucose measurements/meal timing/oral glucose lowering 
medication/insulin administration, if applicable (see Section 6.4.2.1).

Home blood glucose monitoring removed by amendment 6.

[…]

Biomarker sampling removed by amendment 6.

[…]
13.5.2.18 Section 7.1.2.3 Tumor assessments
Old text:
Radiological tumor evaluations (IV [and oral, if indicated, per Imaging Manual] contrast-
enhanced CT/MRI scans of neck, chest, abdomen and pelvis) will be performed during the 
treatment period as well as during the Active follow-up period, the frequency of tumor 
assessment will be determined by investigator per local standard of care of the institution but 
not less than every 16 weeks. Time points for assessments are calculated from Cycle 1 
Day 1.The method chosen at the baseline must be the same throughout the study (see also 
Section 7.3.2):
During treatment, tumor assessments must be performed within 14 days after the last dose 
(Day 15) and before the next dose (Day 1 of the subsequent cycle).
During Active follow-up, tumor assessments will be done until PD is documented or new 
anti-tumor treatment is administered. 
Bone marrow biopsy is mandatory at baseline and to confirm the first CR if there is bone 
marrow infiltration at baseline. It may also be performed at the investigator discretion if there 
is clinical suspicion of bone marrow infiltration. Biopsy will be performed as per local 
standard of care.
In addition, the following procedures will be performed on the days of tumor assessments 
(deviation of ± 2 days is allowed):

Only in patients affected by WM:
o Serum protein electrophoresis.


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o Immunofixation. 
o Serum quantitative IgM test.
For further details on tumor assessments in patients with WM, see Section 7.3.3.
New text:
After amendment 6 is effective, tumor assessments and their frequency as well as 
laboratory/clinical tests for WM patients will follow the institution’s standard of care.
Bone marrow biopsy may be performed at the investigator discretion if there is clinical 
suspicion of bone marrow infiltration. Biopsy will be performed as per local standard of care.
13.5.2.19 Section 7.1.2.4 End-of-treatment visit
Old text:
[…]

Review of the home blood glucose measurements/meal timing/oral glucose lowering 
medication/insulin administration, if applicable (see Section 6.4.2.1).

IV (and oral, if indicated, per Imaging Manual) contrast-enhanced CT/MRI of neck, 
chest, abdomen and pelvis. CT/MRI scans are not required, if the patient discontinues 
due to PD which has been radiologically evaluated within the 4 weeks preceding EOT 
(see Section 7.3.2).

A tumor biopsy is encouraged at the time of progression (optional) to allow 
investigation of copanlisib resistance. In addition, if a tumor biopsy/excision occurs 
during the course of the study based on medical need, a sample should be submitted 
(though no biopsy is required during treatment).

Collection of plasma for tumor genetics and non-genetic biomarker analyses (see 
Section 7.6.1).

Only in patients affected by WM:
o Serum protein electrophoresis, immunofixation and serum quantitative IgM test (to 
be performed only if the last assessment is older than 4 weeks). 
o Serum or plasma viscosity if abnormal at baseline.
New text:
[…]

Review of the blood glucose measurements/meal timing/oral glucose lowering 
medication/insulin administration, if applicable (see Section 6.4.2.1).


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
CT/MRI removed by amendment 6.

Tumor biopsy removed by amendment 6.

Biomarker sampling removed by amendment 6.

Laboratory/clinical tests for LPL/WM patients removed by amendment 6.
13.5.2.20 Section 7.1.2.5 Follow-up periods
Old text:
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 
Safety follow-up, Active follow-up or Survival follow-up (e.g. data analysis). 
New text:
Section removed by amendment 6.
13.5.2.21 Section 7.1.2.5.2 Active follow-up
Old text:
Patients who discontinue study treatment for reasons other than PD will enter the Active 
follow-up period (which also serves as a Safety follow-up), except for patients 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 day of start of treatment until PD is documented 
or new anti-tumor treatment is administered (see Section 7.1.2.3). 
During the Active follow-up period, AEs and SAEs assessed as related to 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.
The end of Active follow-up period is defined when either PD is documented or a new anti-
tumor treatment is administered, whichever occurs first.
New text:
As the study design is modified, patients will be followed for safety only. All patients who 
have already completed the safety follow-up visit at the time the amendment 6 becomes 
effective will discontinue the study.


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13.5.2.22 Section 7.1.2.5.3 Survival follow-up
Old text:
All patients will be followed off study for overall survival at least at 6-month intervals during 
the Survival follow-up period (up to 3 years after the last patient started study treatment), 
independent of the reason for study termination, except for patients who object to follow-up 
data collection. Patients or their healthcare providers will be contacted either in person or by 
telephone.
Information to be recorded at these contacts:

Survival status, including date of contact.

Documentation of the first new anticancer treatment regimen including response, if 
given.

Date and cause of death, if applicable.
New text:
As the study design is modified, patients will be followed for safety only. All patients who 
have already completed the safety follow-up visit at the time the amendment 6 becomes 
effective will discontinue the study.
13.5.2.23 Section 7.3.1 Primary efficacy variable
Old text:
The primary efficacy variable of this study is objective tumor response rate (ORR), which is 
defined as the proportion of patients who have a best response rating over the whole duration 
of the study up to the dates of data cutoffs (for dates of data cutoffs, see details in section 8.1) 
of complete response (CR) or partial response (PR) according to the Lugano 
Classification (21), and for patients with WM, a response rating of CR, very good partial 
response (VGPR), PR, or minor response (MR) according to the Owen criteria (22).
For the other efficacy variables to be analyzed for this study please refer to Section 8.3.1.
New text:
As study primary endpoint was changed to safety by amendment 6, primary efficacy variable 
was removed.


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13.5.2.24
Section 7.3.2 Radiological tumor assessments
Old text:
Radiological tumor assessments with IV (and oral, if indicated, per Imaging Manual) contrast-
enhanced CT/MRI will include neck, chest, abdomen and pelvis, and will be evaluated locally 
at the study site.
The first radiological (IV [and oral, if indicated, per Imaging Manual] contrast-enhanced 
CT/MRI) tumor assessment will be performed at Screening (including WM patients). 
[…]
During the treatment phase as well as during the Active follow-up period, radiological (IV 
[and oral, if indicated, per Imaging Manual] contrast-enhanced CT/MRI) tumor assessment 
will be performed, per local standard of care of the institution but no less than every 16 weeks 
(see Section 7.1.2.3). CT/MRI scans are not required at the EOT visit if the patient 
discontinues due to PD which has been radiologically confirmed within the 4 weeks 
preceding EOT.
[…]
If the patients on placebo treatment had symptoms/signs of clinical progressive disease prior 
to switching to copanlisib treatment, it is recommended to have radiological tumor 
assessments before starting copanlisib therapy unless CT/MRI scans performed within 
4 weeks prior to a scheduled date of the first copanlisib infusion. For patients who previously 
received placebo and will be treated with copanlisib the tumor assessments should be 
continued as the initial schedule. For further instructions please refer to the Imaging Manual.
At each tumor assessment during the course of the study (from baseline to EOT and during 
Active follow-up if applicable) radiological measurement of spleen vertical length (from 
cranial to caudal) must be performed and reported. 
As long as the patient has not experienced PD, investigator’s assessment is sufficient for case 
management. In case of uncertain radiological disease progression the patient may stay on 
treatment at the investigator’s discretion until progression is definitely confirmed on the 
subsequent tumor assessment.
[…]
The same technique (e.g., slice thickness, field of view) should be used for all scans during 
the study treatment period. Preferably all scans should be interpreted by the same 
investigator/radiologist during the study whenever possible. CT/MRI scans must be 
performed with contrast agents and must meet the standard of care for imaging of lesions in 
the respective organ system(s). If IV (and oral, if indicated, per Imaging Manual) contrast-
enhanced CT is medically contraindicated, sites may acquire contrast-enhanced MRI of the 
neck, abdomen and pelvis, and an unenhanced CT of the chest above lung apices to the 
bottom of the adrenals. Chest CT is preferred. Only if a patient develops contra-indication to 
both CT and MRI contrast medium during the treatment phase of the study, the case 
examinations should be continued without contrast. In certain countries MRI should be used 
based on local regulations.


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The primary efficacy variable will be analyzed based on the assessment by the investigator.
New text:
After amendment 6 is effective, tumor assessments and their frequency as well as 
laboratory/clinical tests for WM patients will follow the institution’s standard of care.
Radiological tumor assessments with IV (and oral, if indicated) contrast-enhanced CT/MRI 
will include neck, chest, abdomen and pelvis, and will be evaluated locally at the study site.
The first radiological (IV [and oral, if indicated] contrast-enhanced CT/MRI) tumor 
assessment will be performed at Screening (including WM patients).
[…]
During the treatment phase, radiological (IV [and oral, if indicated] contrast-enhanced 
CT/MRI) tumor assessment will be performed, per local standard of care of the institution 
(see Section 7.1.2.3). 
[…]
If the patients on placebo treatment had symptoms/signs of clinical progressive disease prior 
to switching to copanlisib treatment, it is recommended to have radiological tumor 
assessments before starting copanlisib therapy unless CT/MRI scans performed within 
4 weeks prior to a scheduled date of the first copanlisib infusion. For patients who previously 
received placebo and will be treated with copanlisib the tumor assessments should be 
continued as the initial schedule.
[…]
The same technique (e.g., slice thickness, field of view) should be used for all scans during 
the study treatment period. Preferably all scans should be interpreted by the same 
investigator/radiologist during the study whenever possible. CT/MRI scans must be 
performed with contrast agents and must meet the standard of care for imaging of lesions in 
the respective organ system(s). If IV (and oral, if indicated) contrast-enhanced CT is 
medically contraindicated, sites may acquire contrast-enhanced MRI of the neck, abdomen 
and pelvis, and an unenhanced CT of the chest above lung apices to the bottom of the 
adrenals. Chest CT is preferred. Only if a patient develops contra-indication to both CT and 
MRI contrast medium during the treatment phase of the study, the case examinations should 
be continued without contrast. In certain countries MRI should be used based on local 
regulations.


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13.5.2.25
Section 7.3.3 Tumor assessments in patients with WM
Old text:
[…]
WM patients who have radiologically measurable lesion at Screening will continue having 
radiological assessments and, in addition, will have laboratory tests performed on the same 
days. CT/MRI scans will be done and collected according to the schedule specified in the 
protocol (see Section 7.1.2.3). 
[…]
New text:
[…]
WM patients who have radiologically measurable lesion at Screening will continue having 
radiological assessments and, in addition, will have laboratory tests performed at intervals that 
comply with the institution’s standard of care (see Section 7.1.2.3). 
[…]
13.5.2.26 Section 7.4 Pharmacokinetics / pharmacodynamics
Old text:
PK sampling will be performed in all patients for copanlisib, its metabolite M-1 and other 
metabolites, if needed, on (see flowchart in Section 7.1):

Cycle 1 Day 8: 
Pre- infusion, 5 to 15 min, 55 min (or within 5 min prior to end of infusion) and 
1.5 to 5 h after start of infusion (clarified by amendment 1).
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.

PK sampling associated with 12-lead ECG removed by amendment 1.
After individual patient unblinding, patients receiving placebo who switch to copanlisib will 
have PK assessments reset to the initial schedule as if the patient was restarting the study at 
Cycle 1 Day 1.
Deviations from the specified time points will be documented and taken into account when 
calculating the PK parameters. Those deviations do not qualify as protocol violation. All 
blood samples should be collected, processed, stored, and shipped according to procedures 
outlined in the Laboratory Manual.
Concentration data of copanlisib, its metabolite M-1 and other metabolites, if needed, from 
this study will be analyzed to estimate the individual maximum drug concentration (Cmax) and 
area under the curve (AUCs), and to measure the variability of the PK of copanlisib, its 


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metabolite M-1 and other metabolites, if needed, in this Phase III population. A population 
pharmacokinetic approach will be used for the analysis.
New text:
No further PK samples will be collected. However, blood samples already collected may be 
used for the PK analysis.
13.5.2.27 Section 7.5.1.3 Assessments and documentation of adverse events
Old text:
[…]
AEs to be documented include all AEs that were ongoing at the end of study treatment as well 
as new AEs that, in the opinion of the investigator, could be related to study treatment 
(information may be obtained via phone call). Documentation must be supported by an entry 
in the patient’s file. 
During the Active follow-up period, AEs and SAEs assessed as related to 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. 
The investigator is responsible for the grading of each category mentioned in Section 7.5.1.2. 
For all SAEs the sponsor is to carry out a separate assessment for expectedness, seriousness 
and causal relationship to the study drug.
[…]
New text:
[…]
AEs to be documented include all AEs that were ongoing at the end of study treatment as well 
as new AEs that, in the opinion of the investigator, could be related to study treatment 
(information may be obtained via phone call). Documentation must be supported by an entry 
in the patient’s file. 
The investigator is responsible for the grading of each category mentioned in Section 7.5.1.2. 
For all SAEs the sponsor is to carry out a separate assessment for expectedness, seriousness 
and causal relationship to the study drug.
[…]


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13.5.2.28
Section 7.5.3.6 Glucose measurement on infusion days
Old text:

[…]

On all infusion days: time window of ± 5 min is allowed for glucose measurements, 
except for the pre-dose measurement. If patient needs to take a low glycemic meal, 
then glucose test should be taken prior to meal intake and at 1 h and 2 h after the meal.
New text:

[…]

On all infusion days: time window of ± 10 min is allowed for glucose measurements, 
except for the pre-dose measurement. 
13.5.2.29 Section 7.6.1 Biomarker investigations
Old text:
Overview
There will be several parts to biomarker testing in this study:
1. Tumor-genetic research of fresh (preferred) or archival tumor tissue, and possibly of 
circulating tumor DNA isolated from plasma
2. Non-genetic biomarker testing
3. Genetic biomarker research
Genetic biomarker research of the whole blood requires separate ‘genetic’ research consent 
(optional testing for research). All other analyses are covered by the main ICF. 
Biomarker investigations
The planned biomarker analyses utilize tumor tissue, plasma and blood, and involve the 
analysis of protein and nucleic acids (i.e., RNA and/or DNA) (RNA: ribonucleic acid, DNA: 
deoxyribonucleic acid). Details on the collection, processing, storage and shipment of 
biomarker samples will be provided in separate documents (e.g. sample handling sheets or 
laboratory manual). 
The biomarker results may be reported separately.
Collection and use of biomarker specimens
Tumor Tissue:
Tumor tissue collection will be mandatory at Screening for central pathology review. Patients 
without historical material or fresh tissue biopsy will not be eligible for randomization.
In addition, one or more of the following pre-treatment tumor tissue samples will be collected 
during Screening when available with the purpose of investigating or identifying biomarkers 


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that may be predictive of copanlisib effects/efficacy in NHL and to contribute to better 
understanding the disease. 

Submission of archival tumor tissue from a biopsy performed within 180 days before 
signing of the informed consent.

Submission of fresh tissue from a biopsy performed during Screening (between 
Day -28 and Day -8 prior to the start of study treatment) is highly encouraged when 
the above is not available.

In the absence of either of the above, submission of an older archival tumor tissue 
sample (collected prior to 180 days before signing of the informed consent) is 
mandatory when available.
A tumor biopsy is also encouraged at the time of progression (optional) to allow investigation 
of copanlisib resistance. In addition, if a tumor biopsy/excision occurs during the course of 
the study based on medical need, a sample should be submitted (though no biopsy is required 
during treatment).
Archival formalin-fixed paraffin-embedded (FFPE) tissue may be supplied as a block 
(preferred) or as precut slides. Details on the preparation of slides and number of slides to be 
prepared as well as detailed guidance on fresh biopsy sample preparation and storage will be 
described in separate documents (e.g. Sample Handling Sheets or laboratory manual).
All tumor tissues may be used as a source of RNA or protein for the study of gene and protein 
expression. The tumor tissue may in addition be used as a source of tumor DNA for the 
evaluation of tumor-associated alterations in genes of interest (e.g., PIK3CA and genes 
associated with NHL).
Plasma for tumor genetics biomarker analysis: Blood samples will be obtained and used 
for plasma preparation at the time points as indicated in the study flow chart (see Table 7-1). 
Plasma may be used as a source of circulating tumor DNA for the evaluation of mutations in 
tumor-related genes of interest.
Plasma for non-genetic biomarker analysis: Blood samples will be obtained and used for 
plasma preparation at the time points as indicated in the study flow chart (see Table 7-1). 
Plasma may be used to quantify the circulating levels of various proteins. 
After individual patient unblinding, patients receiving placebo who switch to copanlisib upon 
discretion of the investigator and patient’s consent will have biomarker plasma sampling 
analogous to the initial schedule as if the patient was restarting the study at Cycle 1 Day 1.
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 trials of these investigational drugs and/or literature data. However, the study 
sponsors reserve the right not to conduct all or part of the aforementioned biomarker analysis. 
Data from this biomarker analysis may be correlated with various other data obtained in this 
study (e.g., clinical efficacy, pharmacokinetics, toxicity).


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If a scheduled biomarker sample collection is missed, this should not be regarded as a 
protocol deviation.
New text:
No further biomarker samples will be collected. However tumor tissue, plasma and whole 
blood (if consented) samples collected may be used for the biomarker analysis.
13.5.2.30 Section 7.7 Appropriateness of procedures / measurements
Old text:
The efficacy assessments used in this study include those considered standard of care to 
evaluate objective tumor response rate in patients with iNHL. Although the recently published 
Lugano Classification (21) strongly support the use of PET-CT for staging and response 
assessment of routinely FDG-avid histologies, especially in clinical trials, it was decided to 
use in this study only a CT-based response. 
[…]
New text:
The tumor assessments used in this study include those considered standard of care to 
evaluate objective tumor response rate in patients with iNHL. Although the recently published 
Lugano Classification (21) strongly support the use of PET-CT for staging and response 
assessment of routinely FDG-avid histologies, especially in clinical trials, it was decided to 
use in this study only a CT-based response. 
[…]
13.5.2.31
Section 8.1 General considerations
Old text:
[…]
Due to the decision of stopping enrollment as protocol amendment 5 becomes effective, 
limited number of patients will be included in the analyses. Therefore, the statistical analyses 
included in this study will be focused on descriptive statistics without any hypothesis testing.
Two sets of analyses will be performed at the timing when all treated patients completed at 
least 6 cycles of study treatment.
1) unblinding cutoff: analyze all data available before the unblinding (details in section
6.5); 
2) final analysis: analyze all data available until all treated patients complete at least 6 
cycles of study treatment.


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The data cutoffs and treatment groups included for each analysis are summarized in the 
following table. 
Table 8-1
Analysis data cutoffs and treatment group overview
Analysis cutoff on the 
date of unblinding
Final analysis cutoff4
Patients randomized to 
Copanlisib1


Placebo Patients: Period 1  
(before their PD) 2

Not shown
Placebo Patients: Period 2 
(after PD period 2) 2
Not shown

Placebo Patients: switching to 
Copanlisib per protocol amend 53
NA

1 All patients randomized/assgined into Copanlisib arm
2 Patients randomized into Placebo arm, with at least one tumor response assessment until date of 
unblinding
3 Includes patients switched from Placebo to Copanlisib before their first tumor response assessment
4 When all treated patients complete at least 6 cycles of study treatment
New text:
[…]
Due to the decision of stopping enrollment as protocol amendment 5 becomes effective, 
limited number of patients will be included in the analyses. Therefore, the statistical analyses 
included in this study will be focused on descriptive statistics on safety variables only.
Two sets of analyses will be performed at the primary analysis timing when all patients have 
completed the study treatment and Safety follow-up period (if applicable).
1) unblinding cutoff: analyze all data available before the unblinding (details in 
section 6.5); 
2) final analysis: analyze all data available until all patients have completed the
copanlisib study treatment and Safety follow-up period.
The data cutoffs and treatment groups included for each analysis are summarized in the 
following table. 


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Table 8-1
Analysis data cutoffs and treatment group overview
Analysis cutoff on the 
date of unblinding
Final analysis cutoff2
Patients randomized to Copanlisib1


Placebo Patients: Period 1  
(before their PD)

Not shown
Placebo Patients: Period 2 
(after PD period 2)
Not shown

Placebo Patients: switching to 
Copanlisib per protocol amend 5
NA

1 All patients randomized/assigned into Copanlisib arm 
2 When all patients have completed the study treatment and Safety follow-up period.
13.5.2.32 Section 8.2 Analysis sets
Old text:
The statistical analysis sets are defined as follows:

Full analysis set (FAS): all patients assigned to treatment. Following the intent to treat 
(ITT) principle, the treatment the patient is assigned to will be used in the analysis (as 
assgined rather than as treated).

Safety analysis set (SAF): all patients with at least one intake of study drug. The SAF 
will be analyzed as treated.
All patients with valid PK data will be included in the evaluation of PK concentrations and 
parameters. 
The efficacy variables will be analyzed in the FAS.
The SAF will be used for the analyses of the safety variables. The FAS will be used for the 
display of all other variables. 
New text:
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 analyzed as treated.
All patients with valid PK data may be included in the evaluation of PK concentrations and 
parameters. 
The SAF will be used for the analyses of the safety variables. 


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13.5.2.33 Section 8.3.1 Efficacy variables
Old text:
If PD was reported after a switch to copanlisib treatment in placebo patients (see Section 6.4), 
this information is not used for calculation of primary or secondary efficacy variables.
New text:
Due to the limited number of patients enrolled in this study, the study efficacy objectives and 
analyses were removed and the efficacy variables, including but not limited to date of 
progression, time to progression, and best response will be listed descriptively.
13.5.2.34 Section 8.3.1.1 Primary efficacy variable
Old text:
Objective tumor response rate (ORR) assessed in all patients, which is defined as the 
proportion of patients who have a best response rating up to the dates of data cutoffs (for dates 
of data cutoffs, see details in section 8.1) of complete response (CR) or partial response (PR) 
according to the Lugano Classification (21), and for patients with WM, a response rating of 
CR, very good partial response (VGPR), PR, or minor response (MR) according to the Owen 
criteria (22). Detailed instructions on tumor assessment are provided in Appendix 14.1. In 
addition to the ORR by treatment group, and period, a listing will be provided for all patients 
with their best response, histology type along with other important demographic and disease 
characteristics information.
New text:
Section removed by amendment 6.
13.5.2.35 Section 8.3.1.2 Secondary efficacy variables
Old text:
Duration of response (DOR), defined as the time (in days) from first observed tumor 
response (CR, VGPR, PR or MR) until PD or death from any cause, whichever is earlier. 
DOR will only be defined for patients with at least one CR, VGPR, PR or MR (modified by 
amendment 1). Patients without PD or death at the time of analysis will be considered as 
responders till at the date of their last tumor evaluation. DOR will be summarized by 
descriptive statistics. Further details will be included in the SAP.
Complete response rate (CRR), defined as the proportion of patients who have a best 
response up to the dates of data cutoffs (for dates of data cutoffs, see details in section 8.1) of 
complete response (CR) according to the Lugano Classification (3), and for patients with 
WM, a response rating of CR according to the Owen criteria (4).


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Overall survival (OS), defined as the time (in days) from assignment to study drug until 
death from any cause. OS of patients alive at the time of analysis will be censored at the last 
date they were known to be alive. 
New text:
Section removed by amendment 6.
13.5.2.36 Section 8.3.2 Safety variables
Old text:
Safety variables will include treatment-emergent AEs (TEAEs), SAEs, laboratory parameters, 
and vital signs. The severity of AEs will be graded using the CTCAE v 4.03 dictionary. AEs 
will be classified by the investigator as related or not related to study drug. TEAE is defined 
as any event arising or worsening after start of study drug administration until 30 days after 
the last study drug intake (end of Safety follow-up).
New text:
Safety variables will include treatment-emergent AEs (TEAEs), SAEs, laboratory parameters, 
and vital signs. The severity of AEs will be graded using the CTCAE v 4.03 dictionary. AEs 
will be classified by the investigator as related or not related to study drug. TEAE is defined 
as any event arising or worsening after start of study drug administration until 30 days after 
the last study drug intake (end of Safety follow-up). For TEAE summaries based on placebo 
randomized patients switching to copanlisib (see Table 8–1), the baseline reference period 
will be defined in the SAP.
13.5.2.37 Section 8.4.2 Efficacy
Old text:
Evaluations by investigators will be used for the primary efficacy analyses of primary and 
secondary variables containing radiological tumor assessments.
For variables other than OS, the data collected after switching from placebo to copanlisib will 
be summarized separately using descriptive statistics and frequency tables. Further details will 
be included in the SAP.
New text:
Due to the limited number of patients enrolled in this study, the study efficacy objectives and 
analyses were removed and the efficacy variables, including but not limited to date of 
progression, time to progression, and best response will be listed descriptively.


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13.5.2.38 Section 8.4.3 Safety
Old text:
[…]
In addition, results of physical examination, vital signs, and ECG will be summarized with 
descriptive statistics and/or frequency tables.
New text:
[…]
In addition, results of physical examination, vital signs, and ECG will be summarized in 
accordance with SAP. 
13.5.2.39 Section 8.4.4 Pharmacokinetic data
Old text:
Individual concentration-time data of copanlisib and M-1 will be provided in a clinical study 
report appendix. Sparse copanlisib concentration data from this study, which might be 
augmented with PK data from other studies, will be analyzed to evaluate the variability of the 
copanlisib PK in this Phase III population. The possible effect of relevant covariates on the 
PK of copanlisib might also be evaluated. A population pharmacokinetic approach will be 
applied for these evaluations, which will be described in detail in a separate Modeling & 
Simulation (M&S) Plan and the results will be reported separately in the M&S Report. 
New text:
Individual concentration-time data of copanlisib and M-1 may be provided in a clinical study 
report appendix. Sparse copanlisib concentration data from this study, which might be 
augmented with PK data from other studies, may be analyzed to evaluate the variability of the 
copanlisib PK in this Phase III population. The possible effect of relevant covariates on the 
PK of copanlisib might also be evaluated. A population pharmacokinetic approach will be 
applied for these evaluations, which will be described in detail in a separate Modeling & 
Simulation (M&S) Plan if the results will be reported separately in the M&S Report. 
13.5.2.40 Section 8.6 Determination of sample size
Old text:
All patients assigned to treatment in this study will be included in the analyses. 


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New text:
Determination of sample size has not been applicable since amendment 5 became effective.
13.5.2.41 Section 9.1 Data recording
Old text:
Data recorded from “only screened patients (screening failures)”
Data of 'only screened patients' will be recorded at least as source data, as far as the reason for 
the premature discontinuation is identifiable. At minimum, data to be recorded in the CRF are 
demographic information (patient number, date of birth/age, sex, race and ethnicity), the 
reason for premature discontinuation and date of last visit. These data will be transferred to 
the respective database.
New text:
Data recorded from “only screened patients (screening failures)”
Data of 'only screened patients' will be recorded at least as source data, as far as the reason for 
the premature discontinuation is identifiable. At minimum, data to be recorded in the CRF are 
demographic information (patient number, year of birth/age, sex, race and ethnicity), the 
reason for premature discontinuation and date of last visit. These data will be transferred to 
the respective database.
13.5.2.42 Section 10. Premature termination of the study
Old text:
[…]
The sponsor’s decision was to stop enrollment due to lack of feasibility to complete this study 
in reasonable time frame. Therefore, the study design is modified to reflect an open label 
study. All patients on study treatment will be offered the possibility to continue treatment 
with copanlisib after unblinding procedures are completed.
[…]
New text:
[…]
The sponsor’s decision was to stop enrollment due to lack of feasibility to complete this study 
in reasonable time frame. Therefore, the study design is modified. All patients on study 


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treatment will be offered the possibility to continue treatment with copanlisib after unblinding 
procedures are completed.
[…]
13.5.2.43 Section 11.2 Patient information and consent
Old text:
[…]
Archival tissue obtained from the patients at any time during the course of their iNHL may 
also be used prior to the informed consent date and time if performed as part of the standard 
of practice. CT/MRI must also meet the quality standards of the Imaging Manual.
[…]
New text:
[…]
Archival tissue obtained from the patients at any time during the course of their iNHL may 
also be used prior to the informed consent date and time if performed as part of the standard 
of practice. CT/MRI must also meet the quality per local standards.
[…]
13.5.2.44 Section 12. Reference list
Old text:
38. Atkinson FS, Foster-Powell K, Brand-Miller JC. International Tables of Glycemic Index 
and Glycemic Load Values: 2008. Diabetes Care 2008;31:2281-2283. 
New text: 
38.
Removed by amendment 6.
13.5.2.45 Section 14.7 The average glycemic index of common foods derived from 
multiple studies by different laboratories
Old text:
Foods are categorized as having a low-glycemic index if the glucose reference index is ≤55. 
The summary table below contains glucose reference for common foods, please see 
reference 38 for additional information.


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GI = glycemic index.
Source: (38)
New text:
Appendix 14.7 removed by amendment 6.


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14.
Appendices
14.1
Evaluation of tumor response
Section changed by amendment 1, table clarified by amendment 3 and modified by 
amendment 4.
Tumor response will be evaluated according to Recommendations for Initial Evaluation, 
Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano 
Classification (21).
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
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 (=value 
over 13 cm)
No
Not relevant
SD
Decrease < 50% in the SPD 
from baseline
No criteria for PD
All normal or 
stable
Normal size or 
stable size
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
and be > 13 cm 
Recurrent 
splenomegaly:
the splenic length 
must increase ≥ 2 cm 
from nadir length and 
be > 13 cm 
Progressive 
splenomegaly:
the splenic length 
must increase by > 
50% of the extent 
beyond normal at 
baseline (=value 
over 13 cm) 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
* 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.


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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. 
Table modified by amendment 3 and 4.
Response criteria in patients affected by Waldenström macroglobulinemia (WM):
CR

Absence of serum monoclonal IgM by immunofixation AND normal serum IgM level

Complete resolution of extramedullary disease

Normal bone marrow
VGPR

IgM M protein still detectable by immunofixation BUT ≥ 90% reduction in serum 
IgM level from baseline

Complete resolution of extramedullary disease

No new sings/symptoms of active disease
PR

IgM M protein still detectable by immunofixation BUT ≥ 50% and < 90% reduction in 
serum IgM level from baseline

Reduction in extramedullary disease

No new signs/symptoms of active disease
MR

IgM M protein still detectable by immunofixation BUT ≥ 25% and < 50% reduction in 
serum IgM level from baseline

No new signs/symptoms of active disease
SD

IgM M protein still detectable by immunofixation BUT < 25% reduction and < 25% 
increase in serum IgM level from baseline

No new signs/symptoms of active disease
PD
After PR:

≥ 25% increase in serum IgM level from lowest nadir (an absolute value of 5 g/L is 
required if IgM level is the only criterion)
OR

Progression in clinical features (signs/symptoms) attributable to disease
After CR:

Reappearance of IgM M protein
OR

Recurrence of bone marrow involvement, extramedullary disease, symptoms 
attributable to disease
CR = complete response; IgM = immunoglobulin M; MR = minor response; PD = progressive 
disease; PR = partial response; SD = stable disease; VGPR = very good partial response
Source: Adapted from (22).


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14.2
A list of CYP3A4 inhibitors and inducers
CYP3A4 inhibitors (strong inhibitors are underlined and not permitted during this study)
Indinavir
Nelfinavir
Ritonavir
Saquinavir
Clarithromycin
Itraconazole
Ketoconazole
Nefazodone (withdrawn in the United States)
Grapefruit juice
Erythromycin
Verapamil
Diltiazem
Cimetidine
Amiodarone
Fluvoxamine
Mibefradil (withdrawn in the United States)
Troleandomycin
CYP3A4 inducers (not permitted during this study)
Rifampin
Carbamazepine
Phenobarbital
Phenytoin
Pioglitazone
Rifabutin
St. John’s wort
Troglitazone
Source: (33)


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14.3
ECOG Performance Status
Grade
Description
0
Fully active, able to carry on all pre-diseases performance without restriction.
(Karnofsky 90-100)
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature (e.g., light housework, office work).
(Karnofsky 70-80)
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
(Karnofsky 50-60)
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
(Karnofsky 30-40)
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
(Karnofsky 10-20)
14.4
New York Heart Association (NYHA) Functional Classification
NYHA Class
Symptoms
Not applicable
No cardiac disease
I
No symptoms and no limitation in ordinary physical activity, e.g., shortness of 
breath when walking, climbing stairs etc.
II
Mild symptoms (mild shortness of breath and/or angina) and slight limitation 
during ordinary activity.
III
Marked limitation in activity due to symptoms, even during less-than-ordinary 
activity, e.g., walking short distances (20–100 m).
Comfortable only at rest.
IV
Severe limitations. Experiences symptoms even while at rest. Mostly 
bedbound patients.
Source: (34)


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14.5
Glomerular filtration rate
In accordance with established nephrology practice and guidelines, renal function at baseline 
and throughout the study will be assessed by means of the estimated Glomerular filtration rate 
(GFR), calculated using the Modification of Diet in Renal Disease (MDRD) study 
abbreviated formula.
This equation of 4 variables (serum creatinine level [SCR], age, sex, and ethnicity) is 
recommended by the National Kidney Foundation for use in individuals 18 years or older.
The formula is as follows:
GFR (mL/min/1.73m2) = k x 186 x SCR-1.154 x age-0.203
where k = 1 (men) or 0.742 (women), GFR indicates glomerular filtration rate, and serum 
creatinine level (SCR) is measured in mg/dL.
NOTE: This equation should be used only with those creatinine methods that have not been 
recalibrated to be traceable to IDMS.
If standardized IDMS-traceable creatinine assay is used, please use the calculator provided in 
the following link: http://www.kidney.org/professionals/kdoqi/gfr_calculator (added by 
amendment 1).
The above result should be multiplied by 1.212 for African-Americans.
Patients with a baseline GFR < 30 ml/min calculated by this method will not be allowed to 
participate in the study.
For further information on assessing renal function using GFR estimates, see 35-37.
14.6
Quality of life questionnaire: NCCN-FACT FLymSI-18
Appendix removed by amendment 5.


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14.7
The average glycemic index of common foods derived from multiple 
studies by different laboratories
Appendix removed by amendment 6.

SAP_001.pdf: 
Document Type:  
Statistical Analysis Plan 
Official Title: 
A randomized, double-blind Phase III study of copanlisib versus placebo 
in patients with rituximab-refractory indolent non-Hodgkin’s lymphoma 
(iNHL) - CHRONOS-2 
NCT Number:  
NCT02369016 
Document Date:  
02 FEB 2021 
 


Statistical Analysis Plan
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Title page
A Randomized, Double-blind Phase III Study of Copanlisib versus Placebo 
in Patients with Rituximab-refractory Indolent Non-Hodgkin’s Lymphoma 
(iNHL) – CHRONOS-2 
Phase III copanlisib in rituximab-refractory iNHL
Bayer study drug
BAY 80-6946 / Copanlisib
Study purpose:
Assess the efficacy and safety of copanlisib
Clinical study phase:
III
Date:
02 FEB 2021
Study No.:
BAY 80-6946 / 17322
Version:
3.0
Author:
Confidential
The information provided in this document is strictly confidential and is intended solely 
for the guidance of the clinical investigation.  Reproduction or disclosure of this 
document, whether in part or in full, to parties not associated with the clinical 
investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures.
The approval of the Statistical Analysis Plan is documented in a separate Signature Document.
PPD


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Table of Contents
Abbreviations............................................................................................................................ 3
1.
Introduction ....................................................................................................................... 6
2.
Study Objective ................................................................................................................. 6
3.
Study Design ...................................................................................................................... 6
4.
General Statistical Considerations .................................................................................. 8
4.1
General Principles............................................................................................................ 8
4.2
Handling of Dropouts ...................................................................................................... 8
4.3
Handling of Missing Data................................................................................................ 9
4.4
Interim Analyses and Data Monitoring............................................................................ 9
4.5
Data Rules........................................................................................................................ 9
5.
Analysis Sets..................................................................................................................... 10
5.1
Assignment of analysis sets ........................................................................................... 10
6.
Statistical Methodology................................................................................................... 10
6.1
Population characteristics .............................................................................................. 11
Disposition.................................................................................................................. 11
6.1.1
Protocol Deviations .................................................................................................... 11
6.1.2
Demographic and Baseline Characteristics at Study Entry........................................ 11
6.1.3
Cancer and Other Characteristics at Study Entry ....................................................... 11
6.1.4
Medical History .......................................................................................................... 12
6.1.5
Prior and Concomitant Medication............................................................................. 12
6.1.6
Prior and Concomitant Anti-cancer Therapy and Procedures .................................... 12
6.1.7
Study Drug Administration ........................................................................................ 13
6.1.8
6.2
Efficacy.......................................................................................................................... 13
6.3
Safety ............................................................................................................................. 14
Adverse Events........................................................................................................... 14
6.3.1
Pregnancies................................................................................................................. 16
6.3.2
Clinical Laboratory Evaluations................................................................................. 16
6.3.3
Hyperglycemia............................................................................................................ 17
6.3.4
Vital Signs .................................................................................................................. 17
6.3.5
Hypertension............................................................................................................... 17
6.3.6
Electrocardiogram (ECG) and Cardiac Function ....................................................... 18
6.3.7
6.4
Pharmacokinetics/pharmacodynamics........................................................................... 18
6.5
Biomarker evaluation..................................................................................................... 18
7.
Document history and changes in the planned statistical analysis ............................. 19
8.
References ........................................................................................................................ 20


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Abbreviations
AE
Adverse event
ATC
Anatomical-Therapeutic-Chemical
CRF
Case report form
CSR
Clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee
e.g.
For example, exempli gratia
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRFs
Electronic case report forms
EOT
End of treatment
FL
Follicular lymphoma
FLIPI
Follicular Lymphoma International Prognostic Index
GCP
Good Clinical practice
h
Hour(s)
i.e.
That is, id est
ICF
Informed consent form
IgM
Immunoglobulin M
iNHL
Indolent Non-Hodgkin’s lymphoma
IV
Intravenous
LPL
Lymphoplasmacytoid lymphoma
M-1
Metabolite 1
M&S
Modeling & Simulation
MALT
Marginal-zone lymphoma of mucosa-associated lymphoid tissue
MedDRA
Medical Dictionary for Regulatory Activities


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mg
Milligram
mmHg
Millimeter of mercury
MUGA
Multiple gated acquisition
NCI
National Cancer Institute
NCI-CTCAE
National Cancer Institute – Common Terminology Criteria for Adverse 
Events
NHL
Non-Hodgkin’s lymphoma
NMZL
Nodal marginal-zone lymphoma
NYHA
New York Heart Association
OEE
Overall extent of exposure
PD
Progressive disease
PK
Pharmacokinetic
PT
Preferred Term
SAC
Statistical Analysis Center
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical analysis report
SAS
Statistical Analysis System
SFU
Safety follow-up
SLL
Small lymphocytic lymphoma
SMZL
Splenic marginal-zone lymphoma
SOC
System Organ Class
TEAE
Treatment-emergent adverse event
TESAE
Treatment-emergent serious adverse event
TFL
Table, figure, listing
WHO
World Health Organization


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WHO-DD
WHO Drug Dictionary
WM
Waldenström macroglobulinemia


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1.
Introduction
Indolent NHLs encompass the following low-grade histologic subtypes of B-cell NHL 
included in the 2008 World Health Organization (WHO) classification of lymphoid neoplasm: 
follicular lymphoma (FL), small lymphocytic lymphoma (SLL), lymphoplasmacytic 
lymphoma (LPL), which is defined as Waldenström’s macroglobulinemia (WM) when 
associated with a monoclonal immunoglobulin M (IgM) component and bone marrow 
involvement, splenic marginal-zone lymphoma (SMZL), nodal marginal-zone lymphoma 
(NMZL) and marginal-zone lymphoma of mucosa-associated lymphoid tissue (MALT) (1). 
FL is the second most common subtype of NHL with 25% of newly diagnosed cases (2), 
followed by MALT lymphoma with 7% of all NHLs, while other subtypes are rather rare, 
with SLL, LPL, SMZL and NMZL accounting for 3%, 2%, 2% and 1% of NHL patients, 
respectively.
Indolent NHLs have a relatively good prognosis with a median survival longer than 10 years, 
but they are incurable with current available therapeutic options, especially in advanced 
stages. There are no guideline recommendations or widely accepted standards of care for 
patients beyond first relapse. The treatment given depends on the patient’s condition, 
physician’s preference, and availability of drugs not already used in previous lines of 
treatment. There is therefore a need for drugs with new targets and mechanisms of action that 
are effective and have a safety profile different from that of drugs used in earlier lines of 
treatment. 
Copanlisib, a small molecule PI3K inhibitor, is a targeted agent that works by controlling the 
signaling pathway relevant for the survival and proliferation of iNHL cells. It is currently 
under investigation in various trials enrolling cancer patients and it has been approved for FL 
in the U.S. The evaluation of copanlisib’s anticancer activity via a clinical trial design that 
controls for the natural history of tumor growth minimizes investigator bias in assessing 
treatment outcomes.
The original protocol, Version 1.0, is dated 20 MAY 2014. This statistical analysis plan (SAP) 
v3.0 describes the final analysis for study 17322 and is based on the integrated clinical study 
protocol Version 6.0 (protocol amendment 6), dated 01 DEC 2017. Following sponsor’s 
decision to stop enrollment due to lack of feasibility to complete this study in reasonable time 
frame as protocol amendment 5 became effective, limited number of patients will be included 
in the analyses. The safety analyses will be performed as per the protocol. For other changes 
please refer to section 7 in this SAP. 
2.
Study Objective
The primary objective of this study is:

To assess the safety of copanlisib.
3.
Study Design
Initially this was a randomized, double-blind, two-arm Phase III study to evaluate the efficacy 
and safety of copanlisib as monotherapy in comparison to placebo in patients with rituximab-
refractory iNHL. However, following sponsor’s decision to stop enrollment on 03 MAR 2017 
due to lack of feasibility to complete this study in reasonable time frame, the study design was 
modified as protocol amendment 6 became effective. All patients on study treatment will be 
offered to continue treatment with copanlisib after unblinding procedures are completed.


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The overview of study periods is presented in Figure 3–1.
Figure 3–1 Study Periods
The start of the study period is defined by signing of the informed consent form (ICF). 
A graphical presentation of the overall study design as of amendment 5 is shown in Figure 3–
2. 
Figure 3–2: Overall Study Design
Schedule of procedures is presented in the protocol amendment 6, Table 7–1.
Treatment Period
The start of the treatment period is defined by first administration of study drug (Copanlisib or 
placebo). Copanlisib will be administered IV over approximately 1h at starting dose of 60 mg 
on Days 1, 8 and 15 of each 28-day treatment cycle. Treatment will be continued until 
progressive disease (PD) by radiological assessments or clinical progression (tumor 
evaluations will be made at intervals that comply with the institution’s standard of care [per 
investigator’s assessment]), unacceptable toxicity, or until another criterion is met for 
withdrawal from the study treatment. Before unblinding, patients in the placebo arm will 
receive a placebo IV infusion at the same schedule as that of Copanlisib arm. However, when
placebo patients had PD before unblinding cut-off, they can choose to switch to Copanlisib 
and continue to stay in the study. 
Disease progression (PD) defined in the Lugano Classification (3) and the Owen criteria (4) 
for patients with WM will be assessed.


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All patients, after unblinding procedures are completed, will be offered an opportunity to 
continue this clinical study and receive active treatment with Copanlisib. Patients who are on 
Copanlisib treatment at the time of unblinding will continue Copanlisib treatment. Patients 
who are on placebo at the time of unblinding will switch to Copanlisib treatment after 
unblinding procedures are completed. After individual patient unblinding, patients receiving 
placebo, who switch to Copanlisib will have all study assessments reset to the initial schedule 
of study evaluations (i.e. as if the patient was restarted the study at Cycle 1 Day 1).
An End-of-treatment (EOT) visit will be performed within 7 days after the decision is made to 
discontinue study treatment.
Safety Follow-up Period
Following completion of the EOT visit, patients will enter the Safety follow-up. The Safety 
follow-up (SFU) visit will take place 30 days (window of +5 days allowed) after the last 
administration of study drug.
All patients who have already completed the safety follow-up visit at the time the 
amendment 6 becomes effective will discontinue the study.
4.
General Statistical Considerations
4.1
General Principles
Statistical analyses will be conducted by or under the supervision of the sponsor’s Study 
Statistician, except for the analysis of biomarker data, which, if considered to be performed, 
will be performed by or under the direction of the sponsor’s Genomics and Biomarker 
Statistical Expert. Statistical analyses will be performed by using the software package 
Statistical Analysis System (SAS) release 9.2 or higher (SAS Institute Inc., Cary, NC, USA).
Due to the decision of stopping enrollment, limited number of patients will be included in the 
analyses. Therefore, the statistical analyses included in this study will be focused on 
descriptive statistics on safety variables only. The number of data available and missing data, 
mean, standard deviation, minimum, quartiles, median, and maximum will be calculated for 
metric data. Frequency tables will be generated for categorical data. 
Definition of safety endpoints, analyses strategies, structure of analyses datasets and layout of 
analyses data displays are following Bayer standards as documented in the Bayer standard 
system: Clinical Copanlisib Project Standards, Oncology Therapeutic Area Standards, and 
Global Medical Standards, respectively. Where the given ordering reflects the priority of the 
different standards that is specifications of the latter ones have to be followed only if not 
specified in standards mentioned before. Study-specific specifications may be included in 
addition to the project standards, if needed.
4.2
Handling of Dropouts
A patient who discontinues study participation prematurely (i.e., prior to disease progression) 
for any reason is defined as a “dropout” if the patient has already entered treatment. 
Patients who drop out will not be replaced. 
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, will be 
reported. 


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4.3
Handling of Missing Data
In order to achieve the goal of a well conducted clinical trial according to Good Clinical 
Practice (GCP), every effort should be made to collect all data. However, despite best efforts, 
it may be inevitable that missing or incomplete data are reported. All missing or partial data 
will be presented in the patient data listing as they are recorded on the Case Report Form 
(CRF). Unless noted, missing data will not be estimated or carried forward in any statistical 
analysis. 
The general principle for imputing dates is as follows: 
If an adverse event start date is completely missing or partially missing, then it assumed that 
the start date occurs at the earliest time on-treatment whenever possible.
If a concomitant medication date is completely missing or partially missing, then the stop date 
is imputed to maximize the duration of the concomitant treatment. It should be noted that 
imputation of stop dates only applies to concomitant medications that are not ongoing. 
4.4
Interim Analyses and Data Monitoring
No interim efficacy analyses are planned for this study. 
A Data Monitoring Committee (DMC) is instituted to maximize the safety of the patients 
participating in the study. The DMC includes at least three members, including an 
independent Statistician and Oncologist. Safety review meetings were held as per separate 
DMC charter. 
The report, including tables, listings, and figures, were generated by an independent 
statistician from a Statistical Analysis Center (SAC).  The format and content of these data 
summaries were specified separately from this study SAP.
Decisions on trial termination, amendment, or cessation of patient recruitment based on 
risk/benefit assessment were made after recommendations from the DMC have been assessed 
by the sponsor.
No DMC meeting is planned after the DMC meeting on 21 JUN 2017 with the 
recommendations that the study can continue with finishing follow-up and there is no need for 
another safety meeting as this was considered as a close-out meeting. 
4.5
Data Rules
If time intervals are to be displayed other than days in statistical evaluations, then one year is 
considered to have 365.25 days (average length of a year, including leap years), one month is 
considered to have 30.44 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).
Baseline
Baseline is defined as the last available measurement performed prior to the first dose of 
Copanlisib/placebo study drug administration at Cycle 1 Day 1 for the patients who initially 
received Copanlisib/placebo. For the patients who initially received placebo and switched to 
Copanlisib after unblinding, baseline is defined as the last available measurement prior to the 
first dose of Copanlisib after switching.
Repeated measures


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If there are repeated measurements per time point (e.g. laboratory values, vital signs, etc.), the 
following rules will be used (unless otherwise specified):

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 pre-baseline or baseline 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 value of the 
scheduled measurements at that time point will be used.  No unscheduled 
measurements will be used for any time points besides screening / baseline even when 
measurements at scheduled visits are missing.    
5.
Analysis Sets
5.1
Assignment of analysis sets
Full analysis set (FAS)
All patients who were randomized to treatment arms at the start of the study will be included 
in the FAS. Protocol deviation, demographics, baseline characteristics, medical history, prior 
and concomitant medication, prior and concomitant anti-cancer therapy will be summarized in 
the FAS.
Safety analysis set (SAF)
All patients with at least one administration of study drug will be included in the SAF. The 
SAF will be used for the analyses of study drug exposure, safety and efficacy variables. 
All patients with valid pharmacokinetic (PK) data may be analyzed in the evaluation of PK 
concentrations and parameters.
Patients who signed the informed consent but were not assigned to treatment will be 
considered screening failures. They will be listed separately.
6.
Statistical Methodology
Disposition, protocol deviations, demographics, baseline cancer characteristics, medical 
history, prior and concomitant medication, prior and concomitant anti-cancer therapy, drug 
exposure, efficacy and safety variables will be summarized separately for 2 groups including
patients 

who were randomized to copanlisib until the end of study (copanlisb group)

who were randomized to placebo until switching from placebo to copanlisib after PD 
or after unblinding (placebo group)
Disposition, protocol deviations, concomitant medication, concomitant anti-cancer therapy, 
drug exposure, efficacy and safety variables will also be summarized separately for patients 
who switched from placebo to copanlisib.


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6.1
Population characteristics
Disposition
6.1.1
Disposition will be described by randomized treatment group (Copanlisib / placebo) for 
overview and the study phases of screening, treatment, safety follow-up, active follow-up and 
survival follow-up. Primary reasons for discontinuation from each study phase will be 
summarized.
Disposition for overview and screening will be summarized for all enrolled patients.
Disposition for treatment will be summarized for full analysis set. Disposition for safety 
follow-up will be summarized for safety analysis set.
Protocol Deviations
6.1.2
The summary table for patients with major and minor protocol deviations will be summarized 
for full analysis set. Listings for major protocol deviations and COVID-19 related protocol 
deviations will be provided.
Demographic and Baseline Characteristics at Study Entry
6.1.3
Demographics and baseline characteristics are documented on the electronic Case Report 
Forms (eCRFs) of Demography and vital signs at baseline.
The following demographics and additional baseline characteristics at study entry will be 
summarized for full analysis set:

Age (Years) and Age group (years) <65 and >=65

Sex

Medical history of diabetic (Diabetic / Non-diabetic)

Medical history of arterial hypertension (With / Without)

Ethnicity (Not Hispanic or Latino / Hispanic or Latino / Not reported)

Race (White / Black / Asian / American Indian or Alaska Native / Native Hawaiian or 
Other Pacific Islander / Not reported)

BMI=weight (kg) / [height (m)]²
Cancer and Other Characteristics at Study Entry
6.1.4
Cancer and other baseline characteristics are reported on the eCRFs of Classification of Non-
Hodgkin’s Lymphoma, ECOG Performance Status, Systemic Anti-Cancer Therapy (Prior), 
Vital Signs at baseline, and Cardiac Disease (NYHA assessment).
The following cancer and other baseline characteristics will be summarized for full analysis 
set:

Histology of tumor at study entry

Follicular lymphoma (FL) grade at study entry, if FL

Follicular Lymphoma International Prognostic Index (FLIPI) (5) score (for patients 
with FL) at study entry

Staging of tumor (Ann Arbor classification) at study entry

Number of prior systemic cancer therapy lines (1-3, 3-5, >5)


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
Infiltration seen in bone marrow biopsy as per local assessment

Time from initial diagnosis to randomization (months) 

Time from most recent progression to randomization(months)

Time since first progression to randomization (months)

Number of baseline target lesions (Total number and frequency by group 1-3, 4-6)

Number of baseline non-target lesions (Total number and frequency by group 1-3, 4-6, 
7-8, >8)

Serum IgM level (for WM only) (mg/dL) at baseline

Baseline Eastern Cooperative Oncology Group (ECOG) performance status

New York Heart Association (NYHA) classification (Class I / Class II / Class III / 
Class IV / Not applicable) at baseline

Systolic Blood Pressure (mmHg) at screening

Diastolic Blood Pressure (mmHg) at screening

Baseline HbA1c
Medical History
6.1.5
Medical history (i.e., relevant previous diagnoses, diseases or surgeries) not pertaining to the 
study indication, that started before signing of the informed consent and considered relevant 
to the study will be presented by MedDRA version 22.1 or higher Primary System Organ 
Class (SOC) and Preferred Term (PT). All medications and significant non-drug therapies 
taken within 30 days (window of +5 days allowed) before study entry will be recorded and 
summarized for full analysis set.
Prior and Concomitant Medication 
6.1.6
Prior and concomitant medications will be coded by the World Health Organization Drug 
Dictionary (WHO-DD) Version MAR 2020 or higher. 
Prior and concomitant medications will be summarized based on WHO-DD Anatomical-
Therapeutic-Chemical (ATC) drug class and drug name for full analysis set.
Any medication that has been stopped after first administration of study treatment 
(Copanlisib/ placebo) is considered as concomitant and otherwise as prior.  Note that the same 
medication can appear more than once in the table as it can have several ATC codes. 
Prior and Concomitant Anti-cancer Therapy and Procedures
6.1.7
The prior anti-cancer therapy and procedures are recorded on the eCRFs Diagnostic and 
Therapeutic Procedures (Prior) for iNHL, Systemic Anti-Cancer Therapy (Prior) and 
Radiotherapy (Prior). The concomitant anti-cancer therapy and procedures are recorded on the 
eCRFs Diagnostic and Therapeutic Procedures (Concurrent) for iNHL, Systemic Anti-Cancer 
Therapy (during Follow-Up) and Radiotherapy (during Follow-Up).
The minimum, median, and maximum number of prior systemic anti-cancer therapy lines as 
well as number of patients with 1, 2, 3, ≥4 lines of therapy will be summarized by treatment 
group for FAS.  Time since last systemic anti-cancer therapy will be summarized using 
descriptive statistics by treatment group for FAS.  The time between the start day of last 
course of systemic anti-cancer therapy and the day of confirmation of the most recent 


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progression will also be displayed as a classification table, showing proportions of patients 
with ≤ 6 months vs. > 6 to <12 months vs. ≥12 months, by treatment group. 
The following anti-cancer therapy will be summarized by treatment group for FAS:

prior and concurrent diagnostic and therapeutic procedure 

prior and follow-up radiotherapy

prior and follow-up systemic therapy 
Study Drug Administration
6.1.8
Descriptive statistical summaries of study drug exposure will be provided for the following 
variables:

Overall extent of exposure (OEE) in days:
Defined as the time from the first administration of the first study treatment (dayfirst) until the 
last administration of the last study treatment (daylast), including 7 additional days in order to 
consider the weekly dosing regimen, is calculated as:
OEE (days) = daylast – dayfirst +7.

Number of cycles

Number of infusions during treatment phase and categorized by 1-6, 7-12, 13-18 and 
etc.

Total dose actually administered (mg)
OEE will include interruptions/delays during treatment. As a general rule, and in accordance 
with the Therapeutic Area Standard oncology team and the timing concept, 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. Similarly, the according trailing “drug interruptions” will not 
be used in statistical tables. A footnote will be included, stating that “Interruption becoming 
permanent study treatment discontinuation before resumption of study treatment is not 
accounted as an interruption”.
For patients with dose modification, the total number (%) of subjects with dose reductions, 
interruptions/delays, re-escalations and the total number (%) of dose reductions, 
interruptions/delays, re-escalations and the reasons will be summarized. Number of reduction, 
interruption/delay and re-escalation per subject will also be summarized.
6.2
Efficacy
Due to the limited number of patients enrolled in this study, the study efficacy objectives and 
analyses were removed and the tumor assessment was stopped to be collected since 01 DEC 
2017. Summary of tumor response by investigators’ assessment will be provided. Progression-
free survival and best overall response will also be listed.
Best overall response (BOR) 
BOR is defined as the best response per Cheson criteria (ordered CR, PR, SD, PD, NE) and 
per Owen criteria (ordered CR, very good partial response (VGPR), PR, Minor response(MR), 


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SD, PD, NE) over all post-treatment assessments on or prior to the first progression. Tumor 
assessments after first PD and after start of new anticancer therapy are not considered for best 
overall response. 
Objective response rate (ORR)
ORR is assessed in all patients up to the time of analysis of PFS.  ORR is defined as the 
proportion of patients who have a best response rating over the whole duration of the study 
(i.e. until time of analysis of PFS) of complete response (CR) or partial response (PR) 
according to Cheson criteria Lugano Classification and for patients with WM a response 
rating of CR, very good partial response (VGPR), PR, or minor response (MR) according to 
Owen Criteria. 
Progression-free survival (PFS)
For patients who were randomized to copanlisib until the end of the study and who were 
randomized to placebo until switching to copanlisib after PD or after unblinding, PFS is 
defined as the time (in months) from the randomization date to first disease progression or 
death due to any cause, if death occurs before progression is documented. 
For patients who switched from placebo to copanlisib, PFS is defined as the time (in months) 
from the start date of copanlisib to first disease or death due to any cause, if death occurs 
before progression is documented. 
For details for radiological tumor assessments see protocol section 7.3.2 and for details for 
tumor assessments in patients with WM see protocol section 7.3.3.
PFS for patients without PD or death at the time of analysis will be censored at the last actual 
date of tumor assessment or last biochemical assessment for patients with WM without lesions 
evaluable by imaging.
6.3
Safety
Safety variables will include treatment-emergent adverse events (TEAEs), laboratory 
parameters, ECG, cardiac function, vital signs and other safety measures. 
Adverse Events
6.3.1
Adverse Events (AEs) will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) dictionary Version 22.1. Severity of AEs will be graded using the NCI-CTCAE 
v4.03. AEs will be classified by the investigator as related or not related to study drug.
Treatment emergent adverse events (TEAEs)
TEAEs are defined as any event arising or worsening after start of study drug administration 
until 30 days (window of +5 days allowed) after the last study drug administration (end of 
Safety follow-up). More specifically, for the patients who received Copanlisib until the end of 
study and the patients who received placebo until switching to Copanlisib after PD or after 


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unblinding, the start of study drug administration is referring to the start of Copanlisib or 
placebo after randomization. For the patients switching from placebo to Copanlisib, the start 
of study drug administration is referring to the start of Copanlisib drug administration after 
switching. See Section 4.3 for handling of partial dates for AEs. In the case 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 the following TEAEs by MedDRA (SOC) and (PT) will be provided
for safety analysis set:

Any TEAEs 

Any treatment emergent serious adverse events (TESAEs)

Any TEAEs leading to discontinuation 

Any TEAEs leading to dose modification

Any TEAEs related to protocol procedure

Any study drug related TEAEs 

Any study drug related treatment TESAEs

Any study drug related TEAEs leading to discontinuation 

Any study drug related TEAEs leading to dose modification
The following will be summarized by MedDRA system organ class (SOC) and preferred term 
(PT), and by worst grade based on Common Terminology Criteria Adverse Event (CTCAE) v. 
4.03. 

TEAEs 

TEAEs with incidence ≥10%

Grade 3-5 TEAEs  

Treatment related TEAEs

Treatment related TEAEs incidence ≥5% 

Grade 3-5 treatment related TEAEs  

TESAEs 

Grade 3-5 TESAEs 

Treatment related TESAEs 

Any TEAEs leading to discontinuation 

Any TEAEs leading to dose interruption 

Any TEAEs leading to dose reduction 

Any drug related TEAEs leading to discontinuation 

Any drug related TEAEs leading to dose interruption 

Any drug related TEAEs leading to dose reduction 


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The maximum severity of the TEAEs will be summarized according to the NCI-CTCAE 
toxicity criteria. For each patient, multiple occurrences of the same event will be counted once 
at their maximum severity within a SOC and PT. 
Adverse Events of Special Interest
Non-infectious Pneumonitis is defined as AE of special safety interest. The Standardized 
MedDRA Query (SMQ) 'Interstitial lung disease' with narrow search (i.e. category 2A) will 
be used to select these AEs of special interest. The only relevant NCI CTCAE code is 
AETOXCOD=RTPNM (pneumonitis).
Summary of patients with Non- infectious pneumonitis/Interstitial lung disease requiring 
corticosteroids, antibiotics, or both will be displayed descriptively. All patients with TEAEs of 
special interest by worst CTCAE grade, study drug relatedness and seriousness will be listed.
COVID-19 relevant adverse events
The COVID-19 relevant adverse events will be identified using a high-level term (HLT) of 
coronavirus infection via latest MedDRA version. A subject listing of these AEs will be provided. 
The serious AEs will be flagged in the listing. 
AE listings
Subject listings will be provided for serious TEAEs, TEAEs leading to discontinuation, 
TEAEs leading to interruptions and reductions and TEAEs of special interests including the 
worst CTCAE grade, study drug relatedness, and seriousness.
Death 
Summary table and listings will be provided for 

Subjects who died during treatment or up to 30 days (window of +5 days allowed)
after last dose of study medication

Subjects who died later than 30 days (window of +5 days allowed) after last dose of 
study medication
Pregnancies
6.3.2
The results of pregnancy tests will be listed by specimen type, patient ID, visit and result 
(positive/negative). Any pregnancy will be documented.
Clinical Laboratory Evaluations
6.3.3
Results of the clinical laboratory evaluations (coagulation, hematology, chemistry and 
urinalysis) by worst CTCAE grade post-baseline will be summarized.  Changes in worst grade 
of laboratory toxicities at last pre-treatment value compared to worst grade post-baseline 
value is also provided. Worst grades for laboratory toxicities will be calculated according to 
CTCAE, version 4.03 based on laboratory measurements.
Summary statistics on the values and changes from baseline will also be presented for each 
quantitative clinical laboratory variable, at each post-baseline visit. For tables displaying 


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treatment-emergent laboratory abnormalities, patients with specimen collection between start 
of treatment and 30 days (window of +5 days allowed) after EOT will be included.
Hyperglycemia
6.3.4
Hyperglycemia adverse events using specific MedDRA PT grouping ‘MLG Hyperglycemia’ 
will be summarized by treatment group and by NCI CTCAE worst grade for TEAEs and 
TESAEs.
In addition to the above summary, specific HbA1c evaluation will be performed for each analysis 
group including at baseline and post-baseline-mean, classified by diabetic/non-diabetic.
Patients will be categorized according to their baseline HbA1c values as

< 5.7%

≥ 5.7% – < 6.5%

≥ 6.5%.
Within each group, the descriptive statistics for HbA1c values at end of treatment visit will be 
summarized by treatment group and medical history of diabetic/non-diabetic. Shift table for 
classified HbA1c values from baseline to end of treatment by treatment group and medical 
history of diabetic/non-diabetic will also be provided.
Glucose in CTCAE grade will be displayed by treatment group and medical history of 
diabetic/non-diabetic at pre-dose and at post-dose 0 h, 1 h and 2 h after the end of study drug 
infusion on Cycle 1 Day 1 and at pre-dose and at post-dose 1 h after the end of study drug 
infusion on subsequent visit. 
For patients with hyperglycemia adverse events, the number of patients using 
antihyperglycemic treatment with drug start date on or after their first treatment-emergent 
adverse event will be summarized in overall, and separately for the WHO-DD ATC classes 
for a) insulin and analogues and b) Blood glucose lowering drugs, excluding insulins.  In 
addition, these summaries will be presented separately for the subgroups of patients with vs 
without history of diabetes.
Vital Signs
6.3.5
Results of vital signs will be summarized by visit, including change from baseline where 
appropriate. 
Hypertension
6.3.6
The blood pressure measurements will be recorded on the vital sign eCRF:

Systolic blood pressure (mmHg, measured at 0 h (pre-dose), 30 min (mid-infusion), 60 
min (end of infusion); and 1 h and 2 h after the end of infusion on infusion days)


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
Diastolic blood pressure (mmHg, measured at 0 h (pre-dose), 30 min (mid-infusion), 
60 min (end of infusion); and 1 h and 2 h after the end of infusion on infusion days)
The number of patients with abnormal post-dose systolic/diastolic blood pressure will be 
displayed by visit and worst post-dose TEAE hypertension grade by treatment group and 
medical history of arterial hypertension/no medical history of arterial hypertension. For this 
purpose post-dose systolic/diastolic blood pressure values will be categorized according to 
CTCAE, version 4.03: Grade 1 (systolic 120-139 mmHg or diastolic 80-89 mmHg); Grade 2 
(systolic 140-159 mmHg or diastolic 90-99 mmHg); Grade 3 (systolic ≥ 160 mmHg or 
diastolic ≥ 100 mmHg), grade 4 Life-threatening consequences; urgent intervention indicated.
Hypertension adverse events will be presented using MLG grouping of MLG 
Hypertension for TEAEs and TESAE,
For patients with hypertension adverse events, the number of patients using antihypertensive 
treatment with drug start date on or after their first treatment-emergent adverse event will be 
summarized descriptively.  In addition, the number of patients requiring antihypertensive 
treatment will be presented separately for the subgroups of patients with vs without history of 
hypertension. 
Electrocardiogram (ECG) and Cardiac Function
6.3.7
The overall interpretation of the ECG (normal/abnormal, clinical relevance) and the ECG 
findings will be recorded on the 12-Lead Safety ECG page of CRF. The overall interpretation 
of the MUGA scan/echocardiogram and findings will be recorded on the Cardiac function 
(MUGA/echocardiogram) page of CRF. Frequency table for overall interpretation of the 12-
lead ECG and the ECG diagnosis, as well as the overall interpretation of the echocardiogram 
and the corresponding diagnosis will be summarized by visit. Listing of clinically significant 
abnormal cardiac findings will be provided
6.4
Pharmacokinetics/pharmacodynamics
By the time the protocol amendment 6 became effective, no further PK samples were
collected. However, blood samples already collected may be used for the PK analysis.
Individual concentration-time data of Copanlisib and M-1 may be provided in a clinical study 
report appendix. Further population PK analysis is described in a separate Modeling & 
Simulation (M&S) Plan and results will be reported separately in the M&S Report (Branch 
Trial 20068).
6.5
Biomarker evaluation
The analysis of the exploratory biomarker data, which, if considered to be performed, will be 
performed by or under the direction of the sponsor’s Genomics and Biomarker Statistical 
Expert. This will be described and reported separately.


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7.
Document history and changes in the planned statistical analysis

Approval of SAP v1.0 on 13 APR 2016

SAP v2.0 updated on 14 MAR 2018 according to the protocol amendment 6 on 01 
DEC 2017

Changes in the planned statistical analysis in SAP v3.0
Due to the suspension of enrollment in Chronos-2 study, only a limited number of subjects 
has been enrolled. As discussed with Regulatory, instead of performing two sets of analyses: 
unblinding analysis (cut-off 1) and final analysis (cut-off 2) described in the Protocol, the 
analysis has been simplified. Disposition, protocol deviations, demographics, baseline cancer 
characteristics, medical history, prior and concomitant medication, prior and concomitant anti-
cancer therapy, drug exposure and safety variables will be summarized separately for 2 groups 
including patients 

who were randomized to copanlisib until the end of study (copanlisb group)

who were randomized to placebo until switching from placebo to copanlisib after PD 
or after unblinding(placebo group)
Disposition, protocol deviations, concomitant medication, concomitant anti-cancer therapy, 
drug exposure, efficacy and safety variables will also be summarized separately for patients 
who switched from placebo to copanlisib.
In this statistical analysis plan, progression-free survival will be performed in lieu of the 
protocol mentioned efficacy evaluation of time to progression. 


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8.
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A clinical evaluation of the International Lymphoma Study Group classification of 
non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. 
Blood. 1997;89:3909-18.
3.
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. 
Recommendations for Initial Evaluation, Staging, and Response Assessment of 
Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification. J Clin Oncol. 
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Owen RG, Kyle RA, Stone MJ, Rawstron AC, Leblond V, Merlini G, et al. 
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